WO2016114655A1 - Traitement de maladie neuromusculaire ou neurologique par réduction de la surstimulation des neurotransmetteurs inhibiteurs gabaergiques et/ou glycinergique - Google Patents

Traitement de maladie neuromusculaire ou neurologique par réduction de la surstimulation des neurotransmetteurs inhibiteurs gabaergiques et/ou glycinergique Download PDF

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WO2016114655A1
WO2016114655A1 PCT/NL2016/050021 NL2016050021W WO2016114655A1 WO 2016114655 A1 WO2016114655 A1 WO 2016114655A1 NL 2016050021 W NL2016050021 W NL 2016050021W WO 2016114655 A1 WO2016114655 A1 WO 2016114655A1
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gabaergic
overstimulation
als
activity
disease
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PCT/NL2016/050021
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Lambertus Tuk
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Ry Pharma B.V.
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Priority to PCT/NL2016/050490 priority Critical patent/WO2017065602A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • GABAergic and/or Glycinergic inhibitory neurotransmitter GABAergic and/or Glycinergic inhibitory neurotransmitter
  • the disclosure provides novel methods of treating neuromuscular or neurologic disease, for example, Amyotrophic lateral sclerosis (ALS), through reducing ALS
  • compositions comprising one or more compounds capable of reducing Glycinergic activity and/or one or more compounds capable of reducing GABAergic activity are also provided.
  • Methods for treating one or more symptoms caused by inhibitory neurotransmitter overstimulation e.g., muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, movement difficulties, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction
  • inhibitory neurotransmitter overstimulation e.g., muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, movement difficulties, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction
  • MNDs Motor neuron diseases
  • ALS Amyotrophic lateral sclerosis
  • the disease generally progresses rapidly and is inevitably fatal with respiratory failure as the relatively uniform cause of death.
  • ALS incidence ranges from 1.5 to 2.5 patients per 100,000 annually, with a lifetime risk of circa 1 in 400 persons.
  • the mean age of onset is circa 60 years, with a median survival of two to four years from symptom onset, although a small percentage of patients lives longer than ten years.
  • ALS is part of a broad spectrum of neurodegenerative indications that are
  • PBP Progressive bulbar palsy
  • PMA Progressive muscular atrophy
  • PLS Primary lateral sclerosis
  • Flail arm syndrome Vulpian-PBP
  • ALS symptoms overlap with the group of neuromuscular disorders leading to a gradual muscle weakness and to a common set of physical symptoms including difficulty with speech, difficulty with mobility and fine motor skills as listed in table 1, and with the group of muscle diseases listed in table 2. Furthermore it in this disclosure will be concluded that ALS symptoms clinically relevant overlap with the (neurologic) diseases listed in table 3 and 4. Currently there is no effective treatment available for ALS or ALS like disease.
  • Riluzole (Rilutek®) displays minor efficacy in ALS, only prolonging tracheostomy-free survival with three months. Baclofen has been used for the treatment of anti-spastic treatment in ALS patients and is thought to exert its effects through exerting
  • GABAergic action through binding at GABA-B receptors.
  • One of the objects of the invention is to provide improved treatments for ALS and ALS-like disorders as listed in tables 1, 2, 3 and 4.
  • Symptoms may include those listed in tables 7 and/or 8, preferably muscle wasting, loss of muscle function, respiratory depression, dysphagia, dysarthria, movement difficulties, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and
  • gastrointestinal dysfunction more preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, movement difficulties, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction.
  • Symptoms may include those listed in tables 7a- 7f, preferably tables 7a- 7d.
  • Methods and compositions are provided for treating ALS and ALS-like disorders, such those listed in tables 1, 2, 3 and 4, preferably for the treatment of ALS.
  • the methods comprise decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof, preferably using compounds disclosed in Tables 5 and/or 6.
  • the methods result in an overall (or net) decrease in GABAergic and/or Glycinergic activity.
  • a method for treating one or more symptoms caused by inhibitory neurotransmitter overstimulation e.g., one or more symptoms selected from tables 7 and/or 8, preferably those listed in tables 7a- 7f, more preferably tables 7a- 7d, most preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction
  • the method comprising decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof.
  • glycinergic activity is decreased by administrating a
  • GABAergic activity is reduced by the systemic administration of a therapeutically effective amount of a GABA receptor inhibitor and / or a compound that leads to an increase in availability or efficacy of compounds that exert their action (at least partly) through the GABA receptor causing the reduction of net GABAergic activity.
  • any of the preceding embodiments comprising administering to said individual a therapeutically effective amount of one or more compounds which reduce the net GABAergic inhibitory activity in the central nervous system of said individual.
  • the one or more compounds which reduce GABAergic inhibitory activity is not ginkgo extract or a component of ginko extract (e.g., a ginkgolide or bilobalide).
  • symptoms of the ALS- like disorder include those selected from tables 7 and/or 8 and/or tables 7a- 7f, preferably tables 7a-7d, preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction.
  • a method for treating one or more symptoms caused by inhibitory neurotransmitter overstimulation e.g., one or more symptoms selected from tables 7 and/or 8, preferably those listed in tables 7a- 7f, more preferably tables 7a- 7d, most preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction
  • the method comprising decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof, wherein said glycinergic activity is decreased by administrating a therapeutically effective amount of a compound that modulates the glycine receptor and / or leads to an increase in availability or efficacy of compounds that exert their action through the glycine receptor thereby causing the reduction of Glycinergic activity, and
  • GABAergic activity is decreased by systemically administrating to said individual a therapeutically effective amount of a compound that reduces the net GABAergic activity in the central nervous system of said individual, wherein when the individual is afflicted with ALS, the one or more compounds which reduce
  • GABAergic inhibitory activity is not ginkgo extract or a component of ginko extract (e.g., a ginkgolide or bilobalide).
  • the compound that reduces the net GABAergic activity is a GABA receptor inhibitor and / or a compound that leads to an increase in availability or efficacy of compounds that exert their action (at least partly) through the GABA receptor causing the reduction of net GABAergic activity.
  • a method for treating one or more symptoms caused by inhibitory neurotransmitter overstimulation e.g., one or more symptoms selected from tables 7 and/or 8, preferably those listed in tables 7a- 7f, more preferably tables 7a- 7d, most preferably muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction
  • the method comprising decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof, wherein said glycinergic activity is decreased by administrating a therapeutically effective amount of a compound that modulates the glycine receptor and / or leads to an increase in availability or efficacy of compounds (preferably glycine) that exert their action through the glycine receptor thereby causing the reduction of Glycinergic activity, and where
  • the individual afflicted with ALS or an ALS-like disorder is not afflicted with syphilis or Lyme's disease, more preferably the individual is not afflicted with an infection (in particular a bacterial infection). Preferably the individual does not have an elevated risk of infection (in particular a bacterial infection).
  • a pharmaceutical composition comprising one or more compounds capable of reducing GABAergic activity, preferably selected from Table 5 and one or more compounds capable of reducing Glycinergic activity, preferably selected from Table 6, preferably for use in the manufacture of a medicament.
  • a pharmaceutical composition comprising one or more compounds capable of reducing GABAergic activity, preferably selected from Table 5, for use in the manufacture of a medicament.
  • a pharmaceutical composition comprising one or more compounds capable of reducing Glycinergic activity, preferably selected from Table 6, for use in the manufacture of a medicament.
  • a pharmaceutical composition comprising one or more GABAergic inhibitory activity reducing compounds as disclosed herein for use in the treatment of one or more symptoms caused by inhibitory neurotransmitter overstimulation, preferably selected from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction, gastrointestinal dysfunction and/or symptoms as listed in table 7 and/or 8 and/or tables 7a-7f, preferably tables 7a- 7d, preferably in an individual afflicted with ALS or an ALS-like disorder as disclosed herein.
  • GABAergic inhibitory activity reducing compounds as disclosed herein for use in the treatment of one or more symptoms caused by inhibitory neurotransmitter overstimulation, preferably selected from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze pal
  • a pharmaceutical composition comprising one or more Glycinergic activity reducing compounds as disclosed herein for use in the treatment of one or more symptoms caused by inhibitory neurotransmitter overstimulation, preferably selected from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression and/or symptoms as listed in table 8, preferably in an individual afflicted with ALS or an ALS-like disorder as disclosed herein.
  • Figure 1 Graphical representation of the pivotal role of GABAergic and Glycinergic overstimulation in ALS pathogenesis.
  • FIG. 1 Limb-, bulbar- and respiratory onset ALS are caused by a continuum of separately increasing gradients of GABAergic and Glycinergic overstimulation.
  • FIG. 3 diseases in the MND (motor neuron disease) continuum also are the result of a continuum of separately increasing gradients of GABAergic and Glycinergic mediated recurrent inhibition overstimulation during initial and progressive disease stages where PMA is progressive muscular atrophy, PLS is primary lateral sclerosis, PBP is progressive bulbar palsy, PB is Pseudobulbar palsy.
  • PMA progressive muscular atrophy
  • PLS primary lateral sclerosis
  • PBP progressive bulbar palsy
  • PB Pseudobulbar palsy.
  • FIG. 4 (4A) Diseases where GABAergic and glutaminergic overstimulation occur in parallel do not lead to the clinical manifestation of disease as homeostasis is maintained. (4B) Diseases where glutaminergic overstimulation no longer increases in parallel with GABAergic overstimulation due to, for instance, the occurrence of glutaminergic excitatory overstimulation induced neuronal cell death, will lead to the clinical manifestation of GABAergic overstimulation symptoms at the same time that clinical manifestation related to glutaminergic excitatory overstimulation induced neuronal cell death are observed. (4C) GABAergic overstimulation increases where glutaminergic overstimulation also increases but at a slower pace will lead to the clinical manifestation of GABAergic overstimulation symptoms where over time clinical manifestations develop that are related to glutaminergic excitatory
  • overstimulation induced neuronal cell death the latter depending on the point in time where glutamate overstimulation reaches levels capable of inducing glutaminergic excitatory overstimulation induced neuronal cell death.
  • glutamate overstimulation reaches levels capable of inducing glutaminergic excitatory overstimulation induced neuronal cell death Depending on the threshold for GABAergic and glutaminergic overstimulation symptoms, clinical manifestations of glutaminergic excitatory overstimulation induced neuronal cell death may appear before GABAergic overstimulation symptoms become apparent. (4D) Diseases where GABAergic overstimulation occurs in the absence of glutaminergic overstimulation will lead to the clinical manifestation of GABAergic overstimulation in the absence of glutaminergic excitatory overstimulation induced neuronal cell death.
  • the present invention is based, in part, on the surprising finding that the GABAergic and Glycinergic inhibitory neurotransmitter systems are at least partly responsible for the onset, progression, and/or clinical profile of ALS and ALS-like disorders.
  • ALS central nervous system's most abundant excitatory neurotransmitter glutamate leads to excitatory neuronal death, and consequently leads to the clinical manifestation of ALS.
  • This theory finds its origin in the in ALS patients observed 100% elevated plasma serum glutamate levels, the 100% to 200% increased glutamate levels in cerebrospinal fluid (CSF) (Spreux-Varoquaux 2002), the deficiency of leukocyte glutamate dehydrogenase and the in ALS patients observed glutamate transport system defects that can lead to decreased clearance of extracellular glutamate.
  • CSF cerebrospinal fluid
  • Excitotoxicity is the pathological process by which nerve cells are damaged and killed through excessive stimulation by the glutamate excitatory neurotransmitter system leading to overstimulation of the glutamate receptors such as the NMDA and AMPA receptor.
  • Pathologically high levels of glutamate cause excitotoxicity by allowing high levels of calcium ions to enter the cell, activating enzymes such as phospholipases, endonucleases, and proteases that damage vital cell structures such as the cytoskeleton, membrane, and DNA.
  • Excitotoxicity is involved in neurodegenerative diseases of the central nervous system (CNS) such as multiple sclerosis (MS),
  • Alzheimer's disease AZA
  • amyotrophic lateral sclerosis ALS
  • Parkinson's disease a neurotransmitter glutamate
  • alcoholism or alcohol withdrawal and especially over-rapid benzodiazepine withdrawal
  • Huntington's disease The excitatory neurotransmitter glutamate is therefore currently seen as the most important contributor to the ALS pathogenesis and has become a major target for the development of new ALS treatments.
  • Many current clinical trials aim at reducing the ALS disease burden through reducing the observed elevated levels of glutamate.
  • the examples herein demonstrate that in the presence of an overstimulated inhibitory neurotransmitter system, an excitatory reaction can be expected that aims at maintaining neuromotor function and homeostasis and that can lead to
  • overstimulated inhibitory neurotransmitter system can lead to elevated glutamate levels (as observed in ALS), which can lead to glutamate-mediated excitatory motoneuronal cell death (as observed in ALS), which can lead to clinical
  • ALS is a disease where GABAergic and Glycinergic mediated recurrent inhibition overstimulation progressively increases over time leading to either GABAergic and Glycinergic overstimulation clinical manifestations during disease onset, and to both GABAergic and Glycinergic overstimulation clinical manifestations becoming identifiable during progressive disease.
  • the effect of overstimulation on clinical symptoms is depicted in Figures 1 and 2.
  • it can be concluded that late stage clinical manifestations of ALS are related to both GABAergic and Glycinergic overstimulation, where bulbar onset ALS is related to the clinical manifestation of GABAergic overstimulation and limb onset ALS is related to the clinical manifestation of Glycinergic overstimulation.
  • GABAergic inhibitory overstimulation is at the basis of neurologic diseases listed in table 3 including frontotemporal dementia, dementia, Alzheimer's disease, Multiple Sclerosis, Huntington's disease, Duchenne muscular dystrophy, Peripheral Neuropathy, schizophrenia, dementia, restless legs syndrome and Parkinson's disease, where progressive and diffuse neuronal clinical manifestations present themselves in combination with clinical manifestations as observed in GABAergic overstimulated ALS patients. These diseases can therefore be classified as a common group based on their clinical symptoms.
  • the disclosure further provides that GABAergic and /or Glycinergic inhibitory overstimulation is the cause of these disorders and that these disorders can be effectively treated by reducing
  • GABAergic and/or Glycinergic activity is at the basis of other diseases listed in table 4 including diabetes, mitochondrial disease, and lysosomal storage disorders.
  • GABAergic overstimulation is at the basis of other diseases listed in table 4 including diabetes, mitochondrial disease, and lysosomal storage disorders.
  • the present disclosure relates to decreasing inhibitory and/or GABAergic and/or
  • Glycinergic overstimulation When excitatory overstimulation is involved in disease pathology, the administration of a GABA activity antagonist would be predicted to lead to severe seizures. Surprisingly, the present disclosure demonstrates that the inhibitory system is overstimulated in ALS and ALS-like disorders. The methods disclosed herein comprise decreasing GABAergic activity without leading to severe seizures.
  • the disclosure provides a method for treating a disorder in an individual, preferably wherein the disorder is ALS or an ALS-like disorder as disclosed herein.
  • "treating" includes reducing the onset, severity, and/or progression of one or more sympoms of the disorder.
  • the disclosure provides a method for treating one or more symptoms of said disorder, preferably wherein said symptoms are selected from table 7 and/or 8 and/or tables 7a- 7f, preferably tables 7a-7d, preferably from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction.
  • the methods comprise decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof, in particular in the central nervous system.
  • the invention relates to reducing inhibitory activity that is mediated by the GABA and glycine neurotransmitter systems.
  • GABAergic compounds which increase the inhibitory activity of GABA in the central nervous system e.g., GABA receptor agonists
  • CNS depressants that have been used for inhibitory action including sedation, anti-convulsant activity, anxiolysis, muscle relaxant, anterograde amnesia and anesthetic activity.
  • GABA receptor antagonists Compounds which decrease the inhibitory activity of GABA in the central nervous system lead to excitatory action that, when overstimulated, can lead to seizures.
  • GABAergic and/or Glycinergic inhibitory activity refers to the "net" activity of the central nervous system.
  • systemic administration of compounds reducing GABAergic action leads to a reduction of inhibitory activity.
  • these compounds When such compounds become available in specific brain regions including the thalamus, ventrolateral thalamus, (Thai), internal segment of globus pallidus (GPi), substantia nigra pars reticulata (SNr), subthalamic nucleus (STN), external segment of globus pallidue (GPe), neostriatum, cerebral ventricle, subdural space and intrathecal space, these compounds can also exert increases or decreases in glutamate excitatory activity outside these regions.
  • Thai ventrolateral thalamus, internal segment of globus pallidus (GPi), substantia nigra pars reticulata (SNr), subthalamic nucleus (STN), external segment of globus pallidue (GPe), neostriatum, cerebral ventricle, subdural space and intrathecal space
  • these compounds can also exert increases or decreases in glutamate excitatory activity outside these regions.
  • the present invention is preferably directed to providing a
  • administration includes both enteral administration (e.g., orally and rectally) and parenteral (e.g., intraveneous, subcutaneous or intramuscular) or topical (e.g. topical admistration through creams, nasally and through eye drops).
  • the administration is enteral.
  • the invention also relates to the systemic administration using formulations that are known to increase the distribution and availability of compounds (in)to the CNS, for example through the administration of the compounds through formulations that increase the bio-availabilty of compounds into the CNS such as for example, but not limited to, lipid formulations.
  • the invention also relates to systemic administration through formulations that lead to the sustained release of the compound and that consequently lead to increased concentrations of the compound in the CNS.
  • the disclosure does not encompass the direct, localized administration of compounds to a particular brain region, such as the intracranial administration described in US5735814.
  • US5735814 is concerned with modulating glutamate excitation for treatment of ALS, Huntington's Disease, and Parkinson's Disease.
  • glutamate hyperexcitation is not the cause of the diseases mentioned in US5735814, but rather a physiologic reaction aimed at reestablishing homeostasis.
  • the methods do not comprise direct, i.e., local, administration (e.g., via brain infusion at particular locations) of a GABAergic or glycinergic reducing activity compound as described herein to the ventrolateral thalamus (Thai), internal segment of globus pallidus (GPi), substantia nigra pars reticulata (SNr), subthalamic nucleus (STN), external segment of globus pallidus (GPe), neostriatum, cerebral ventricle, subdural space, or intrathecal space.
  • methods do not comprise the direct administration referred to in US5735814 in patients afflicted with Parkinson's disease, ALS, or Huntington's disease.
  • the method comprises decreasing GABAergic net inhibitory activity.
  • the "net" inhibitory activity of the CNS is then decreased.
  • Such antagonists may reduce the amount of GABA released by an individual neuron, or groups of neurons, or in some parts of the neuronal system but their overall net effect on the whole is an increase of inhibitory activity as for example reflected in their efficacy in reducing seizures rather than provoking these. Accordingly, it is clear that the administration of an AMPA receptor antagonist does not decrease GABAergic net activity and is not encompassed by the invention.
  • GABAergic inhibitory activity is reduced by the systemic administration of a GABA receptor antagonist and / or a compound that leads to an increase in availability or efficacy of compounds that exert their action through the GABA receptor causing the net reduction of inhibitory activity.
  • the compound is a GABA receptor antagonist.
  • the method comprises decreasing Glycinergic activity.
  • decreasing Glycinergic activity is through modulation of the Glycine receptor.
  • glycinergic inhibitory activity is decreased by the administration of a glycine receptor antagonist.
  • the method comprises decreasing GABAergic and Glycinergic activity.
  • the method also comprises the administration of an additional compound for decreasing glutaminergic activity for maintaining the equilibrium between the excitatory and inhibitory systems for avoiding seizures.
  • the methods disclosed herein also comprise a step of diagnosing an individual as having ALS or an ALS like disorder. Such diagnosing steps are well within the purview of a skilled person.
  • the following data may be collected: patient symptomology, creatine kinase blood levels, electrical activity in the muscle (e.g., using an electromyogram), and genetic testing (e.g., for familial forms of ALS).
  • the methods disclosed herein comprising a step of diagnosing an individual having ALS or an ALS like disorder as exhibiting a symptom selected from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction.
  • the ALS-like disorder presents at least one of the symptoms in table 7 and/or 8 and/or tables 7a-7f, preferably tables 7a- 7d.
  • the ALS-like neuromuscular disorder presents at least one of, preferably all of, the following symptoms: muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction. It is understood that the symptoms do not need to be present in the same individual, but rather, that the symptoms are a characteristic of a particular disorder in the patient population as a whole.
  • an individual to be treated exhibits one or more symptoms selected from tables 7 and/or 8 and/or tables 7a- 7f, preferably tables 7a- 7d.
  • an individual to be treated exhibits one or more symptoms selected from tables 7 and/or 8 and/or tables 7a- 7f, preferably tables 7a- 7d.
  • an individual to be treated exhibits one or more symptoms selected from tables 7 and/or 8 and/or tables 7a- 7f, preferably tables 7a- 7d.
  • an individual to be treated exhibits one or more symptoms selected from tables 7 and/or 8 and/or tables 7a- 7f, preferably tables 7a- 7d.
  • the individual to be treated exhibits one or more symptoms selected from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and gastrointestinal dysfunction.
  • the presence of these symptoms can be readily determined by a physician.
  • the method comprising determining whether the individual exhibits at least one or more of the symptoms.
  • the symptoms are muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria and / or eye movement difficulties.
  • the disorder is selected from ALS, MND, progressive muscular atrophy (PMA), flail arm MND, flail leg MND, primary lateral sclerosis (PLS), progressive bulbar palsy (PBP), pseudobulbar palsy (PB), Duchenne muscular dystrophy (DMD), Facioscapulohumeral muscular dystrophy (FSHD), Friedreich's ataxia,
  • PMA progressive muscular atrophy
  • PPS primary lateral sclerosis
  • PBP progressive bulbar palsy
  • PB pseudobulbar palsy
  • DMD Duchenne muscular dystrophy
  • FSHD Facioscapulohumeral muscular dystrophy
  • Friedreich's ataxia ALS, MND, progressive muscular atrophy (PMA), flail arm MND, flail leg MND, primary lateral sclerosis (PLS), progressive bulbar palsy (PBP), pseudobulbar palsy (PB), Duchenne muscular dystrophy (DMD), Facioscapulohumeral muscular dystrophy (FSHD), Friedreich
  • Frontotemporal dementia Frontotemporal degeneration
  • Behavioral variant FTD bv-FTD
  • Primary progressive aphasia PPA
  • FTD movement disorders Dementia, Pugilist dementia, Alzheimer's disease (ALZ), Vascular dementia, Dementia with Lewy bodies (DLB), Progressive supranuclear palsy (PSP),
  • MS Corticobasal degeneration, Multiple Scleroses (MS), Huntington's disease (HD), Peripheral Neuropathy (PN), Parkinson's disease (PD), Schizophrenia, Diabetes, and Traumatic brain injury (TBI) or other diseases listed in tables 1, 2, 3 or 4
  • the disorder is selected from ALS, FTD-ALS, FTD, dementia, Alzheimer's disease (ALZ), Huntington's disease, Parkinson's disease, Duchenne muscular dystrophy, Multiple Scleroses, peripheral neuropathy, schizophrenia, diabetes, Facioscapulohumeral muscular dystrophy.
  • the disorder is not ALS, Parkinson's disease, or Huntington's disease.
  • an ALS-like disorder is a disorder with one or more symptoms as listed in Table 7, 8 or 7a- 7f, preferably tables 7a-d, wherein the one or more symptoms results from inhibitory neurotransmitter overstimulation.
  • the disclosure demonstrates that the symptoms listed in Tables 7 and 8 and 7a- 7f when presented in disorders such as those listed in Tables 1-4 are the result of GABAergic and/or Glycinergic
  • ALS and ALS-like disorders may also be referred to herein as inhibitory neurotransmitter overstimulation disorders.
  • the present disclosure is the first to recognize that inhibitory neurotransmitter overstimulation is a common pathology linking the disorders listed in Tables 1-4.
  • the disorder is a muscular dystrophy, an inflammatory myopathy, an MND, a
  • the disorder is ALS.
  • the disclosure provides a method and pharmaceutical compositions for treating one or more symptoms of said disorder, preferably wherein said symptoms are selected from muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction, gastrointestinal dysfunction and/or symptoms listed in table 7 and/or 8 and/or tables 7a- 7f, preferably tables 7a- 7d, in an individual afflicted with ALS or an ALS-like disorder.
  • the methods comprise decreasing GABAergic and/or Glycinergic inhibitory activity in an individual in need thereof, for example by administering the pharmaceutical compositions disclosed herein.
  • the method comprises decreasing GABAergic activity.
  • the method comprises decreasing Glycinergic activity.
  • the method comprises decreasing GABAergic and Glycinergic activity.
  • the method also comprises the administration of a further compound for decreasing glutaminergic activity for maintaining the equilibrium between the excitatory and inhibitory systems for avoiding seizures.
  • a therapeutically effective amount of a compound capable of reducing GABAergic activity and/or Glycinergic inhibitory activity is administered to an individual in need thereof.
  • tables 7 and 8 and tables 7a- 7f preferably tables 7a- 7d
  • GABAergic and/or Glycinergic inhibitory activity should be decreased in the individual based on the symptoms an individual presents. For example, when an individual having an ALS or ALS-like disorder presents with symptoms selected from table 7, then GABAergic activity should be decreased. When an individual having an ALS or ALS-like disorder presents with symptoms selected from table 8, then GABAergic activity, Glycinergic activity, or both activities should be decreased. Most disorders will benefit from decreasing both GABAergic and Glycinergic activities. However, diabetes, due to its specific symptomology/pathology as first described herein, can also be treated by decreasing GABAergic activity alone.
  • mammals e.g., primates, domesticated animals including dogs, cats, sheep, cattle, goats, pigs, mice, rats, and rabbits.
  • the individual is a human.
  • the disclosure further provides pharmaceutical compositions comprising a compound reducing GABAergic activity and/or a compound reducing Glycinergic activity.
  • the composition comprises a compound reducing GABAergic activity.
  • the composition comprises a compound reducing Glycinergic activity.
  • the composition comprises a compound reducing GABAergic activity and a compound reducing Glycinergic activity. Said compositions are useful for the treatments disclosed herein. The compounds reducing GABAergic or Glycinergic activity described herein are therefore useful for the preparation of medicaments for the treatments disclosed herein.
  • the neuromuscular disease is not associated with an elevated risk of seizure.
  • elevated risk refers to a significantly increased risk of seizures in the general patient population as compared to a control population.
  • an individual in need thereof is administered a pharmaceutical composition which decreases GABAergic and/or Glycinergic activity.
  • the GABAergic and Glycinergic inhibitory neurotransmitter pathways have been extensively studied. A skilled person is therefore well aware of suitable means to reduce GABAergic and Glycinergic overstimulation.
  • suitable means for reducing activity include reducing GABA and / or Glycine levels available for binding to receptors, GABA and / or Glycine synthesis inhibition, stimulation of GABA and / or Glycine metabolism, the prevention of binding of GABA and / or Glycine to their receptors through
  • GABAergic or Glycinergic mediated recurrent inhibition overstimulation Suitable means for reducing GABA activity also include modulation of protein kinase C. It is also clear to a skilled person that a compound may be chosen which decreases both GABAergic and Glycinergic activity. Such compounds may be preferred in disorders which result from overstimulation of both the GABAergic and Glycinergic systems.
  • a compound for reducing GABAergic activity is a GABA receptor antagonist.
  • a compound for reducing Glycinergic activity is a glycine receptor antagonist.
  • a "direct” GABAergic activity reducer exerts its effects directly on the GABAergic pathway, for example, by directly targeting GABA (synthesis, uptake, etc.) or a GABA receptor.
  • An "indirect” GABAergic activity antagonist exerts its effects on a different neurotransmitter system, which in turn alters GABAergic activity.
  • the GABAergic and /or Glycinergic activity reducer exerts its action to the GABA receptor or to the Glycine receptor.
  • the GABAergic and /or Glycinergic activity reducer exerts its action to the GABA receptor or to the Glycine receptor.
  • the GABAergic and /or Glycinergic activity reducer exerts its action to the GABA receptor or to the Glycine receptor.
  • Glycinergic activity reducer exerts its action through interacting with both the GABA receptor and the Glycine receptor, preferably the GABAergic and /or Glycinergic activity reducer is Bicuculline, Picrotoxin, Salicylidene salicylhydrazide, Flumazenil, Gabazine (SR 95531), Thiocolchicoside, 6,2-dihydroflavone, RU5135, cicutoxin, Ro 15- 4513, Ro 15-4603, FG 7142, BTD-001, RG- 1662, strychnine, CGP 36742, SGS-742 or Tutin.
  • the GABAergic and /or Glycinergic activity reducer is Bicuculline, Picrotoxin, Salicylidene salicylhydrazide, Flumazenil, Gabazine (SR 95531), Thiocolchicoside, 6,2-dihydroflavone, RU5135, cicutoxin, Ro 15- 4513, Ro 15-
  • the compound is a 6-Lactam with GABA antagonistic activity, preferably the ⁇ -Lactam is selected from penicillin, cephalosporin, and a carbapenem. More preferably the ⁇ -Lactam is a penicillin, more preferably penicillin G. Preferably the compound is selected from Table 5.
  • the compound is a GABA receptor inhibitor.
  • a GABA receptor inhibitor refers to a compound that reduces the activity or expression of the GABA receptor and includes compounds, e.g., antisense oligonucleotides as well as compounds that bind to the GABA receptor and prevent or reduce GABAergic activity.
  • a preferred GABA receptor inhibitor is a GABA receptor antagonist.
  • partial receptor agonists can also act as a competitive antagonist in the presence of a full agonist.
  • GABA receptor partial agonists are not encompassed by the invention.
  • the GABA receptor inhibitor specifically inhibits GABA-A, GABA-B,
  • GABA-C or other receptor subtypes with higher affinity than it inhibits other GABA receptor subtypes.
  • differences in binding between the GABA-A, GABA-B, GABA-C or other GABA subtype receptors can for example be established by determining receptor affinity as reflected in the Kd or IC50 values of a GABA receptor inhibitor for each of the GABA receptor subtypes, as for example established in in vitro receptor binding or functional assays.
  • the GABA receptor inhibitor is selected from a selective GABA- A receptor inhibitor, a selective GABA-B receptor inhibitor, or a selective GABA-C receptor inhibitor.
  • the inhibitor is a selective GABA-B receptor inhibitor, more preferably a GABAB antagonist from Table 5.
  • the GABA receptor inhibitor when the individual is afflicted with ALS, the GABA receptor inhibitor is not a GABA-A receptor inhibitor.
  • the GABA receptor inhibitor when the individual is afflicted with ALS, the GABA receptor inhibitor is a selective GABA-B receptor inhibitor.
  • the compound is a GABAA antagonist selected from a fluoroquinine or a 6-Lactam.
  • suitable compounds reducing GABAergic activity include compounds having one or more of the following properties:
  • inverse agonists, antagonists, partial agonists to the GABA binding site of the GABA receptor preferably selected from Bicuculline, Picrotoxin, Salicylidene salicylhydrazide, Flumazenil, Gabazine (SR 95531), Thiocolchicoside, 6,2-dihydroflavone, RU5135, Ro 15-4513, Ro 15- 4603 or FG 7142.
  • inverse agonists for example, inverse agonists, antagonists, partial agonists to the alcohol binding site of the GABA receptor
  • Preferred compounds reducing GABAergic activity are selected from table 5, preferably a GABA receptor antagonist.
  • GABAergic activity has been shown to be clinically feasible through the administration of the GABA receptor antagonist flumazenil leading to the reversal of GABAergic effects of benzodiazepine administration, even leading to sublingual applications. Furthermore, GABAergic activity in cats can be reduced through the administration of compounds reducing GABAergic activity such as GABA antagonists picro toxin and bicuculline (Hockman et al. 1996).
  • the one or more compounds which reduce GABAergic activity is not ginkgo extract (in particular the extract of Ginkgo biloba) or a component of ginko extract (e.g., a ginkgolide or bilobalide).
  • Ginkgolides include natural ginkgolides, e.g., ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, and ginkgolide M, as well as synthetic ginkgolides and their derivates such as compounds of the formula:
  • W, X, Y and Z represent independently the H, OH, linear or branched alkoxy or O-GS radicals, GS-OH representing a mono- or a disaccharide, or one of their derivatives or analogues, it being understood that at least one of W, X, Y or Z represents an O-GS radical.
  • GS-OH representing a mono- or a disaccharide, or one of their derivatives or analogues
  • Ginkgolides are known to have a number of different effects incuding hippocampal insulin receptor binding, affecting 5HT1A receptor density, increasing extracellular dopamine levels, increasing the muscarin receptor population in the hippocampus, binding to the kainite excitatory amino acid site, activatin the
  • Pregnane X ligand- activated nuclear hormone receptor displaying Antioxidant/Antiinflammatory effects that can compensate for the SOD1 deficiency, inhibiting
  • MAO Monoamine oxidase
  • the one or more compounds which reduce GABAergic activity is not ginkgo extract (in particular the extract of Ginkgo biloba) or a component of ginko extract (e.g., a ginkgolide or bilobalide).
  • the one or more compounds which reduce GABAergic activity is not ginkgo extract (in particular the extract of Ginkgo biloba) or a component of ginko extract (e.g., a ginkgolide or bilobalide).
  • methods and pharmaceutical compositions are provided for treating muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and/or gastrointestinal dysfunction) in an individual afflicted with ALS or an ALS-like disorder, the method comprising decreasing GABAergic and/or
  • the one or more compounds which reduce GABAergic activity is not ginkgo extract (in particular the extract of Ginkgo biloba) or a component of ginko extract (e.g., a ginkgolide or bilobalide).
  • linalool is not a GABA antagonist (see, e.g., Brum et al. Phytother Res. 2001 Aug;15(5):422-5) and is therefore not a compound which reduces GABAergic activity as disclosed herein.
  • Suitable compounds that indirectly reduce GABAergic activity include those which interact with the activity of the GABAergic neurotransmitter system through interactions with other neurotransmitter systems selected from the dopamine neurotransmitter system, the glutamine neurotransmitter system, the acetylcholine neurotransmitter system, the serotonin neurotransmitter system, the norepinephrine neurotransmitter system, the epinephrine neurotransmitter system, the protein kinase C system, and the histamine neurotransmitter system.
  • the Glycinergic activity reducing compound modulates the glycine receptor and / or leads to an increase in availability or efficacy of compounds that (at least partly) exert their action through the glycine receptor thereby causing the reduction of Glycinergic activity.
  • Such compounds have one or more of the following properties: a. Decreasing Glycine synthesis b. Decreasing Glycine uptake in neuron cell vesicles
  • inverse agonists, antagonists, partial agonists to the GABA binding site of the GABA receptor preferably selected from Bicuculline,
  • the Glycinergic activity reducing compound is a Glycine receptor antagonist.
  • Suitable compounds that indirectly reduce Glycinergic activity include those which interact with the activity of the Glycinergic neurotransmitter system through interactions with other neurotransmitter systems selected from the dopamine neurotransmitter system, the glutamine neurotransmitter system, the acetylcholine neurotransmitter system, the serotonin neurotransmitter system, the norepinephrine neurotransmitter system, the epinephrine neurotransmitter system, and the histamine neurotransmitter system.
  • Preferred compounds reducing Glycinergic activity are found in table 6, preferably a glycine receptor antagonist.
  • the compounds reducing GABAergic activity and / or Glycinergic activity provided herein, also referred to as "compounds”, include polypeptides, small molecules, and nucleic acid based inhibitors.
  • the compound is a nucleic acid molecule (such as an antisense oligonucleotide, an RNA interference molecule) or a binding molecule (e.g., an antibody or antibody fragment), or a small molecule receptor antagonist.
  • the compound is a nucleic acid molecule whose presence in a cell causes the degradation of or inhibits the function, transcription, or translation of its target gene in a sequence-specific manner.
  • exemplary nucleic acid molecules include aptamers, siRNA, artificial microRNA, interfering RNA or RNAi, dsRNA, ribozymes, antisense oligonucleotides, and DNA expression cassettes encoding said nucleic acid molecules.
  • Suitable target genes for reducing GABAergic activity include GABRA1, Gabral,
  • GABRG2 GaBRA2, Gabra2, GABRA3, Gabra3, GABRA4, Gabra4, GABRA5, Gabra5, GABRA6, Gabra6, GABRB1, Gabrbl, GABRB2, Gabrb2, GABRB3, Gabrb3, GABRG1, Gabrgl, GABRG2, Gabrg2, GABRG3, Gabrg3, GABRD, Gabrd, GABRE, Gabre, GABRQ, Gabrq, GABRP, Gabrp, GABRR1, Gabrrl, GABRR2, Gabrr2, GABRR3, Gabrr3, GABBR1, Gabbrl, GABBR2, Gabbr2, KCTD8, Kctd8, KCTD12, Kctdl2, Kctdl2b, KCTD16, Kctdie, SLC6A1, Slc6al, SLC6A13 (Hs), Slc6al3 (Mm), Slc6al3 (Rn), SLC6A11 (Hs), Slc6all (Mm), Sl
  • Suitable target genes for reducing Glycinergic activity include GLRAl, Glral, GLRA2, Glra2, GLRA3, Glra3, GLRA4, Glra4, GLRB, Glrb, SLC32A1 (Hs), Slc32al (Mm), Slc32al (Rn), GATM (Hs), Gatm (Mm), Gatm (Rn), SLC6A9 (Hs), Slc6a9 (Mm), Slc6a9 (Rn), SLC6A5 (Hs), Slc6a5 (Mm), Slc6a5 (Rn), SLC6A14 (Hs), Slc6al4 (Mm), Slc6al4 (Rn), SLC6A7 (Hs), Slc6a7 (Mm), Slc6a7 (Rn), MT-ATP8 (Hs), mt-Atp8 (Mm), Mt-atp8 (Rn), ATP
  • the nucleic acid molecule is an antisense oligonucleotide.
  • Antisense oligonucleotides generally inhibit their target by binding target mRNA and sterically blocking expression by obstructing the ribosome. AONs can also inhibit their target by binding target mRNA thus forming a DNA-RNA hybrid that can be a substance for RNase H. AONs may also be produced as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides, oligonucleotide mimetics, or regions or portions thereof. Such compounds have also been referred to in the art as hybrids or gapmers. Methods for designing and modifying such gapmers are described in, for example, U.S. Patent Publication Nos. 20110092572 and
  • AONs typically comprise between 12 to 80, preferably between 15 to 40, nucleobases.
  • the AONs comprise a stretch of at least 8 nucleobases having 100% complementarity with the target mRNA.
  • the nucleic acid molecule is an RNAi molecule, i.e., RNA interference molecule.
  • RNAi molecules include siRNA, shRNA, and artificial miRNA.
  • siRNA comprises a double stranded structure typically containing 15 to 50 base pairs and preferably 19 to 25 base pairs and having a nucleotide sequence identical or nearly identical to an expressed target gene or RNA within the cell.
  • An siRNA may be composed of two annealed polynucleotides or a single polynucleotide that forms a hairpin structure.
  • shRNA small hairpin RNA
  • these shRNAs are composed of a short, e.g.
  • siRNA molecules are well known to one of skill in the art (Hajeri et al. 2009). Methods of administration of therapeutic siRNA is also well- known to one of skill in the art (Manjunath et al. 2010, Guo et al., 2010).
  • siRNA molecule comprises an antisense strand having about 15 to about 30 (e.g., about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30) nucleotides, wherein the antisense strand is complementary to a RNA sequence or a portion thereof encoding.
  • the nucleic acid molecule inhibitors may be chemically synthesized and provided directly to cells of interest.
  • the nucleic acid compound may be provided to a cell as part of a gene delivery vehicle.
  • a gene delivery vehicle is preferably a liposome or a viral gene delivery vehicle. Liposomes are well known in the art and many variants are available for gene transfer purposes.
  • Vectors comprising said nucleic acids are also provided.
  • a “vector” is a recombinant nucleic acid construct, such as plasmid, phase genome, virus genome, cosmid, or artificial chromosome, to which another DNA segment may be attached.
  • the term “vector” includes both viral and nonviral means for introducing the nucleic acid into a cell in vitro, ex vivo or in vivo.
  • Non-viral vectors include plasmids, liposomes, electrically charged lipids (cytofectins), DNA-protein complexes, and biopolymers.
  • Viral vectors include retrovirus, ade no- associated virus (AAV), pox, baculovirus, vaccinia, herpes simplex, Epstein-Barr and adenovirus vectors.
  • Vector sequences may also contain one or more regulatory regions, and/or selectable markers useful in selecting, measuring, and monitoring nucleic acid transfer results (transfer to which tissues, duration of expression, etc.). Lentiviruses have been previously described for transgene delivery to the hippocampus (van Hooijdonk 2009)
  • nucleic acids there are a variety of techniques available for introducing nucleic acids into viable cells.
  • the techniques vary depending upon whether the nucleic acid is transferred into cultured cells in vitro, or in vivo in the cells of the intended host.
  • Techniques suitable for the transfer of nucleic acid into mammalian cells in vitro include the use of liposomes, electroporation, microinjection, cell fusion, DEAE-dextran, the calcium phosphate precipitation method, etc.
  • the currently preferred in vivo gene transfer techniques include transfection with viral (typically retroviral) vectors and viral coat protein-liposome mediated transfection (Dzau et al 1993).
  • the compound is a "binding agent" that specifically binds to a target and inhibits the function of a target, more preferably the compound is a binding agent or small molecule.
  • Preferred targets for reducing GABAergic activity include GABA receptors and preferred targets for reducing Glycinergic activity include glycine receptors.
  • Binding agents include antibodies as well as non-immunoglobulin binding agents, such as phage display-derived peptide binders, and antibody mimics, e.g., affibodies, tetranectins (CTLDs), adnectins (monobodies), anticalins, DARPins (ankyrins), avimers, iMabs, microbodies, peptide aptamers, Kunitz domains, aptamers and affilins.
  • CTLDs tetranectins
  • adnectins monobodies
  • anticalins DARPins (ankyrins)
  • DARPins ankyrins
  • avimers iMabs, microbodies, peptide aptamers, Kunitz domains, aptamers and affilins.
  • antibody includes, for example, both naturally occurring and non- naturally occurring antibodies, polyclonal and monoclonal antibodies, chimeric antibodies and wholly synthetic antibodies and fragments thereof, such as, for example, the Fab', F(ab')2, Fv or Fab fragments, or other antigen recognizing immunoglobulin fragments.
  • Antibodies which bind a particular epitope can be generated by methods known in the art.
  • polyclonal antibodies can be made by the conventional method of immunizing a mammal (e.g., rabbits, mice, rats, sheep, goats). Polyclonal antibodies are then contained in the sera of the immunized animals and can be isolated using standard procedures (e.g., affinity chromatography, immunoprecipitation, size exclusion chromatography, and ion exchange chromatography).
  • Monoclonal antibodies can be made by the conventional method of immunization of a mammal, followed by isolation of plasma B cells producing the monoclonal antibodies of interest and fusion with a myeloma cell (see, e.g., Mishell, et al., 1980). Screening for recognition of the epitope can be performed using standard immunoassay methods including ELISA techniques, radioimmunoassays, immunofluorescence, immunohistochemistry, and Western blotting (Ausubel, et al., 1992) . In vitro methods of antibody selection, such as antibody phage display, may also be used to generate antibodies (see, e.g.,
  • compositions comprising compounds as described herein and, optionally, a pharmaceutically acceptable carrier, filler, preservative, adjuvant, solubilizer, diluent and/or excipient is also provided.
  • a pharmaceutically acceptable carrier, filler, preservative, adjuvant, solubilizer, diluent and/or excipient may for instance be found in Remington: The Science and Practice of Pharmacy, 20th Edition. Baltimore, MD: Lippincott Williams & Wilkins, 2000.
  • the compound When administering the compounds thereof to an individual, it is preferred that the compound is dissolved in a solution that is compatible with the delivery method.
  • a solution that is compatible with the delivery method.
  • the solution is a physiological salt solution.
  • the levels of GABAergic and/or Glycinergic activity are reduced in the individual gradually as a too fast decrease in GABAergic or Glycinergic
  • overstimulation reduction therefore should be gradual and preferably a well monitored dose titration is used.
  • Treatment may further be in the presence of compounds that are capable of gradually decreasing glutaminergic excitatory action for reducing the risk at and duration and severity of epileptic seizures.
  • Treatment preferably begins as soon as disorder is diagnosed.
  • Early treatment with the compounds disclosed herein can not only alleviate or reduce the symptoms disclosed in tables 7 and 8 and tables 7a- 7f, preferably tables 7a- 7d, but can also delay or prevent their onset.
  • Actual dosage levels of the pharmaceutical preparations described herein may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic or limiting toxicity to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound, the route of administration, the timing of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • Optimal dosing can be determined on the basis of pharmacokinetic parameters such as Clearance, Volume of distribution, fraction unbound to protein, (elimination) half- life etc. and on the basis of pharmacodynamic parameters such as receptor affinity, potency, and GABA inhibition activity, etc.
  • optimal dosing can be determined by titration of individual patients or groups of patients to maximal efficacy in the absence of seizures.
  • seizures may be an unavoidable side-effect of treatment for some cases. This is especially true for more severe forms of the disorders.
  • Muscle relaxant treatments such as neuromuscular blockers and midazolam (in hospital setting) and nasal or buccal midazolam or rectal diazepam (in home settings) can be used to reduce the risk at occurrence, duration and/or severity of seizures. Other factors which are useful to consider when determining the optimal dose are patient convenience and patient compliance.
  • the dosage of the antagonists is reduced slowly over the treatment period, i.e., is tapered down.
  • a therapeutically effective amount refers to the dosage needed to treat one or more of the following symptoms in an individual afflicted with ALS or an ALS-like disorder: muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction, gastrointestinal dysfunction and/or symptoms as listed in table 7 and/or 8 and/or tables 7a- 7f, preferably tables 7a- 7d.
  • a therapeutically effective amount of said compound if administered in a healthy patient, may be ssociated with the induction of seizures or increased risk of seizures.
  • lower dosages are also encompassed by the invention.
  • compounds displaying GABA antagonism may also display efficacy in the treatment of other diseases or symptoms.
  • 6- lactams with GABA antagonistic activity can also be used as antibiotics for the treatment of infections.
  • the present invention however does not relate to the
  • ⁇ -lactams such as penicillin are used as antibiotics, but are also capable of inhibiting GABA-A receptors and are a preferred compound of the invention.
  • the dosage of penicillin G used to treat infections is provided in the table below.
  • penicillin is administered at a dosage higher than that listed in the table.
  • lower dosages are also important to the consumer.
  • lower doses are sufficient in individuals having renal impairment (and therefore impaired penicillin clearance).
  • Lower doses are also sufficient when administered, for example, at the early stages of disease when GABAergic inhibitor activity is only mildly overstimulated or as a "maintenance treatment" after GABAergic activity has been reduced by treatment.
  • streptococci including S. pneumoniae
  • Penicillin G is administered in divided doses, usually every 4 to 6 hours with the exception of meningococcal meningitis/septicemia, i.e., every 2 hours.
  • the invention relates in some
  • antagonistic activity also displays antibiotic activity. High doses of antibiotics such as penicillin G have been administered in order to treat particularly dangerous
  • the present disclosure is the first recognition that such antibiotics can be used to treat ALS or an ALS-like disorder because of their GABA antagonistic effects, in particular to treat a symptom such as muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction or gastrointestinal dysfunction in an individual afflicted with ALS or an ALS-like disorder.
  • the present treatment is independent from the antibiotic effects of beta-lactams on bacteria.
  • the current invention for penicillin G relates to the treatment of ALS symptoms with penicillin G dosages that are higher than those that would be used to treat the symptoms not related to the invention in that patient.
  • This not only applies to penicillin G, but also applies to other antibiotics displaying GABA antagonistic activity. Furthermore, this applies to all compounds that next to displaying GABA antagonistic activity, in addition also display efficacy in symptoms not related to the current invention.
  • the individual afflicted with ALS or an ALS-like disorder is not afflicted with syphilis or Lyme's disease, more preferably the individual is not afflicted with an infection (in particular a bacterial infection).
  • the individual does not have an elevated risk of developing or being afflicted with an infection (in particular a bacterial infection).
  • an infection in particular a bacterial infection.
  • a person having an "elevated risk" of infection refers to a person having a significantly and/or clinically relevant higher risk of infection than the general population (for example, in patients where antibiotic prophylaxis treatment is warranted).
  • the present disclosure provides the use of GABAergic activity reducing compounds, such as beta-lactams, for treating ALS or an ALS-like disorder (in particular a symptom such as muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction or gastrointestinal dysfunction) in an individual that would not otherwise have the need for treatment with a beta-lactam (i.e., such individual not suffering from or having an elevated risk of suffering from an infection) .
  • a beta-lactam i.e., such individual not suffering from or having an elevated risk of suffering from an infection
  • the methods further comprise decreasing glutaminergic activity in said individual.
  • the individual is administered a
  • compositions are well-known to a skilled person and include riluzole and/or other compounds that reduce glutaminergic activity such as AP7 (2-amino-7- phosphonoheptanoic acid), CPPene (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-l- phosphonic acid), Selfotel, Amantadine, Atomoxetine, AZD6765, Chloroform,
  • Methoxetamine Nitromemantine, Nitrous oxide, Phencyclidine, Rolicyclidine, Tenocyclidine. Methoxydine, Tiletamine, Xenon, Neramexane, Eliprodil, Etoxadrol, Dexoxadrol, WMS-2539, NEFA, Remacemide, Delucemine, 8A-PDHQ, Aptiganel (Cerestat, CNS- 1102), HU-211, Rhynchophylline, Ketamine, CNQX, DNQX, NS102, Kynurenic acid, Tezampanel, NBQX, GYKI-52,466, GYKI-53,655, Perampanel, Talampanel. Table 1: Progressive neuromuscular disorders relevant to this disclosure leading to a gradual muscle weakness and to a common set of physical symptoms including difficulty with speech, difficulty with mobility and fine motor skills:
  • myopathies Myotonia Congenita (MC), Thomsen disease, Becker's disease, Paramyotonia (PP), Paramyotonia Congenita (PC), Periodic Paralysis (Hypokalemic), Periodic Paralysis (Hyperkalemic), Kearns- Sayre syndrome (KSS),
  • SMA Muscular Atrophy
  • SMA1 Werdnig-Hoffman disease
  • SMA, SMA2 Intermediate Spinal Muscular Atrophy
  • SMA3, KW Juvenile Spinal Muscular Atrophy
  • Kugelberg-Walander disease Endocrine abnormalities myopathies, Hyperthyroid myopathy
  • HYPTM Hypothyroid myopathy
  • SBMA spinal and bulbar muscular atrophy
  • SMA juvenile muscular atrophy
  • SMA autosomal dominant distal spinal muscular atrophy
  • Cerebellar ataxia Ataxic cerebral palsy, Sensory ataxia, Vestibular ataxia, Stroke related ataxia, Wilson's disease, Athetoid cerebral palsy, Dyskinetic cerebral palsy, ADCP, Bilirubin encephalopathy, Ataxia Telangiectasia, Friedreich's Ataxia, Spino Cerebellar Ataxias (SCA)
  • Table 2 Overview of other muscular and neurologic diseases relevant to this disclosure (source: Muscle Disease The Netherlands, www.spierziekten.nl).
  • Restless legs syndrome (RLS), Willis-Ekbom disease, Wittmaack-Ekbom syndrome, Guillain-Barre syndrome (GBS), Acute idiopathic demyelinating polyneuropathy, Chronic idiopathic demyelinating polyneuropathy, Acute inflammatory polyneuropathy, Chronic inflammatory polyneuropathy, Landry ascending paralysis, Polyneuroradiculopathy, Arthrogryposis multiplex congenita (AMC), Becker myotonia congenital, Becker myotonia, Brody disease, Brody syndrome, Carnitine Deficiency, Primary Carnitine Deficiency, Chronic idiopathic axonal polyneuropathy (CIAP), Congenital muscle dystrophy (CMD), Congenital fibre type disproportion myopathy, Small fiber peripheral neuropathy, fibromyalgia, Hereditary neuropathy with liability to pressure palsies (HNPP), Hereditaire Spastician Paraparese (HSP), Strumpell disease
  • Multifocal Motor Neuropathy MN
  • Myasthenia gravis with antibodies against AChR AChr MG
  • Proximal myotonic myopathy PROMM
  • Non dystrophic myotonia NDM
  • Neuralgic amyotrophy NA
  • Plexus brachialis neuropathy Poliomyelitis anterior acuta
  • Thomsen myotonia congenita Thomsen myotonia, Werdnig Hoffmann disease
  • Glycogen storage disease type I Coats' Disease
  • retinal telangiectasis bilateral Sensorineural Hearing Loss
  • Hypercarbic Respiratory Insufficiency autism
  • remote poliomyelitis Dystonia
  • Table 3 Overview of neurologic diseases relevant to this disclosure.
  • Frontotemporal dementia (FTD), dementia, Alzheimer's disease (ALZ), Multiple Sclerosis
  • MS Huntington's disease
  • DMD Duchenne muscular dystrophy
  • PN Neuropathy
  • PD Parkinson's disease
  • bv-FTD Behavioral variant FTD
  • PPA Primary progressive aphasia
  • Pugilist dementia vascular dementia
  • Dementia with Lewy bodies DLB
  • Lewy body dementia Progressive supranuclear palsy
  • PSP Progressive supranuclear palsy
  • TBI Traumatic brain injury
  • arylsulfatase B deficiency arylsulfatase A deficiency
  • MPS type VII arylsulfatase A deficiency
  • Sly syndrome beta- glucuronidase deficiency
  • Glycoproteinos Aspartylglucosaminuria Fucosidosis, Alpha-fucosidosis, a- es Mannosidosis, ⁇ -Mannosidosis, Mucolipidosis I (sialidosis), Schindler disease
  • gangliosidosis Tay-Sachs disease, Tay-Sachs/GM2 gangliosidosism, Sandhoff s disease, Sandhoff disease/GM2 gangliosidosis, Krabbe's disease, Metachromatic leucodystrophy, Niemann-Pick disease type A, Niemann-Pick disease type B, sphingomyelinase deficiency
  • Glycogen Glycogen storage disease type II (Pompe's disease)
  • NCL/CLN4 disease Northern Epilepsy/variant late infantile CLN8, Santavuori-Haltia/Infantile CLN1/PPT disease, Beta-mannosidosis
  • Leukodystrophy Multiple sulfatase deficiency, Pycnodysostosis, I- Cell Disease, Phosphotransferase deficiency, Psychomotor retardation, Corneal clouding, Retinopathy, mucolipidin 1 deficiency, Kanzaki disease, alpha-N -acetylgalactosaminidase deficiency, progressive neuromotor deterioration, coarse facial features, dysostosis multiplex, angiokeratoma corporis diffusum, hepatosplenomegaly, growth retardation, alpha-N -acetyl neuraminidase deficiency, mild form cholesterol ester storage disease, Cholesteryl Ester Storage Disease, beta-glucosidase deficiency, infantile globoid-cell leukodystrophy, galactosylceramidase deficiency, alpha-galactosidase A, GM1
  • gangliosidosis Morquio B disease, beta-galactosidase deficiency, GM2 gangliosidoses, disseminated lipogranulomatosis, ceramidase deficiency, subcutaneous nodules, flesh-colored papules, periarticular tumors or nodules, osteopenia, Sulfatase-modifying factor- 1 mutation,
  • mucopolysaccharidosis mucopolysaccharidosis, proptosis, ichthyosis, progressive leukoencephalopathy, cathepsin A deficiency, deficiency of lysosomal beta-galactosidase and neuraminidase as a result of a defect in the protective protein/cathepsin A (PPCA), renal Fanconi syndrome
  • PPCA protective protein/cathepsin A
  • GABAA antagonist (-)-a-thujone, (+)-a-thujone and (-)-6-thujone, (+)-6-thujone,
  • DMCM Dihydrosecurinine
  • Extracts from the plant Ginkgo biloba Extracts of plants containing C17 conjugated polyactylene with a terminal hydroxyl group and an allylic hydroxyl group attached at C14, Extracts of plants containing cicutoxin, virol A, virol C, isocicutoxin, or oenanthotoxin, Extracts of plants from the genus Thuja, Extracts of the Cicuta species plant, Extracts of the Oenanthe crocata plant, Extracts of the plant arborvitae, Extracts of the plant common sage, Extracts of the plant family Apiaceae, Extracts of the plant family Menispermaceae, Extracts of the plant genus Anamirta, Extracts of the plant genus Oenanthe, Extracts of the plant grand wormwood (Artemisia absinthium), Extracts of the plant junipers, Extracts of the plant mugwort, Extracts of the plant Nootka Cypress,
  • Isopregnanolone (sepranolone), L-655,708, Laudanosine, Leptazol, Lidocain, Lindane, Morphine, Muira puama, Naloxone, Naltrexone, Oenanthotoxin, Pentetrazol (metrazol), Phenylsilatrane, Picrotin, Picrotoxin, Picrotoxinin, piperidine- 4-sulphonic acid, Pitrazepin, Pregnenolone sulfate, PWZ-029, Quinine, Radequinil, RG- 1662, Rol5-4513, Ro4938581, RU5135, RU-5135, Salicylidene salicylhydrazide (SCS), Sarmazenil, Securinine, L-Securinine, Sinomenine,
  • GABAA channel blockers [35S]TBPS, picrotoxin, TBPS
  • GABAB antagonist [3H]CGP 62349, [125I]CGP 64213, [125I]CGP 71872,
  • GABAc antagonist Muscimol, CACA, 4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3- ol hydrochloride (THIP), SKF 97541, 1,2,5,6- Tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA)
  • bromoacetylalprenololmenthane broxaterol, cimaterol, cirazoline, denopamine, dopexamine, etilefrine,
  • prochlorperazine promazine, quetiapine, raclopride, remoxipride, risperidone, spiperone, spiroxatrine,
  • stepholidine sulpiride, sultopride, tetrahydropalmatine, thiethylperazine, thioridazine, thiothixene, tiapride, trifluoperazine, trifluperidol, triflupromazine, ziprasidone
  • Akt inhibitor X aloisine, aloisine A, alsterpaullone, alsterpaullone 2-cyanoethyl, alvocidib, aminopurvalanol A, arachidonic acid, AST-487, AT-7519, ATM kinase inhibitor, ATM/ATR kinase inhibitor, aurora kinase inhibitor III, aurora kinase/Cdk inhibitor, axitinib, balanol, barasertib- hQPA, BAY 11-7082, Bcr-abl inhibitor GNF-2, BI-2536, bisindolylmaleimide IV BMS-345541,BMS-387032, Bohemine, Bosutinib, BPIQ-I, Brivanib, Canertinib, casein kinase I inhibitor, casein kinase II inhibitor III, Cdc2-like kinase inhibitor, Cdk/Crk inhibitor, C
  • Doramapimod Dorsomorphin, Dovitinib, EGFR inhibitor, EGFR/ErbB-2 inhibitor, EGFR/ErbB-2/ErbB-4 inhibitor, Enzastaurin, ERK inhibitor II, ERK inhibitor III, Erlotinib, Fascaplysin, Fasudil, Fedratinib, Flt-3 inhibitor, Flt-3 inhibitor II, Flt-3 inhibitor III, Foretinib, GDC-0879,
  • Staurosporine STO609, SU11274, SU11652, SU- 14813, SU6656, SU9516, Sunitinib, Syk inhibitor, Syk inhibitor II, Syk inhibitor III, tamatinib, tandutinib, TG- 100- 115,
  • TGF-beta RI inhibitor III TGF-beta RI kinase inhibitor, Tofacitinib, Tozasertib, Tpl2 kinase inhibitor, TWS 119, Vandetanib, Vatalanib, VEGF receptor 2 kinase inhibitor I, VEGF receptor 2 kinase inhibitor II, VEGF receptor 2 kinase inhibitor IV, VEGF receptor tyrosine kinase inhibitor II, VEGF receptor tyrosine kinase inhibitor III, VX-702,
  • bromoacetylalprenololmenthane broxaterol, cimaterol, cirazoline, denopamine, dopexamine, etilefrine,
  • Table 7 Symptoms related to overstimulation of GABAergic activity
  • Acute pain syndromes Agitation, Anxiety, Apathy, Aphasia, Aspartylglucosaminuria, Athetoid cerebral palsy, Attention dysfunction, auditory hallucinations, Autism,
  • Behavioral changes Behavioral disturbances, bilateral, Bladder dysfunction, Bulbar palsy, Cardiomyopathy, Chorea, Chronic pain syndromes, Cognitive dysfunction, Cognitive impairment, Constipation, Corticobasal degeneration, decline in mental abilities, decreased blink rate, deficient ocular pursuit, deficits of normal emotional responses, deficits of normal thought processes, Delusions, Dementia, Depression, Difficulties with blowing cheeks, Difficulties with cognition, Difficulties with cognitive speech, Difficulties with judgment, Difficulties with lip seal, Difficulties with memory, Difficulties with mood and behaviour, Difficulties with organizing thought, Difficulties with reasoning, Diplopia, Disinhibition, disordered speech, disordered thoughts,
  • Mitochondrial disease Moodiness, Mucopolysaccharidoses, Multiple enzyme deficiency, negative neurologic symptoms, Neurological symptoms, Neuronal Ceroid Lipofuscinoses, Nystagmus, Oculomotor gaze palsy, olfactory hallucinations, Ophthalmoplegia, optic neuritis, optic neuropathy, Palsy, paralysis of extraocular muscles, Paranoia,
  • Paresthesia Parkinsonism, Perseveration, Personality changes, Phosphenes, pigmentary retinopathy, positive neurologic symptoms, poverty of speech, Problem solving dysfunction, problems with abstract thinking, problems with attention, problems with cognition, problems with cognitive flexibility, problems with inhibiting inappropriate actions, problems with initiating appropriate actions, problems with mood, problems with planning, problems with rule acquisition, problems with selecting relevant sensory information, progressive external ophthalmoplegia, Progressive non-fluent aphasia, Pseudobulbar symptoms, psychomotor regression, psychomotor retardation, Psychosis, Ptosis, Reduced IQ, Restless legs, Restless legs syndrome, Restlessness or fidgeting, Retinal dysfunction, Semantic dementia, Sensory problems, short-term memory loss, Sialorrhoea, sideroblastic anemia, sleep problems, slowed cognitive speed, social withdrawal, Speech changes, Sphingolipidoses, Stress, subacute necrotizing
  • encephalomyelopathy Subacute visual failure, Supranuclear gaze palsy, tactile hallucinations, Tongue muscle wasting, Tongue spasticity, Traumatic brain injury, Trouble eating, utilization behaviour, Vascular dementia, vertical gaze palsy, visual hallucinations, visual-spatial difficulties, Visual-spatial dysfunction, Visuospatial difficulties, wandering or restlessness, Weakening of the soft patelate, word-finding difficulties, Yawning
  • Athetoid cerebral palsy Bulbar palsy, Cardiomyopathy, Chorea, Difficulties with blowing cheeks, Difficulties with lip seal, Dysarthria, Dyskinetic cerebral palsy,
  • cardiomyopathy hypotonia, mask-like face expression, Palsy, Parkinsonism,
  • encephalomyelopathy Supranuclear gaze palsy, Tongue muscle wasting, Tongue spasticity, Weakening of the soft patelate, Amyotrophy, Ataxia, Automatic muscle dysfunction, Balance problems, Bradykinesia, Coordination dysfunction, Decreased facial expression, Difficulties with fine motor control, dysdiadochokinesia, Dysmetria, Dyssynergia, Facial movements including grimaces, Falls, falls backwards, Fine movement dysfunction, Flail arms, Flail legs, General lack of coordination, grasp reflex, Hand pill-rolling tremor, Head turning to shift eye position, hypertonia, hypotonia, Involuntary muscle dysfunction, Limb coordination problems, loss of muscle coordination, Muscle atrophy, Muscle dystrophy, Muscle myopathy, Muscle stiffness, muscle stiffness especially in the neck and upper body, muscle wasting, muscle function loss, myoclonus, Myotonia, Paralysis, Paraparesis, Paraplegias, Postural instability, Problems
  • Bladder dysfunction Constipation, elevated cerebrospinal fluid protein concentrations of lactate, elevated cerebrospinal fluid protein concentrations of pyruvate, exocrine pancreas dysfunction, Fatigue, Gastric dysmotility, Gastrointestinal dysfunction, Glycogen storage disease, Glycoproteinoses, growth hormone deficiency, hearing loss, hypoparathyroidism, incontinence, lactic acidemia, lactic acidosis, Lipidoses,
  • Lysosomal transport defects manifestations of diabetes type I, Manifestations of diabetes type II, Mitochondrial disease, Mucopolysaccharidoses, Multiple enzyme deficiency, Neuronal Ceroid Lipofuscinoses, sideroblastic anemia, sleep problems, Sphingolipidoses, osteopenia, neuropathy
  • Ophthalmoplegia optic neuritis, optic neuropathy, paralysis of extraocular muscles, pigmentary retinopathy, progressive external ophthalmoplegia, Ptosis, Retinal dysfunction, Subacute visual failure, Reading difficulties, vertical gaze palsy,
  • Acute pain syndromes anacusis, auditory hallucinations, Chronic pain syndromes, Deafness, gustatory hallucinations, Hallucinations, Hearing impairment, Hearing loss, Hypoesthesia, Impaired sense of smell, impaired sensation of pain, olfactory hallucinations, Paresthesia, Phosphenes, Sensory problems, tactile hallucinations, visual hallucinations, Numbness and tingling of the limbs, Sensory neuropathy, alien
  • Table 7e Symptoms overlapping for cognitive and neuromuscular aspects
  • Cognitive impairment Corticobasal degeneration, decline in mental abilities, deficits of normal emotional responses, deficits of normal thought processes, Delusions, Dementia, Depression, Difficulties with cognition, Difficulties with cognitive speech, Difficulties with judgment, Difficulties with memory, Difficulties with mood and behaviour, Difficulties with organizing thought, Difficulties with reasoning,
  • to comprise and its conjugations is used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.
  • verb "to consist” may be replaced by "to consist essentially of meaning that a compound or adjunct compound as defined herein may comprise additional component(s) than the ones specifically identified, said additional component(s) not altering the unique characteristic of the invention.
  • an element means one element or more than one element.
  • GABAergic activity refers to the GABA neurotransmitter system. Neurons that release GABA as a neurotransmitter are called GABAergic neurons and the physiological result of GABA neurotransmitter release is called GABAergic action.
  • a reduction in "GABAergic activity” refers to a reduction in, e.g., the production/release of the GABA neurotransmitter as well as for example the reduction in the ability of GABA to be detected by the post-synaptic neuron (e.g., by inhibiting the binding of GABA to a post-synaptic receptor), or other direct or indirect modulations to the GABA neurotransmitter system that result in the decrease of action exerted by the GABA neurotransmitter system.
  • Glycinergic activity refers to the Glycine neurotransmitter system. Neurons that release Glycine as a neurotransmitter are called Glycinergic neurons and the physiological result of Glycine neurotransmitter release is called Glycinergic action.
  • a reduction in “Glycinergic activity” refers to a reduction in, e.g., the production/release of the Glycine neurotransmitter as well as for example the reduction in the ability of Glycine to be detected by the post-synaptic neuron (e.g., by inhibiting the binding of Glycine to a post-synaptic receptor), or other direct or indirect modulations to the Glycine neurotransmitter system that result in the decrease of action exerted by the Glycine neurotransmitter system.
  • Glutaminergic activity refers to the glutamate neurotransmitter system. Neurons that release glutamate as a neurotransmitter are called Glutaminergic neurons and the physiological result of glutamate neurotransmitter release is called Glutaminergic action. A reduction in "Glutaminergic” refers to a reduction in, e.g., the
  • glutamate neurotransmitter production/release of the glutamate neurotransmitter as well as for example the reduction in the ability of glutamate to be detected by the post-synaptic neuron (e.g., by inhibiting the binding of glutamate to a post-synaptic receptor), or other direct or indirect modulations to the glutamate neurotransmitter system that result in the decrease of action exerted by the glutamate neurotransmitter system.
  • treating includes prophylactic and/or therapeutic treatments.
  • prophylactic or therapeutic treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • Example 1 Relating ALS disease to the disease epilepsy
  • Elevated glutamate levels in ALS cause motoneuron cell death leading to the clinical manifestation of ALS, while elevated glutamate levels in epilepsy lead to the clinical manifestation of epilepsy through the occurrence of epileptic seizures.
  • highly elevated glutamate concentrations in ALS patients do not lead to highly elevated epileptic seizure incidences.
  • Example 2 GABAergic and Glycinergic inhibitory neurotransmitter systems in ALS With the excitatory glutamate CSF levels increased in ALS up to 800% relative to healthy subjects without leading to increased seizure incidences and the
  • the inhibitory neurotransmitter system comprising of the GABA inhibitory
  • neurotransmitter system or the glycine inhibitory neurotransmitter system could be responsible for their clinical presentation in patients.
  • the analysis is as follows:
  • Example 3 Increased levels of inhibitory neurotransmitter GABA can lead to muscle wasting symptoms as observed in ALS
  • the GABAergic system is also capable of exerting strong muscle relaxant activity as can be deducted from the pharmacological effects of benzodiazepine treatment.
  • Benzodiazepines are a pharmacologically well-known and validated compound class that exert their pharmacological action by increasing the affinity of GABA for the GABA receptor leading to GABAergic stimulation that is capable of weakening muscles in a similar way as observed in ALS, i.e. through the inhibition of
  • Example 4 GABAergic overstimulation can lead to muscle dysfunction as observed in ALS
  • GABAergic overstimulation can be concluded to even be capable of leading to complete muscle blockades. This is demonstrated for the pharmacologically well-known and validated compound class of GABAergic benzodiazepine agonists that when overdosed lead to fatal respiratory muscle dysfunction.
  • neurotransmitter system can lead to clinical manifestations on the dysfunction, atrophy and wasting of muscles as is observed in ALS.
  • SSADHD motor delay including the hampering of fine motor skills, a clinical manifestation that this disease shares with ALS disease, and that considering the above can be attributed to an the overactive GABA inhibition system in SSADHD as reflected by the in SSADHD patients elevated GABA concentrations. It further can be concluded that the in SSADHD observed seizures occur in the presence of two to four fold elevated GABA levels implicating that the elevated GHB levels are high enough to provoke seizures. Based upon the above it further can be concluded that GABAergic overstimulation is implicated in SSADHD muscle wasting symptoms and that the SSADHD clinical profile provides further evidence for the role of GABAergic overstimulation in muscle wasting clinical profiles as observed in SSADHD and ALS.
  • Example 6 GABAergic overstimulation can lead to respiratory depression as observed in ALS
  • GABAergic stimulation is capable of exerting strong and even fatal muscle relaxant activity as is demonstrated for the GABAergic pharmacological class of
  • benzodiazepine agonists that when overdosed lead to fatal respiratory depression.
  • Fatal respiratory depression for the majority of late stage ALS patients is the final cause of death and, like in GABA mediated benzodiazepine agonist overdosing, results from a fatal weakening of respiratory muscles.
  • GABAergic inhibitory neurotransmitter system overstimulation can lead to clinical manifestations on respiratory depression as observed in ALS, and on the respiratory related fatalities as observed in ALS.
  • Example 7 GABAergic overstimulation can lead to dysphagia as observed in ALS Difficulties with swallowing (dysphagia) is another important clinical feature of ALS that can be explained by GABAergic inhibitory system overstimulation. It was reported that dysphagia could be induced through the administration of GABAergic inhibitory system stimulating compounds muscimol and diazepam (Hockman et al. 1996).
  • GABA antagonists picrotoxin and bicuculline not only further confirming the role of GABAergic stimulation in dysphagia, but also demonstrating that GABAergic overstimulation related clinical manifestations of ALS can be reduced through the administration of compounds that reduce GABAergic overstimulation. It therefore can be concluded that GABAergic inhibitory system overstimulation can lead to clinical manifestations on dysphagia as also are observed in ALS.
  • Example 8 GABAergic overstimulation can cause dysphagia as observed in ALS in the absence of glutaminergic overstimulation
  • GABAergic (over)stimulation in the absence of glutaminergic excitatory (over) stimulation can lead to dysphagia as observed in ALS patients (see previous section) provides further evidence that GABAergic overstimulation alone causes dysphagia as observed in ALS, without requiring the glutaminergic excitatory neurotransmitter system to also be over stimulated. On the basis of this observation it therefore can be concluded that relative to glutaminergic overstimulation, GABAergic overstimulation is leading in the pathogenesis of ALS.
  • Example 9 GABAergic overstimulation can lead to dysarthria as observed in ALS Yet another clinical feature that can be attributed to GABAergic stimulation is the in ALS patients observed slurred speech (dysarthria), a clinical feature it shares with those observed after the ingestion of alcohol / ethanol in humans.
  • ALS patients observed reduced capability of completing voluntary saccadic eye movements, i.e. the quick, simultaneous movements of both eyes in the same direction.
  • GABAergic stimulation leading to a reduced capability of saccadic eye movements as observed after the administration of GABAergic pharmacological class of benzodiazepine agonists it can be concluded that GABAergic overstimulation can lead to reduced eye movement as observed in ALS.
  • reduced eye movement capabilities are also observed in SSADHD, a disease where GABA levels are increased two to four fold, further evidencing that GABAergic overstimulation can lead to eye moving difficulties as observed in ALS.
  • GABAergic inhibitory neurotransmitter system overstimulation can lead to clinical manifestations on saccadic eye movements as observed in ALS.
  • Example 11 GABAergic overstimulation can lead to oculomotor and supranuclear gaze palsy as observed in ALS
  • GABAergic stimulation can be concluded to be involved in bladder dysfunction as GABAergic overstimulation through the administration of GABA receptor agonists muscimol and baclofen has been shown to lead to a dose-dependent inhibition of micturition with progressive increases in bladder capacity and residual volume, and a decrease in micturition pressure ending with urinary retention and dribbling incontinence. It therefore can be concluded that GABAergic stimulation can lead to bladder dysfunction as observed in ALS.
  • Example 13 GABAergic overstimulation can lead to gastrointestinal dysfunction as observed in ALS patients
  • Example 14 GABAergic overstimulation can lead to soccer concussion related ALS ALS has been shown to be predominant in soccer players (Chio et al. 2005) where it is postulated that soccer related concussions can lead to (micro)traumas that can lead to the development of ALS.
  • overstimulation is not specifically related to (micro)traumas or to increased GAD67 levels.
  • Example 15 GABAergic overstimulation can explain SOD predisposition in ALS
  • Genetic mutations in the genome coding for the first superoxide dismutases enzyme (SOD1) are known to lead to ALS predisposition.
  • SOD1 malfunctioning induced structural oxidative stress in ALS patients therefore can lead to structural inflammation processes that of a comparable nature to those observed due to soccer concussions related (micro)traumas and GABAergic overstimulation, and that can lead to the clinical manifestation of ALS as observed in soccer related ALS patients.
  • structural inflammation pathway will make ALS a disease of many causes, which is consistent with the absence of epidemiologic relations in the ALS patient population. It therefore is concluded that the genetic SOD predisposition of ALS is caused by oxidative stress induced structural inflammation leading to GABAergic overstimulation eventually causing clinical manifestations as observed in ALS.
  • Glycine is the inhibitory neurotransmitter involved in neurologic systems that are controlled by both GABAergic inhibitory mediated neurotransmission and Glycinergic neurotransmitter mediated neurotransmission, a physiological process also known as the recurrent inhibition of motoneurons.
  • recurrent inhibition is concluded to be present in motoneurons that are involved in locomotion and posture of the body. This based upon the observation that recurrent inhibition is particularly strong in and between motoneuron pools active during the stance phase of locomotion and during upright stance (posture), is fairly strong among neck motoneurons that control the movement of a fairly large mass (i.e. the head), and is relatively weak in motoneurons controlling trunk muscles such as the thoracic intercostal and phrenic motoneurons which is related to the rudimentary postural functions of these motoneurons.
  • quadriceps stabilization movement or carries the body during standing, strong limb motoneurons lifting of relatively large movement and lifting of heavy
  • anterior tibal stabilization movement or carries the body during standing, strong limb motoneurons lifting of relatively large movement and lifting of heavy
  • peroneus brevis stabilization movement or carries the body during standing, strong limb motoneurons lifting of relatively large movement and lifting of heavy
  • ECR muscle stabilization movement or carries the body's pulse during strong limb motoneurons lifting of relatively large standing, movement and are
  • neck muscle stabilization movement or carries the body's head during strong limb motoneurons lifting of relatively large standing and movement
  • Phrenic motoneurons Respiratory control Passes motor information to the weak Respidiaphragm ratory oppononens pollicis stabilization, movement or moves the body's thumb to the absent bulbar muscle motoneurons lifting of relatively small fingers of the same hand
  • Mastication muscle food mastication & Mastication or chewing is important absent bulbar motoneurons swallowing for the mastication and swallowing
  • Ear muscle tensor food mastication & Mastication or chewing is important absent bulbar tympani
  • motoneurons swallowing for the mastication and swallowing
  • Swallowing prevention swallowing & yawning prevents entry of food into the absent bulbar muscle (tensor veli nasopharynx during swallowing and
  • the mylohyoid elevates the hyoid absent bulbar muscle (mylohyoid and the tongue which particularly is
  • Eye movement muscle movement of relatively small Moves the body's eyes absent bulbar (occulomotor muscles) masses
  • Example 17 GABAergic and Glycinergic overstimulation explain ALS onset of disease differentiation
  • Glycinergic mediated recurrent inhibition overstimulation also is implicated in ALS it can be expected that, depending on the system being most overstimulated during early stages, ALS will present itself as a disease where the GABAergic onset effects occur in a different time space from the Glycinergic mediated recurrent inhibition overstimulation effects, and ALS patients presenting with
  • GABAergic overstimulation symptoms such as dysarthria and dysphagia (also known as bulbar onset ALS), or with Glycinergic mediated recurrent inhibition overstimulation symptoms such as muscle weakness in arms and legs (also known as limb onset ALS).
  • Example 18 Glycinergic overstimulation explains the ALS split-hand syndrome The ALS split-hand syndrome is unique to the ALS indication. ALS hand muscle wasting preferentially affects the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) muscles, with relative sparing of the abductor digiti minimi (ADM).
  • APB abductor pollicis brevis
  • FDI first dorsal interosseous muscles
  • This peculiar pattern of dissociated atrophy of the intrinsic hand muscles is termed the split hand and is rarely seen in diseases other than ALS with rare exceptions in nonALS related autosomal dominant distal spinal muscular atrophy, spinocerebellar ataxia type 3 (Machado- Joseph disease) and juvenile muscular atrophy, as well as spinal and bulbar muscular atrophy (SBMA) and remote poliomyelitis (Eisen et al. 2012).
  • the physiological mechanisms underlying the split hand in ALS are incompletely understood.
  • ALS split hand syndrome can be explained on the basis of differences in the extent of Glycine mediated recurrent inhibition for hand muscles involved in a precision grip relative to muscles that (also) are involved in a power grip.
  • Napier (1956) differentiated hand grips into [1] precision grips where fingers and thumb press against each other as for example in pen writing without lifting relatively heavy masses and [2] power grips where fingers, palm and thumb clamp down on an object with the thumb making counter pressure for lifting relatively heavy masses as for example in gripping a hammer, carrying a frying pan or during pull-ups.
  • motoneurons are not subject to Glycine mediated recurrent inhibition. This is consistent with the demonstrated absence of Glycine mediated recurrent inhibition in the abductor digiti minimi motoneurons as summarized in table 9.
  • APB and FDI muscles involved in the opposition and extension of the thumb (APB) these can be concluded to be also involved in the hand's power grip and countering gravity and / or maintaining inertia of the body. Consequently the ABP and FDI muscles will be subject to Glycine mediated recurrent inhibition, explaining their difference in disease onset relative to the ADM muscle that is not subject to Glycine mediated recurrent inhibition, and as such clarifying the until now unresolved clinical manifestation of the ALS split hand syndrome.
  • the current disclosure not only for the first time explains the ALS disease specific split hand syndrome but also further confirms the role of Glycinergic mediated recurrent inhibition overstimulation in ALS.
  • Example 19 ALS onset manifestation is differentiated by GABAergic and
  • ALS onset manifestation can be attributed to the overstimulation pathway that is most pronounced during initial ALS disease. This is summarized in tables 11 to 13 where ALS disease onset symptoms are classified upon their relation to GABAergic and / or Glycinergic overstimulation:
  • Table 11 ALS BULBAR onset symptoms classification based upon GABA and/ or Glycine overstimulation.
  • Table 12 ALS LIMB onset symptoms classification based upon GABA and/or Glycine overstimulation.
  • GABAergic overstimulation onset of disease leads to symptoms that currently are classified as bulbar onset of ALS, that combined GABAergic and Glycinergic overstimulation onset of disease leads to symptoms that currently are classified as limb onset ALS, and that onset of disease where GABAergic and Glycinergic overstimulation are both present with
  • GABAergic overstimulation being most pronounced leads to onset symptoms that currently are classified as respiratory onset ALS.
  • Table IS ALS LIMB progressive symptoms classification based upon GABA and/or Glycine overstimulation.
  • Table 16 ALS RESPIRATORY progressive symptoms classification based upon
  • Figure 1 summarizes tables 11-16 graphically, demonstrating the pivotal role of GABAergic and Glycinergic overstimulation in the pathogenesis of ALS.
  • Figure 2 shows that limb-, bulbar- and respiratory onset ALS, and progressive ALS are the result of a continuum of separately increasing gradients of GABAergic and
  • Figure 3 depicts how varying degrees of GABAergic and Glycinergic overstimulation lead to the clinical symptoms of ALS-like diseases.
  • the progressive muscular atrophy (PMA) disease pathway can be understood by the initial Glycinergic overstimulation related limb onset symptoms that during progressive disease also leads to GABAergic overstimulation related dysphagia, and where 50% of patients develop typical ALS clinical manifestations (Silani et al. 2011).
  • Flail arm and flail leg MND variants are initially localized forms with
  • PLS Primary lateral sclerosis
  • PBP Progressive bulbar palsy
  • PB Pseudobulbar palsy
  • FTD is a syndrome of progressive changes in behavior and language due to loss of function of neurons in the frontal and temporal lobes.
  • FTD usually has relatively little effect on the parts of the nervous system that control movement, and so many FTD patients remain physically strong and relatively agile until late in the illness.
  • the disease also involves motoneurons.
  • FTD with motoneuron disease FTD with ALS (FTD -ALS).
  • ALS-FTD On the other side, from the ALS indication perspective, approximately 30% of ALS patients develops signs of frontal lobe decline, which affects organizational function and behavior as observed in FTD. Patients with ALS-FTD may present with features of either FTD or ALS where additional symptoms develop with progressive disease where all ALS-FTD patients experience the gradual and progressive decline in functioning.
  • this disclosure demonstrates that the ALS clinical manifestations dysarthria, dysphagia, sialorrhoea, the weakening of the soft palate, muscle wasting and spasticity of the tongue, difficulties with lip seal and blowing cheeks, bladder dysfunction, the oculomotor related aspects of late stage oculomotor and supranuclear gaze palsy are not attributable to Glycine overstimulation as these clinical manifestations are not related to countering gravity or inertia, and therefore can be attributable solely to GABAergic overstimulation. Furthermore, with [1] GABAergic neurotransmission being relevant in
  • manifestation of disease not only includes ALS symptoms but also includes personality changes that may be regarded as a first sign of the progression of disease into the development of ALS-FTD.
  • GABAergic overstimulation therefore is concluded to not only manifest itself in ALS symptoms, but also in the frontotemporal aspects of ALS, thus implicating GABAergic overstimulation in ALS-FTD where an increasingly over stimulated GABAergic system impacts both motoneurons and frontotemporal neuron cells leading to a reactive overstimulation of the glutaminergic systems and to glutaminergic overstimulation neuronal cell death of these neurons as observed for motoneuron cells in ALS.
  • Frontotemporal dementia or frontotemporal degeneration is a disease indication that separates itself from ALS-FTD in that regard that FTD can be seen as a disease where FTD clinical symptoms occur in the absence of motoneuron related symptoms associated with ALS though it here will be concluded that considerable overlap exists between the clinical manifestations of ALS and FTD.
  • FTD is defined as a group of disorders caused by progressive neuron cell degeneration in the frontal or temporal lobes of the brain that leads to reduced function in the frontal and temporal lobes which control planning, judgment, emotions, speech, understanding speech and certain types of movement.
  • FTD accounts for ten to fifteen percent of all dementia cases and as such is less common than Alzheimer's disease, vascular dementia and Lewy body dementia. FTD is grouped into three main categories that initially have different clinical manifestations based upon the affected frontotemporal lobes that with progressive disease symptoms becoming increasingly overlapping:
  • behavioral variant FTD impacts personality and behavior and initially manifests itself with subtle changes but with progressive disease leads to disinhibition and a loss of restraint in personal relations and social life.
  • PPA primary progressive aphasia
  • PPA may manifest itself as semantic dementia in combination with declining language comprehension or as progressive non-fluent aphasia where patients lose the ability to generate words, speech becomes halting, tongue tied and ungrammatical, and the ability to read and write becomes impaired.
  • PPA patients have trouble finding the right words, mostly due to difficulty in coordinating the muscles they need to speak
  • FTD movement disorders subtype affects involuntary and automatic muscle function, but also impairs language and behavior.
  • FTD movement disorder may manifest itself as corticobasal degeneration causing shakiness, lack of coordination, and muscle rigidity and spasms, or as progressive supranuclear palsy (PSP), causing walking and balance problems, falls, muscle stiffness especially in the neck and upper body.
  • PSP progressive supranuclear palsy
  • FTD movement disorders as such can be regarded as a manifestation of FTD that is in between FTD and ALS-FTD.
  • GABAergic overstimulation being implicated in ALS-FTD
  • GABAergic neurotransmission being relevant in frontotemporal nerve signalling
  • FTD frontotemporal nerve cells located in close proximity to the by ALS and ALS-FTD impacted motoneuron cells
  • [5] the clinical manifestation of FTD movement disorders that are in between the clinical manifestation of the FTD and ALS-FTD disorders it can be concluded that GABAergic overstimulation is implicated in the clinical manifestations of ALS, ALS-FTD, FTD-ALS and FTD.
  • GABAergic overstimulation not only occurs in motoneuron cells in the co-presence of GABAergic overstimulation in other neuron cells as observed in ALS patients, but that GABAergic overstimulation of frontotemporal brain regions can also occur in the absence of GABAergic motoneuron overstimulation. This leads to the conclusion that GABAergic overstimulation besides leading to motoneuron cell death can also lead to cell death of non-motoneuron nerve cells.
  • an increasingly overstimulated GABAergic system affects frontotemporal neuron cells leading to clinical manifestation of disease that is related to the affected frontotemporal part of the brain, and to clinical manifestations that are directly related to GABAergic overstimulation symptoms such as speech problems, movement disorders leading to shakiness, lack of coordination, muscle rigidity and spasms, walking and balance problems, falls, muscle stiffness but also affecting GABA mediated eye movements.
  • GABAergic overstimulation not only can impact motoneuron functioning but that GABAergic overstimulation can also impact general neuron function, even in the absence of by GABAergic
  • GABAergic overstimulation can manifest itself as a progressive disease where diffusively overlapping neurological neurologic symptoms present themselves in combination with symptoms that can be related to GABAergic overstimulation as observed in ALS.
  • Example 22 GABAergic overstimulation in dementia
  • Dementia is a broad category of brain diseases that cause long term loss of the ability to think and reason clearly in a way that is severe enough to affect a person's daily functioning. Except for a few treatable types in most cases no cure exists for dementia. Cholinesterase inhibitors are used early in the disease course but only provide slight benefit and treatment therefore focusses on cognitive and behavioral interventions, and the education and providing of emotional support to the caregiver.
  • Dementia affects a patient's ability to think, reason and remember clearly. The most common affected areas include memory, visual-spatial, language, attention, and problem solving. Most types of dementia occur in a slow and progressive nature where the process affecting the brain precedes the manifestation of disease for a long time.
  • Circa ten percent of dementia patients display mixed dementia, usually a combination of ALZ and another type of dementia such as frontotemporal dementia or vascular dementia.
  • Additional psychological and behavioral problems that affect dementia patients include: disinhibition, impulsivity, depression, anxiety, agitation, delusions, hallucinations, memory distortions, wandering or restlessness, emotional reactions when put in circumstances beyond abilities, incontinence, balance problems and falls, tremor, speech and language difficulty and trouble eating or swallowing.
  • AD Alzheimer's disease
  • vascular dementia vascular dementia
  • frontotemporal dementia progressive supranuclear palsy
  • corticobasal vascular dementia
  • Alzheimer's • ALZ brain atrophy is the most common form of dementia disease representing 75% of cases.
  • hippocampus Other parts of the brain that will show atrophy include the temporal and parietal lobes but brain atrophy in ALZ can be variable and diffuse.
  • vascular dementia The symptoms of vascular dementia depend on where in the brain the strokes have occurred and whether the affected vessels are large or small.
  • Dementia Dementia with Lewy bodies is a dementia that has the primary with Lewy symptoms of visual hallucinations and Parkinsonism.
  • Parkinsonism includes tremor, rigid muscles, and a face without emotion.
  • PPA Primary progressive aphasia
  • PPA may manifest itself as semantic dementia in combination with declining language comprehension or as progressive non- fluent aphasia where patients lose the ability to generate words, speech becomes halting, tongue tied and ungrammatical, and the ability to read and write becomes impaired.
  • FTD • FTD movement disorders affect involuntary and automatic muscle movement function where this disorder also impairs language and behavior. disorders • FTD movement disorder may manifest itself as corticobasal
  • Progressive • Progressive supranuclear palsy is a form of dementia that is supranuclear characterized by problems with eye movements.
  • PSP palsy
  • PSP PSP
  • Other key symptoms of PSP include falls backwards, balance problems, slow movements, rigid muscles, irritability, apathy, social withdrawal and depression.
  • Patients may display frontal lobe signs such as perseveration, a grasp reflex and utilization behavior.
  • Parkinson'sarthria Because of the combination of rigidity and slow movements with diffuse other neurological disease manifestations PSP can be misdiagnosed as Parkinson's disease.
  • Brains scans of PSP patients generally demonstrate midbrain atrophy where other brain regions appear to be unaffected.
  • Corticobasal degeneration is a rare form of dementia that is degeneration characterized by many different types of neurological problems that progress over time.
  • Other common limb symptoms include jerky movements of one or more limbs (myoclonus), symptoms that are different in different limbs (asymmetric).
  • Affected limbs may be rigid or have muscle contractions causing dystonia.
  • degeneration is the posterior frontal lobe and parietal lobe where many other parts of the brain also can be affected.
  • GABAergic overstimulation symptoms i.e. the occurrence of diffuse and overlapping neurologic symptoms of a progressive nature in the presence of symptoms that can be directly related to symptoms as observed in GABAergic overstimulated ALS patients such as difficulties with speech, swallowing, bowel control (incontinence), eye
  • GABAergic stimulation also is implicated in other forms of dementia.
  • GABA as the major neurotransmitter in the brain regions affected by dementia, and the diffuse clinical manifestations of dementia being linked to differences in brain regions affected, it can be concluded that GABAergic overstimulation not only occurs in motoneurons as affected in ALS, or in brain regions as affected in FTD, but that GABAergic overstimulation can also occur in other separate parts of the brain leading to progressively overlapping and diffuse neurological manifestations of which the clinical manifestation depends on the brain regions affected by GABAergic
  • GABAergic overstimulation of the hippocampus and temporal and parietal lobes brain regions in combination with a diffuse pattern of brain atrophies in other brain regions leads to the clinical manifestation of ALZ (Alzheimer's disease)
  • ALZ Alzheimer's disease
  • PSP PSP
  • GABAergic overstimulation of the cerebral cortex and the basal ganglia brain regions leads to the clinical manifestation of corticobasal degeneration.
  • alcohol related dementia as alcohol exerts its action through GABA receptor modulationand the increase of dementia symptom severity after administration of the GABA receptor modulating benzodiazepine agonist diazepam.
  • glutamate The role of glutamate is well-known in the epilepsy indication and has been quantified where increased glutamate levels were reported for newly diagnosed epilepsy patients of 0.260 ⁇ 0.067 ⁇ /L (mean ⁇ SD) relative to 0.204 ⁇ 0.049 ⁇ /L for control subjects (Kalviainen, 1993), indicating a statistically significant and clinically relevant 30% glutamate level elevation.
  • GABAergic overstimulation is at the basis of the progressively overlapping diffuse clinical manifestation of different forms of dementia.
  • MS is another neurologic disease displaying the typical occurrence of diffuse and overlapping neurologic symptoms of a progressive nature in the presence of symptoms that can be directly related to symptoms as observed in GABAergic overstimulated ALS patients such as difficulties with speech, swallowing, bowel control, eye movements and other muscle functioning.
  • disphagia eye movement dysfunction
  • nystagmus optic neuritis
  • diplopia eye nerve system problems
  • phosphenes eye nerve system problems
  • fatigue and acute or chronic pain syndromes bladder and bowel difficulties
  • cognitive impairment aphasia
  • emotional symptomatology such as major depression.
  • MS classifies as being a disease where diffuse neuronal clinical manifestations such as cognitive impairment, unstable mood, fatigue and depression present themselves in the presence of GABAergic overstimulation clinical manifestations as observed in GABAergic overstimulated ALS patients such as eye muscle movement problems, problems with speech (dysarthria), difficulties with swallowing (dysphagia), musculoskeletal weakness, spasms and ataxia,
  • HD Huntington's disease
  • chromosome 4 leading to the clinical manifestation of a neurodegenerative disorder that affects muscle coordination and leads to cognitive decline and behavioral symptoms.
  • HD is yet another neurologic disease where diffuse and progressive neurological behavior and dementia symptoms are accompanied by the presence of clinical manifestations that also are observed in GABAergic overstimulated ALS patients such as movement disorders, muscle dysfunction, difficulties with swallowing (dysphagia) and difficulties with speech (dysarthria).
  • GABAergic stimulation due to the observation that HD patients display decreased levels of GABA, a finding that based upon the current disclosure can be concluded to be inconsistent with the clinical manifestation of HD displaying symptoms that are also observed in GABAergic overstimulated ALS patients.
  • This clinical observation can be explained through the observation that GABAergic stimulation can occur at many physiological levels and that lower GABA concentrations in certain brain regions can implicate GABAergic overstimulation in other upstream GABAergic neurons and / or brain regions. It here therefore is concluded that like in ALS treatment, GABAergic stimulation will not be efficacious in HD, where reducing GABAergic stimulation will be efficacious. Based upon the above, it is concluded that GABAergic overstimulation is implicated in HD.
  • PD is a degenerative disorder of the central nervous system.
  • the motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain. The cause of this cell death nor that of PD in general currently are unknown.
  • Parkinson's disease is more common in older people, with most cases occurring after the age of 50.
  • the pathology of the disease is characterized by the accumulation of alpha- synuclein into Lewy bodies in neurons and the reduced formation and activity of dopamine in certain neurons located in the midbrain.
  • Lewy bodies are the pathological hallmark of idiopathic PD, and distribution of the Lewy bodies throughout the Parkinsonian is different for each individual. Consequently, the anatomical distribution of the Lewy bodies is often directly related to the expression and degree of the clinical symptoms of each individual.
  • PD symptoms can be classified into motor symptoms affecting movement and posture, neuropsychiatric symptoms affecting mood, cognition, behavior and thought, sensory and sleep symptoms, where non-motor symptoms often precede motor symptoms. A full overview of PD clinical manifestation is given below.
  • PD motor symptoms are tremor, rigidity, slowness of movement, and postural instability where tremor is the most apparent and well-known symptom. Though around 30% of individuals with PD do not have tremor at disease onset, most develop this during progressive disease. A feature of tremor is pill-rolling, the tendency of the index finger of the hand to get into contact with the thumb and perform together a circular movement. The term derives from the similarity between the movement in people with PD and the earlier pharmaceutical technique of manually making pills (Cooper et al. 2008).
  • Bradykinesia is another characteristic feature of PD, and is associated with difficulties along the whole course of the movement process, from planning to initiation and finally execution of a movement.
  • Initial manifestations are problems when performing daily tasks which require fine motor control such as writing and sewing.
  • Rigidity is stiffness and resistance to limb movement caused by increased muscle tone, an excessive and continuous contraction of muscles .
  • rigidity In early stages of Parkinson's disease, rigidity is often asymmetrical and it tends to affect the neck and shoulder muscles prior to the muscles of the face and extremities. With progressive disease rigidity typically affects the whole body and reduces the ability to move.
  • Postural instability is typical in the late stages of the disease, leading to impaired balance and frequent falls leading to bone fractures. Instability is often absent in the initial stages but increases with progressive disease.
  • PD causes neuropsychiatric disturbances which can range from mild to severe.
  • Cognitive disturbances can occur in the initial stages of the disease and increase in prevalence with progressive disease.
  • the most common cognitive deficit in affected individuals is executive dysfunction, which can include problems with planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions, and selecting relevant sensory information.
  • Cognitive difficulties include attention and slowed cognitive speed.
  • PD In addition to cognitive and motor symptoms PD can impair other body functions. Constipation and gastric dysmotility can be severe enough to cause discomfort and even endanger health. PD is related to several eye movement difficulties and vision abnormalities such as decreased blink rate, dry eyes, deficient ocular pursuit (eye tracking) and saccadic movements (fast automatic movements of both eyes in the same direction), difficulties in directing gaze upward, and blurred or double vision. Other recognized symptoms include problems with speech and swallowing.
  • PD classifies itself as a disease where diffuse neuronal clinical manifestations such as cognitive impairment, dementia and depression present themselves in the presence of GABAergic overstimulated ALS patients such as eye muscle movement problems, problems with speech (dysarthria), difficulties with swallowing
  • PD pathology is characterized by the accumulation of alpha- synuclein into Lewy bodies in neurons that are the pathological hallmark of idiopathic PD, where distribution of the Lewy bodies is different for each patient. Consequently, the anatomical distribution of the Lewy bodies is often directly related to the expression and degree of the clinical symptoms of each individual.
  • This for the PD indication specific a-Synuclein accumulation further implicates GABAergic overstimulation in PD as a-Synuclein accumulation has been demonstrated to reduce GABAergic inhibitory transmission in a model of multiple system atrophy and as such can be seen as a reaction to GABAergic
  • GABAergic and / or Glycinergic overstimulation can also lead to dopaminergic overstimulation induced dopaminergic neuronal cell death.
  • GABAergic and / or Glycinergic overstimulation is implied in the loss of dopamine producing cells in PD.
  • Example 26 GABAergic overstimulation causes PD rest tremors
  • the PD specific pill-rolling tremor clinical manifestation originates from the movement of muscles that are solely involved in the hand precision grip and not in the hand power grip and as such are not controlled by Glycine mediated recurrent inhibition (see also section 3).
  • the PD pill-rolling tremor therefore provides insight into the pathogenesis of PD as it demonstrates the differentiated impact on muscles that are, or are not under control of Glycine mediated recurrent inhibition.
  • PD predominantly is GABAergic overstimulation disease related and not a Glycinergic overstimulation disease related as muscle
  • GABAergic overstimulation that is implicated in PD.
  • the third neurotransmitter that could be involved in the PD resting tremor is the glutaminergic excitatory that, like the Glycinergic system, based upon this observation can also be concluded to be of less relevance than GABAergic overstimulation, which is further confirmed by the observation that glutaminergic overstimulation would lead to clinical manifestations in both GABAergic mediated resting muscle function and GABAergic and Glycinergic mediated active muscle function.
  • Example 27 GABAergic overstimulation is implied in restless legs syndrome (RLS) Similar to the PD clinical manifestation of rest tremors restless legs syndrome (RLS) too can be concluded to be caused by the differentiated impact of PD on muscles that are, or are not under the influence of Glycine mediated recurrent inhibition.
  • RLS restless legs syndrome
  • RLS is a GABAergic related as it demonstrates that muscles under control of Glycine mediated recurrent inhibition behave different from muscles that are not under such influence. It here therefore is concluded that GABAergic overstimulation is implicated in restless legs syndrome.
  • GABAergic treatments an observation that also further implicates GABAergic overstimulation in rest tremors and PD.
  • Example 28 GABAergic overstimulation in Duchenne muscular dystrophy (DMD)
  • DMD Duchenne muscular dystrophy
  • DMD is disease where GABAergic overstimulation clinical manifestations as dysphagia, dysarthria and eye movement difficulties present themselves in the presence of muscle wasting and atrophy.
  • DMD patients with lowered IQ scores that is related to another GABAergic overstimulation implicated clinical manifestation, i.e. cognitive dysfunction.
  • DMD is caused by the absence or disruption of the protein dystrophin which is found in skeletal muscle and neurons in particular regions of the CNS leading to neuron loss.
  • GABA has been implicated in DMD (Keuh et al. 2011) providing further evidence for the role of GABAergic overstimulation in DMD.
  • the DMD clinical manifestation is caused by GABAergic overstimulation that is a consequence of the absence of the protein dystrophin in DMD patients.
  • the DMD pathogenesis is expanded to a genetically inherited disease where dystrophin absence leads to GABAergic overstimulation that determines the clinical manifestation of DMD.
  • DMD can be treated by reducing GABAergic
  • DMD is neuromuscular disease rather than a muscular dystrophy disease, and / or that the neuromuscular aspects of DMD are more important for understanding the clinical manifestation of DMD than the muscular dystrophy aspects of DMD.
  • PN is a term for a group of conditions in which the peripheral sensory, motor and / or autonomic nervous system is damaged. Diabetes (both type 1 and type 2) is the most common cause of PN, where a wide range of other causes are also leading to PN such as physical injury to the nerves, viral infections, or side effect of certain medications (see table 20) including the long term use of epilepsy treatment with phenytoin.
  • PN classifies itself as a disease where diffuse neuronal clinical manifestations such as sensitory impairment, present themselves in the presence of clinical
  • GABAergic overstimulated ALS patients such as eye muscle movement problems, difficulties with swallowing (dysphagia), motoneuron and musculoskeletal weakness, muscle spasms and twitching, incontinence and difficulties with regulation of intestinal motility Bayer et al. 2002).
  • GABAergic overstimulation in PN is further confirmed by the observation that PN can be caused by excessive alcohol intake for years, a process that is related to GABAergic overstimulation due to the GABAergic action of alcohol at the GABA receptor. This is even further confirmed by the observation that the long term use of GABAergic anti-epilepsy medication such as phenytoin causes PN implicating GABAergic overstimulation even further in PN.
  • Schizophrenia's diffuse neurological manifestations comprise positive and negative symptoms. Positive symptoms are delusions, disordered thoughts and speech, and tactile, auditory, visual, olfactory and gustatory hallucinations, typically regarded as manifestations of psychosis.
  • Negative symptoms are deficits of normal emotional responses or of other thought processes. These include flat expressions or little emotion, poverty of speech, inability to experience pleasure, lack of desire to form relationships, and lack of motivation.
  • GABAergic overstimulation symptoms include dysphagia and eye movement difficulties that even can be used for quantifying schizophrenia disease
  • GABAergic stimulation through alcohol abuse can cause the development of a chronic substance-induced psychotic disorder, and exposure to GABAergic related cannabis to the developing brain lead increases the risk of schizophrenia in a dose dependent matter, providing further evidence for the implication of GABAergic overstimulation in schizophrenia.
  • Glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with schizophrenia further implying GABAergic overstimulation in schizophrenia as blocking the function of the glutaminergic excitatory neurotransmitter system can lead to similar clinical manifestations as stimulation of GABAergic activity. Further evidence is provided by the observation that benzodiazepine withdrawal can lead to a long lasting withdrawal syndrome resembling schizophrenia that even can lead to the misdiagnosis of schizophrenia.
  • Example 31 GABAergic overstimulation is implicated in diabetes
  • GABAergic overstimulation is implicated in diabetes related PN (see previous section) is of even further relevance as GABAergic stimulation is also known to stimulate insulin release from the pancreatic 6-cells.
  • GABAergic overstimulation impacts diabetes not only in the clinical manifestation of NP, but also in the clinical manifestation of diabetes itself.
  • GABAergic stimulation leading to the release of insulin from pancreatic ⁇ -cells structural GABAergic overstimulation will lead to depletion of these cells and to an altered homeostasis of the insulin glucose system.
  • GABAergic overstimulation therefore can be concluded to be a factor implicated in diabetes that is higher in the disease hierarchy than glucose or insulin.
  • FSHD Facioscapulohumeral muscular dystrophy
  • FSHD was first described in 1885 by Landouzy and Dejerine, the reason for which FSHD also is known as Landouzy- Dejerine Muscular Dystrophy.
  • Other names for the disease are Facioscapulohumeral Disease, Facio-Scapulo-Humeral Muscular Dystrophy, Fascioscapuohumeral Muscular Dystrophy, and Scapuohumeral
  • Muscular Dystrophy for FSHD patients where no demonstrable facial weakness is observed.
  • Other diseases related to FSHD are Coats' Disease also known as retinal telangiectasis, Bilateral Sensorineural Hearing Loss and Hypercarbic Respiratory Insufficiency.
  • Facioscapulohumeral muscular dystrophy or FSHD is the most prevalent of the nine primary types of muscular dystrophy affecting adults and children.
  • the major symptom of FSHD is the progressive variable weakening and loss of skeletal muscles.
  • FSHD is disease where GABAergic overstimulation clinical manifestations as dysphagia, dysarthria and eye movement difficulties present themselves in the presence of muscle dystrophy and as such is another disease where GABAergic overstimulation symptoms present themselves in the presence of muscle
  • GABAergic overstimulation is implicated in those patients where no genetic mutations are present, but also can be part of the pathogenesis between the genetic mutation and the clinical manifestation of FSHD in those patients where genetic mutations are present. Based upon the above it therefore can be concluded that GABAergic overstimulation is implicated in FSHD.
  • Friedreich's ataxia is an autosomal recessive inherited disease that causes progressive damage to the nervous system. It manifests in initial symptoms of poor coordination such as gait disturbance. It can also lead to scoliosis, heart disease and diabetes, but does not affect cognitive function. The disease progresses until a wheelchair is required for mobility.
  • the genetic mutation causing Friedreich's ataxia leads to reduced expression of the mitochondrial protein frataxin. Over time this deficiency causes the clinical manifestations listed above, as well as frequent fatigue due to effects on cellular metabolism.
  • the ataxia of Friedreich's ataxia results from the degeneration of nerve tissue in the spinal cord, in particular sensory neurons essential (through connections with the cerebellum) for directing muscle movement of the arms and legs. Friedreich's ataxia presents itself before 25 years of age with progressive staggering or stumbling gait and frequent falling. Lower extremities are more severely involved. The symptoms are slow and progressive.
  • Friedreich's ataxia symptoms include the following clinical manifestations that in this disclosure have been shown to be GABA mediated: muscle weakness in the arms and legs, loss of coordination, vision impairment, slurred speech, and spine curvature (scoliosis) that is related to muscle dysfunction.
  • Cerebellar ataxia is a form of ataxia originating in the cerebellum and is characterized by symptoms that in this application are concluded to be GABA related such as the inability to coordinate balance, gait, extremity and eye movements. Furthermore, ataxia can be induced by GABAergic stimulation compounds such as alcohol and benzodiazepines, further implying GABAergic overstimulation in ataxia.
  • Sensory ataxia is a form of ataxia (loss of coordination) caused not by cerebellar dysfunction but by loss of sensory input into the control of movement.
  • Sensory ataxia is distinguished from cerebellar ataxia by the presence of near-normal coordination when the movement in question is visually observed by the patient, but marked worsening of coordination when the eyes are shut.
  • Patients with sensory ataxia usually complain of loss of balance in the dark, typically when closing their eyes in the shower or removing clothing over the head.
  • Vestibular ataxia is the clinical manifestation of ataxia due to dysfunction of the vestibular system. In slow-onset, chronic bilateral cases of vestibular dysfunction, these characteristic manifestations may be absent, and disequilibrium may be the sole presentation.
  • Ataxia can be caused by focal lesions of the central nervous system such as stroke, brain tumor, and MS, and can also be caused by Wilson's disease. Ataxic cerebral palsy is clinically observed in approximately 5-10% of all cases of cerebral palsy and causes problems in coordination, specifically in their arms, legs, and trunk. Athetoid cerebral palsy or dyskinetic cerebral palsy (together abbreviated as ADCP) is a type of cerebral palsy primarily associated with damage to the basal ganglia in the form of lesions that occur during brain development due to bilirubin encephalopathy and hypoxic-ischemic brain injury. ADCP is characterized by both hypertonia and hypotonia, due to the affected individual's inability to control muscle tone. Clinical diagnosis of ADCP typically occurs within 18 months of birth and is primarily based upon motor function and neuroimaging techniques.
  • Example 35 Analysis of failed ALS clinical trials
  • GABAergic stimulation currently is thought to be beneficial in ALS as it may reduce the clinical effects of the in ALS patients observed glutaminergic excitatory overstimulation.
  • glutaminergic excitatory overstimulation is the cause of ALS symptoms, and reduction of glutaminergic activity can be beneficial to ALS patients.
  • This vision has led to clinical investigations into the efficacy of GABAergic stimulation in ALS patients through the administration of the
  • GABAergic stimulating compound gabapentin that failed to demonstrate beneficial effect in ALS patients, even leading to the observation that a combined analysis of the two trials revealed more rapid ALS disease progression after gabapentin treatment (Miller et al. 2001). This observation can be explained by the further GABAergic stimulation with gabapentin in ALS patients whereas disclosed herein GABAergic function already is overstimulated in ALS.
  • Example 36 Physiological and molecular pathways in GABAergic and Glycinergic overstimulation
  • GABAergic and/or Glycinergic overstimulation may be caused by neurons or glial cells that due to stress challenges are no longer able to maintain cellular functions, including those functions that are important for maintaining high intracellular GABA and Glycine levels.
  • a general mechanism explaining GABAergic and Glycinergic overstimulation is related to the fact that the building up and maintenance of high intracellular
  • GABA and Glycine levels cost neuronal and glial cells high amounts of energy, for GABA synthesis even leading to the necessity to couple GABA synthesis directly to the major energy source for a cell, i.e. the tricarboxylic acid (TCA or Krebs) cycle, through the GABA shunt.
  • TCA tricarboxylic acid
  • intracellular Glycine concentrations also are highly elevated relative to extracellular concentrations up to 3 - 6 mM. Similar as for GABA, this indicates that intracellular Glycine concentrations also may no longer be maintained when neuronal cells are exposed to processes such as inflammation, infection, repetitive trauma or aging, or to processes of a genetic origin.
  • Glutamate intracellular levels of between 0.5 to 1 mM are below the intracellular concentrations of GABA and Glycine in in glial cells, indicating that intracellular glutamate levels may be maintained longer than those of GABA and Glycine in glial cells, as such also implicating glial cells rather than neuronal cells in
  • GABAergic and/or Glycinergic overstimulation This in the current example, where GABAergic and / or Glycinergic overstimulation is caused by stress challenges, indicates that glutamate excitatory action is a reaction to GABA and / or
  • GABAergic and Glycinergic overstimulation therefore can be caused through neuronal cells no longer being able to maintain high
  • GABA and / or Glycine intracellular concentrations of GABA and / or Glycine due to processes such as inflammation, infection, repetitive trauma, aging, energy consuming processes or other processes that impact normal cell function.
  • the resulting chronic release (leakage) of GABA and / or Glycine leads to clinical manifestation of GABAergic and /or Glycinergic overstimulation diseases as described in this disclosure.
  • GABA and / or Glycine due to the release of GABA and / or Glycine, homeostatic processes lead to an increase in glutaminergic activity leading to glutamate excitatory neuronal cell death leading to the further clinical manifestation of GABAergic and /or Glycinergic overstimulation diseases as described in this disclosure.
  • neuronal cell function therefore may be impacted by processes such as inflammation, infection, repetitive trauma, aging, energy consuming processes or other processes including those of a genetic origin that impact normal cell function through impacting at molecular levels involved in the energy processes required for maintaining the high intracellular GABA and / or Glycine concentrations.
  • GABAergic and / or Glycinergic overstimulation may be caused by molecular functions involved in the TCA (Krebs) cycle, mitochondrial function or ATPases such as ATPase6 and ATPase8.
  • mitochondrial diseases can lead to clinical manifestations of GABAergic overstimulation (see also the examples on mitochondrial diseases and on metabolic muscle disease herein) and the mitochondrial implication in the SODl predisposition in ALS making mitochondrial processes an interesting target for modulating GABAergic and / or Glycinergic overstimulation.
  • mitochondrial DNA mutations involved in GABA and Glycine receptor coupling processes in neuronal and glial cells such as through ATPases, and APTase modulation through for example beta-adrenergic agonists.
  • ATPase 6 and ATPase 8 being coded for by mitochondrial DNA, and mitochondrial disease leading to progressive clinical manifestations depending on [1] which cells over time develop dysfunctional mitochondrial DNA and mitochondria and [2] the energy requirement of the types of cells augmenting those cells with high energy requirements such as muscles and brain cells, not only further implicates ATPase, ATPase 6 and ATPase 8, mitochondria and mitochondrial DNA, but also GABAergic and Glycinergic overstimulation the disease disclosed herein.
  • GABAergic and / or Glycinergic overstimulation is implicated in autism, Huntington's disease (HD), Ataxia Telangiectasia, Friedreich's Ataxia, Multiple Sclerosis (MS) and Spino Cerebellar Ataxias (SCA).
  • Mitochondrial DNA (mtDNA) deletion syndromes predominantly comprise the following overlapping phenotypes: [1] Kearns-Sayre syndrome (KSS), [2] Pearson syndrome, and [3] progressive external ophthalmoplegia (PEO), where Rarely Leigh syndrome also can be a manifestation of a mtDNA deletion.
  • KSS Kearns-Sayre syndrome
  • PEO progressive external ophthalmoplegia
  • Kearns-Sayre syndrome is a multisystemic disorder defined by [1] onset before age 20 years, [2] pigmentary retinopathy and Progressive External ophthalmoplegia (PEO), where at least one of the following must also be present:
  • Other frequent but not invariable clinical manifestations of KSS include short stature, hearing loss, dementia, limb weakness, diabetes mellitus, hypoparathyroidism, and growth hormone deficiency.
  • Pearson syndrome is a usually fatal disorder of infancy characterized by sideroblastic anemia and exocrine pancreas dysfunction.
  • PEO Progressive external ophthalmoplegia
  • KSS ophthalmoplegia
  • the mitochondrial DNA Deletion Syndromes represent an indication where GABAergic related muscle dysfunction such as eye ptosis, paralysis of the extraocular muscles (ophthalmoplegia), and variably severe proximal limb weakness presents itself in the presence of other clinical manifestations that also can be related to GABAergic overstimulation such as eye movement difficulties. Even further, GABA has been implicated in pigmentary retinopathy with
  • GABAergic treatments such as vigabatrin and gabapentin causing the clinical manifestation of pigmentary retinopathy.
  • GABA is implicated in cardiac conduction blocking as it inhibits vagus nerve outflow mediated through the GABAB receptor.
  • GABA is even further implicated by the in these syndromes observed high cerebrospinal fluid protein concentrations of lactate that is involved in GABA metabolism and pyruvate that is chemically related to GABA also and may be formed from compounds involved in GABA metabolism such as succinate semialdehyde and L-alanine.
  • the in mitochondrial deletion observed cerebellar ataxia presents symptoms that in this disclosure have been shown to be related to GABAergic and / or Glycinergic overstimulation such as inability to coordinate balance, gait, extremity and eye movements. Furthermore, lesions to the cerebellum in this indication can cause dyssynergia, dysmetria, dysdiadochokinesia, dysarthria and ataxia of stance and gait, where symptoms related to dementia and diabetes mellitus in this application have been shown to be related to GABAergic overstimulation.
  • GABA is implicated in Sideroblastic Anemia and impacts exocrine pancreas function.
  • Leigh syndrome (or subacute necrotizing encephalomyelopathy) is characterized by onset of symptoms that in this disclosure are concluded to be GABA related such as the presence of elevated lactate levels in blood and/or CSF and is associated with psychomotor retardation or regression.
  • Neurologic features include hypotonia, spasticity, movement disorders (including chorea), cerebellar ataxia, and peripheral neuropathy.
  • Extraneurologic manifestations may include hypertrophic cardiomyopathy. About 50% of affected individuals die by age three years, most often as a result of respiratory or cardiac failure.
  • Neurogenic muscle weakness, ataxia, and retinitis pigmentosa is characterized by clinical manifestations that in this application have been concluded to be GABA related such as proximal neurogenic muscle weakness with sensory neuropathy, ataxia, and pigmentary retinopathy.
  • Leber hereditary optic neuropathy is characterized by onset of symptoms that in this application are concluded to be GABA related such as postural tremor, peripheral neuropathy, nonspecific myopathy, and movement disorders.
  • GABA related such as postural tremor, peripheral neuropathy, nonspecific myopathy, and movement disorders.
  • MS multiple sclerosis
  • GABAergic overstimulation related. Furthermore, GABAergic overstimulation in this disclosure has been shown to be implicated in the LHON clinical manifestation of bilateral, painless, subacute visual failure. Even further, like for the in this application demonstrated GABAergic disease ALS, the LOHN eye pathology involves superoxide dismutase predisposition implicating GABAergic
  • LSDs lysosomal storage disorders
  • Clinical manifestations of LSDs therefore vary according to the predominant cell type involved and LSDs present themselves with GABAergic overstimulation clinical manifestations such as movement disorders, ocular pathology and central nervous system dysfunction.
  • GABA is implicated as LSDs present themselves as diseases leading to changes in GABAergic neurons that display axonal spheroid formation that is specifically confined to GABAergic neurons. Based upon the above it therefore can be concluded that GABAergic overstimulation is implicated in lysosomal storage disorders.
  • Example 40 The pivotal role of GABAergic and Glycinergic overstimulation in the pathogenesis of neuromuscular and neurologic disease
  • GABAergic and Glycinergic overstimulation herein have been demonstrated to be important contributors to a number of important neuromuscular ad neurologic disease pathogenesis pathways.
  • inhibitory GABAergic and Glycinergic overstimulation clinical manifestations are observed comprising of diffuse and progressive neurologic manifestations in the presence of GABAergic overstimulation symptoms such as muscle wasting, loss of muscle function, loss of muscle coordination, respiratory depression, dysphagia, dysarthria, loss of muscle coordination, eye movement difficulties, oculomotor gaze palsy, supranuclear gaze palsy, bladder dysfunction and / or gastrointestinal dysfunction.
  • a novel neurologic disease pathogenesis can be constructed that explains the observations above through a novel understanding of the continuum of the inhibitory GABAergic / Glycinergic overstimulation in relation to glutaminergic overstimulation in the diseases reviewed in this disclosure.
  • Diseases where GABAergic and / or Glycinergic overstimulation occurs in parallel with glutaminergic overstimulation will not lead to the clinical manifestation of disease as the parallel increase in GABAergic and Glycinergic overstimulation will not disrupt the net balance between the systems leading to maintained
  • GABAergic overstimulation increases where glutaminergic overstimulation also increases but at a slower pace will lead to the clinical manifestation of GABAergic overstimulation symptoms where over time clinical manifestations may develop that are related to glutaminergic excitatory overstimulation induced neuronal cell death, the latter depending on the point in time where glutamate overstimulation reaches levels capable of inducing glutaminergic excitatory overstimulation induced neuronal cell death.
  • This pathogenesis also can apply to the observed clinical manifestations in diseases such as ALS, ALZ, MS, PD, HD, alcoholism or alcohol withdrawal and over-rapid benzodiazepine withdrawal.
  • GABAergic overstimulation occurs in the absence of, or very weak glutaminergic overstimulation will lead to the clinical manifestation of GABAergic overstimulation in the absence of glutaminergic excitatory overstimulation induced neuronal cell death which is the observed clinical manifestation in the other diseases herein (see the tables for full overview).
  • glutamate overstimulation induced neuronal cell death due to the absence of excessive glutamate overstimulation induced neuronal cell death it can be expected that in such diseases symptoms will be less severe than in diseases where glutamate overstimulation leads to neuronal cell death, which is consistent with the observation that in such diseases symptoms are less severe and life expectancy is higher as for example in ALS.
  • the absence of neuronal cell death in such diseases implicates that GABAergic and / or Glycinergic overstimulation symptoms may be reversible, where in diseases where neuronal cell death occurs this may not be the case.
  • Patients presenting with ALS or an ALS-like disorder will be treated by the administration of compounds reducing GABAergic overstimulation.
  • GABAergic overstimulation should be gradual as a too fast decrease in GABAergic overstimulation in the co-presence of elevated excitatory glutamate levels may lead to increased incidences at (epileptic) seizures and to other side effects related to reducing GABAergic activity.
  • Administration therefore should start with low individualized dosages that are gradually increased as long as no side effects occur or until side effects are present that can be regarded as acceptable in the light of the severity of the condition of the patient.
  • Individualization of dosage here can be related to correcting for body weight, body surface area, age, creatinine clearance, smoking habits and other factors know to impact individual pharmacokinetic and pharmacodynamic efficacy.
  • rescue medication that is of GABAergic nature for countering side effects that are related to the reduction of GABAergic activity such as epileptic seizures and / or other side effects.
  • An example of such rescue medication is diazepam that can be administered rectally outside hospitals and intravenously or intramuscular inside hospitals, or midazolam than can be administered buccal and nasal outside hospitals and intravenously and
  • Individualized dosing may be (partly) based upon EEG activity and other clinical endpoints indicative for an increased risk at epileptic seizures and other side effects related to the reduction of GABAergic activity, and upon current practices in oncology where narrow therapeutic index treatments also are being applied successfully through active clinical and safety endpoint monitoring and dose titration schedules optimizing the balance between safety and efficacy.
  • dosage can be further increased as the risk as glutaminergic side effects (including seizures) has decreased and individualized dosing is to be re-established and re-evaluated on a regular basis.
  • Treatment further may be by co- administering medication aiming at the reduction of glutaminergic overstimulation leading to a gradual decline of glutaminergic overstimulation, as such leading to an even further reduced risk as side effects such as (epileptic) seizures.
  • Example 42 Treatment by reducing Glycinergic overstimulation
  • Patients presenting with ALS or an ALS-like disorder will be treated through the administration of compounds reducing Glycinergic overstimulation.
  • Glycinergic activity therefore should start with low individualized dosages that are gradually increased as long as no side effects occur or until side effects are present that can be regarded as acceptable in the light of the severity of the condition of the patient.
  • Individualization of dosage here can be related to correcting for body weight, body surface area, age, creatinine clearance, smoking habits and other factors know to impact individual pharmacokinetic and pharmacodynamic efficacy.
  • Glycinergic nature for countering side effects that are related to the reduction of Glycinergic activity such as epileptic seizures and / or other side effects.
  • An example of such rescue medication is diazepam that can be administered rectally outside hospitals and intravenously or intramuscular inside hospitals, or midazolam than can be administered buccal and nasal outside hospitals and intravenously and intramuscular inside hospitals.
  • Individualized dosing may be (partly) based upon clinical and safety endpoints indicative for an increased risk at side effects related to the reduction of Glycinergic activity such as tremors, and upon current practices in oncology where narrow therapeutic index treatments also are being applied successfully through active clinical and safety endpoint monitoring and dose titration schedules optimizing the balance between safety and efficacy.
  • Example 43 FSHD treatment through reducing GABAergic overstimulation Patients presenting with FSHD or related disease can be treated through the administration of compounds reducing GABAergic overstimulation.
  • GABAergic overstimulation should be gradual as a too fast decrease in GABAergic overstimulation in the co-presence of elevated excitatory glutamate levels may lead to increased incidences at (epileptic) seizures and to other side effects related to reducing GABAergic activity.
  • Administration therefore should start with low individualized dosages that are gradually increased as long as no side effects occur or until side effects are present that can be regarded as acceptable in the light of the severity of the condition of the patient.
  • Individualization of dosage here can be related to correcting for body weight, body surface area, age, creatinine clearance, smoking habits and other factors know to impact individual pharmacokinetic and pharmacodynamic efficacy.
  • rescue medication that is of GABAergic nature for countering side effects that are related to the reduction of GABAergic activity such as epileptic seizures and / or other side effects.
  • An example of such rescue medication is diazepam that can be administered rectally outside hospitals and intravenously or intramuscular inside hospitals, or midazolam than can be administered buccal and nasal outside hospitals and intravenously and
  • Individualized dosing may be (partly) based upon EEG activity and other clinical endpoints indicative for an increased risk at epileptic seizures and other side effects related to the reduction of GABAergic activity, and upon current practices in oncology where narrow therapeutic index treatments also are being applied successfully through active clinical and safety endpoint monitoring and dose titration schedules optimizing the balance between safety and efficacy.
  • dosage can be further increased as the risk as glutaminergic side effects (including seizures) has decreased and individualized dosing is to be re-established and re-evaluated on a regular basis.
  • Treatment further may be by co- administering medication aiming at the reduction of glutaminergic overstimulation leading to a gradual decline of glutaminergic overstimulation, as such leading to an even further reduced risk as side effects such as (epileptic) seizures.
  • Example 44 FSHD treatment through reducing Glycinergic overstimulation FSHD patients presenting with disease that can be related to the manifestation of glutaminergic excitatory induced neuronal cell death can be treated through the administration of compounds reducing Glycinergic overstimulation (see preferred antagonists disclosed herein).
  • Glycinergic activity therefore should start with low individualized dosages that are gradually increased as long as no side effects occur or until side effects are present that can be regarded as acceptable in the light of the severity of the condition of the patient.
  • Individualization of dosage here can be related to correcting for body weight, body surface area, age, creatinine clearance, smoking habits and other factors know to impact individual pharmacokinetic and pharmacodynamic efficacy.
  • Glycinergic nature for countering side effects that are related to the reduction of Glycinergic activity such as epileptic seizures and / or other side effects.
  • An example of such rescue medication is diazepam that can be administered rectally outside hospitals and intravenously or intramuscular inside hospitals, or midazolam than can be administered buccal and nasal outside hospitals and intravenously and intramuscular inside hospitals (Silbergleit et al. 2012).
  • Individualized dosing may be (partly) based upon clinical and safety endpoints indicative for an increased risk at side effects related to the reduction of
  • Glycinergic activity such as tremors
  • narrow therapeutic index treatments also are being applied successfully through active clinical and safety endpoint monitoring and dose titration schedules optimizing the balance between safety and efficacy.
  • Treatment is dependent on the efficacy of treatment as the reduction of Glycinergic overstimulation can be expected to lead to a corresponding reduction of glutaminergic excitatory overstimulation.
  • dosage can be further increased as the risk as glutaminergic side effects (including seizures) has decreased and individualized dosing is to be re-established and re-evaluated on a regular basis.
  • Treatment further may be by co- administering medication aiming at the reduction of glutaminergic overstimulation leading to a gradual decline of glutaminergic overstimulation, as such leading to an even further reduced risk as side effects such as (epileptic) seizures.
  • Example 45 Treatment for loss of muscle coordination through reducing GABAergic overstimulation
  • ALS Another clinical feature that can be attributed to GABAergic stimulation is the in ALS patients observed loss of muscle coordination which is a feature ALS shares with the clinical manifestations observed after the ingestion of alcohol / ethanol in humans.
  • alcohol being a GABAergic stimulant through its binding to the GABA receptor thereby increasing the receptor's affinity for GABA, it can be concluded that GABAergic stimulation can lead to difficulties with coordination of movement as observed in ALS patients.

Abstract

L'invention concerne de nouveaux procédés de traitement de maladie neuromusculaire ou neurologique, par exemple, la sclérose latérale amyotrophique (SLA), par réduction de la surstimulation de l'activité des neurotransmetteurs inhibiteurs GABAergiques et/ou glycinergique. L'invention concerne également des compositions pharmaceutiques comprenant un ou plusieurs composés capables de réduire l'activité glycinergique et/ou un ou plusieurs composés capables de réduire l'activité GABAergique. L'invention concerne également des procédés de traitement d'un ou de plusieurs symptômes provoqués par une surstimulation des neurotransmetteurs inhibiteurs (par exemple, la fonte musculaire, la perte de la fonction musculaire, la perte de coordination musculaire, la dépression respiratoire, la dysphagie, la dysarthrie, les difficultés du mouvement de l'œil, la paralysie du regard oculomotrice, la paralysie du regard pseudobulbaire, le dysfonctionnement de la vessie et le dysfonctionnement gastro-intestinal) chez un individu souffrant de SLA ou d'un trouble de type SLA.
PCT/NL2016/050021 2015-01-12 2016-01-12 Traitement de maladie neuromusculaire ou neurologique par réduction de la surstimulation des neurotransmetteurs inhibiteurs gabaergiques et/ou glycinergique WO2016114655A1 (fr)

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