WO2018229764A1 - Traitement de la sclérose en plaques avancée ou progressive - Google Patents

Traitement de la sclérose en plaques avancée ou progressive Download PDF

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WO2018229764A1
WO2018229764A1 PCT/IL2018/050648 IL2018050648W WO2018229764A1 WO 2018229764 A1 WO2018229764 A1 WO 2018229764A1 IL 2018050648 W IL2018050648 W IL 2018050648W WO 2018229764 A1 WO2018229764 A1 WO 2018229764A1
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agent
glutamate
multiple sclerosis
subject
levels
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PCT/IL2018/050648
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English (en)
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David Mirelman
Rina Aharoni
Aharon Rabinkov
Ruth Arnon
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Yeda Research And Development Co. Ltd.
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Publication of WO2018229764A1 publication Critical patent/WO2018229764A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y206/00—Transferases transferring nitrogenous groups (2.6)
    • C12Y206/01—Transaminases (2.6.1)
    • C12Y206/01001—Aspartate transaminase (2.6.1.1), i.e. aspartate-aminotransferase
    • 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

Definitions

  • the present invention in some embodiments thereof, relates to methods of treating advanced or progressive multiple sclerosis using agents that reduce blood glutamate levels.
  • the amino acid L-glutamic acid (glutamate) is a major excitatory neurotransmitter in the nervous system mediating many of the excitatory transactions between neurons in the central nervous system.
  • glutamate is a major excitatory neurotransmitter in the nervous system mediating many of the excitatory transactions between neurons in the central nervous system.
  • This biochemical pathway also serves as an endogenous neuroprotective mechanism, which functions by removing the synaptically released glutamate from the extracellular space and converting it to the nontoxic amino acid glutamine before toxicity occurs.
  • the removal of glutamate from the extracellular space into brain takes place via specific glutamate transporters that co-transport glutamate and sodium ions.
  • the driving force for this co-transport resides in the concentration gradient between the high extracellular and low intracellular concentrations of sodium ions.
  • the excitotoxic potential of glutamate i.e., defined as the ability of excess glutamate to overexcite neurons and cause their death
  • glutamate i.e., defined as the ability of excess glutamate to overexcite neurons and cause their death
  • failure or reduction in the transport process such as under ischemic conditions, results in accumulation of glutamate in the extracellular synaptic fluid and excessive stimulation of excitatory receptors, a situation that leads to neuronal and glia cell death and subsequently to loss of brain function.
  • Glu glutamate
  • MS Multiple Sclerosis
  • CNS central nervous system
  • MS central nervous system
  • CNS central nervous system
  • the clinical pattern of MS ranges from an inflammatory relapsing-remitting form of the disease (typically the initial presentation) to chronic progressive disease (e.g. without flairs and remissions).
  • Various mechanisms are implicated in the pathogenesis of MS, among them inflammation, demyelination and neurodegeneration.
  • MS is mediated by inflammatory immune cells, which are a source of extracellular glutamate and express on their cell surface several types of functional glutamate receptors [Macrez, et al. Lancet Neurol (2016) 15(10): 1089-1102; Levite, J Neural Transm (2017) doi: 10.1007/s00702-016-1661-z], however, the current understanding of the involvement of glutamate in MS disease progression is contradictory.
  • Glutamate excitotoxicity is a potential mechanism involved in the pathogenesis of MS. These studies indicate dysregulation of the glutamatergic system in the pathogenesis of MS and have indicated that excessive glutamate (Glu) might contribute to disease process or to the relapsing stages of the disease [Azevedo et al., Ann Neurol (2014) 76: 269-278; Cianfoni A. et al., AJNR Am. J. Neuroradiol (2007) 28: 272-277; Macrez et al., Lancet Neurol (2016) 15: 1089-102; Sarchielli et al., Arch Neurol (2003) 60: 1082-1088].
  • MacMillan teaches that progressive MS exhibits decreasing glutamate and glutamine levels in white matter over a two-year period [MacMillan et al, Mult Scler. (2016) 22(1): 112-6] and Obert states that glutamate and glutamine levels in white matter were not significantly modified over a two year period [Obert et al., PLoS ONE (2016) 11(9): e0162583].
  • Glu receptor antagonists e.g. AMPA/kainate antagonist NBQX
  • EAE experimental autoimmune encephalomyelitis
  • MS therapeutics namely Fingolimod, dimethyl fumarate and their respective metabolites Fingolimod- phosphate and monomethyl fumarate
  • Fingolimod reduces glutamate-mediated intracortical excitability in relapsing -remitting MS.
  • Glatiramer acetate-Copaxone ® an immunomodulator drug for MS, reverses TNF-a-induced alterations of striatal glutamate-mediated excitatory postsynaptic currents in EAE-afflicted mice [Levite, (2017), supra].
  • scavenging of excess brain glutamate can be carried out by intravenous administration of agents which are able to decrease blood glutamate levels (e.g. recombinant preparation of the enzyme, Glutamate Oxaloacetate Transaminase (GOT) and/or oxaloacetate) [Perez-Mato et al., Cell Death and Disease (2014) 5, e992; Ruban et al. Neurodegener Dis. (2015) 15(4):233-42].
  • GOTA Glutamate Oxaloacetate Transaminase
  • Campos et al. have further shown the capacity of GOT to remove glutamate from the brain by means of blood glutamate degradation, and suggest the applicability of this enzyme as an efficient and novel neuroprotective tool against ischemic stroke [Campos et al., Journal of Cerebral Blood Flow & Metabolism (2011) 31, 1378-1386].
  • a method of treating advanced or progressive multiple sclerosis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agent which reduces blood glutamate levels and enhances brain to blood glutamate efflux, to thereby treat the advanced or progressive multiple sclerosis in the subject.
  • a method of treating multiple sclerosis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agent which reduces blood glutamate levels and enhances brain to blood glutamate efflux and an agent for the treatment of multiple sclerosis, to thereby treat the multiple sclerosis in the subject.
  • the multiple sclerosis is an advanced or progressive multiple sclerosis.
  • the progressive multiple sclerosis comprises a primary-progressive MS (PPMS).
  • PPMS primary-progressive MS
  • the progressive multiple sclerosis comprises a secondary-progressive MS (SPMS).
  • SPMS secondary-progressive MS
  • the progressive multiple sclerosis comprises a progressive-relapsing MS (RSPMS).
  • the advanced multiple sclerosis comprises a relapsing remitting MS involving neuronal damage.
  • administering is via a peripheral route.
  • administering is via an intravenous route.
  • administering is effected at least once a day.
  • the agent which reduces blood glutamate levels is formulated for administration via a peripheral route.
  • the agent which reduces blood glutamate levels is formulated for administration via an intravenous route.
  • the agent which reduces blood glutamate levels is for administration via a peripheral route.
  • the agent which reduces blood glutamate levels is for administration via an intravenous route.
  • the agent which reduces blood glutamate levels is for administration at least once a day.
  • the agent which reduces blood glutamate levels is at least one glutamate modifying enzyme.
  • the at least one glutamate modifying enzyme is selected from the group consisting of a transaminase, a dehydrogenase, a decarboxylase, a ligase, an aminomutase, a racemase and a transferase.
  • the at least one glutamate modifying enzyme is a glutamate oxaloacetate transaminase (GOT) or a glutamate pyruvate transaminase (GPT).
  • GTT glutamate oxaloacetate transaminase
  • GPT glutamate pyruvate transaminase
  • the glutamate oxaloacetate transaminase is a Glutamate Oxaloacetate Transaminase 1 (GOTl).
  • the glutamate oxaloacetate transaminase is a recombinant GOTl (rGOTl).
  • the rGOTl is comprised in a protein preparation comprising Glutamate Oxaloacetate Transaminase 1 (GOTl) polypeptide molecules, wherein 100 % of the GOTl polypeptide molecules have an alanine at position 1 of the GOTl polypeptide, and wherein the GOTl polypeptide molecules constitute at least 95 % of the proteins in the preparation.
  • the protein constitutes at least 98 % of the molecules in the preparation.
  • the rGOTl is comprised in a pharmaceutical composition comprising the protein preparation of some embodiments of the invention as the active agent and a pharmaceutically acceptable carrier.
  • the GOT1 comprises an amino acid sequence at least 90 % homologous to SEQ ID NO: 3.
  • the GOT1 comprises the amino acid sequence as set forth in SEQ ID NO: 3.
  • the agent which reduces blood glutamate levels comprises a glutamate modifying enzyme and a co-substrate thereof.
  • the glutamate modifying enzyme comprises glutamate oxaloacetate transaminase (GOT) and the co-substrate thereof comprises oxaloacetate.
  • the glutamate modifying enzyme comprises glutamate pyruvate transaminase (GPT) and the co-substrate thereof comprises pyruvate.
  • GPT glutamate pyruvate transaminase
  • the agent which reduces blood glutamate levels comprises a glutamate modifying enzyme and a co-factor thereof.
  • the glutamate modifying enzyme comprises glutamate oxaloacetate transaminase (GOT) or a glutamate pyruvate transaminase (GPT) and the co-factor thereof comprises pyridoxal phosphate.
  • the therapeutically effective amount is an amount of the agent capable of reducing glutamate levels in a central nervous system (CNS) of the subject.
  • CNS central nervous system
  • the CNS is a cerebrospinal fluid (CSF).
  • CSF cerebrospinal fluid
  • the therapeutically effective amount is an amount of the agent capable of reducing glutamate levels in a cerebrospinal fluid (CSF) of the subject.
  • CSF cerebrospinal fluid
  • the agent which reduces blood glutamate levels is administered to the subject in combination with an agent for the treatment of multiple sclerosis.
  • the agent for use further comprises the use of an agent for the treatment of multiple sclerosis.
  • the agent for the treatment of multiple sclerosis is selected from the group consisting of an anti-inflammatory drug, an immunosuppressant drug, an immunomodulatory drug, a neuroprotective drug and a cognitive enhancing drug.
  • the agent for the treatment of multiple sclerosis is selected from the group consisting of a beta interferon, glatiramer (Copaxone ® ), fingolimod (Gilenya ® ), natalizumab (Tysabri ® ), mitoxantrone (Novantrone ® ), teriflunimide (Aubagio ® ), BG-12 (Tecfidera ® ), alemtuzumab (Lemtrada ® ), daclizumab (Zinbryta ® ), ocrelizumab (Ocrevus ® ), amantadine (Symmetrel ® ), amitriptyline (Elavil ® ), nortriptyline, modafinil (Provigil ® ), and dalfampridine (Ampyra ® ).
  • a beta interferon glatiramer
  • fingolimod Gailenya ®
  • the subject is a human subject.
  • FIGs. 1A-C are graphs illustrating the effect of rGOT suppression therapeutic treatment on severe EAE.
  • C57BL/6 mice were induced with EAE by subcutaneous injection of the 35-55 peptide of MOG.
  • rGOT treatment was applied to mice with severe clinical manifestations, scores 2-3, starting 11-14 days from disease induction, by daily intraperitoneal injections, 20 ⁇ g per mouse per day (1 mg/kg), in 0.1 ml phosphate Buffered saline (PBS). Control mice with identical clinical scores were similarly injected by PBS (untreated controls).
  • FIG. 1A Clinical manifestations from the day of treatment initiation, shown as the average daily scores + standard error.
  • Figure IB Area under curve for the treatment period + standard error.
  • Figure 1C survival curve.
  • FIGs. 2A-C are graphs illustrating the effect of rGOT suppression therapeutic treatment on mild EAE.
  • C57BL/6 mice were induced with EAE by subcutaneous injection of the 35-55 peptide of MOG.
  • rGOT treatment was applied to mice with mild clinical manifestations, scores 1-1.5, starting 11-14 days from disease induction, by daily intraperitoneal injections, 20 ⁇ g per mouse per day (1 mg/kg), in 0.1 ml phosphate Buffered saline (PBS). Control mice with identical clinical scores were similarly injected by PBS (untreated controls).
  • FIGs. 3A-C are graphs illustrating the effect of rGOT treatment on EAE manifestations when applied as suppression therapeutic treatment for severe disease.
  • mice with clinical scores of 2- 3, namely hind leg weakness (2) or hind leg complete paralysis (3) were daily treated by rGOT (7 mice), they show significant reduction in disease manifestations compared to control mice that were injected by PBS (untreated controls, 6 mice).
  • Figure 3A Considerable differences can be seen in the clinical score along the treatment period.
  • Figure 3C Significant differences are seen in the disease induced mortality.
  • FIGs. 4A-C are graphs illustrating the effect of rGOT treatment on EAE manifestations when applied as suppression therapeutic treatment on mild disease.
  • mice with clinical scores of 1- 1.5, namely loss of tail tonicity (1) and tendency for hind leg weakness (1.5) were daily treated by rGOT (6 mice), the effect on the disease manifestations compared to control mice that were injected by PBS (untreated controls, 8 mice) was less significant.
  • Figure 4A - Minor differences can be seen in the clinical score along the treatment period.
  • Figure 4C - Insignificant differences are shown in disease induced mortality between rGOT and PBS treated mice.
  • FIGs. 5A-B are graphs illustrating the effect of rGOT -treatment, when applied as suppression therapeutic treatment, on glutamate levels.
  • Figure 5 A in the cerebrospinal fluid (CSF), and Figure 5B - in the blood serum.
  • CSF cerebrospinal fluid
  • FIGs. 5A-B are graphs illustrating the effect of rGOT -treatment, when applied as suppression therapeutic treatment, on glutamate levels.
  • Figure 5 A - in the cerebrospinal fluid (CSF) CSF
  • Figure 5B in the blood serum.
  • the levels of glutamate in the blood serum were not significantly affected by EAE induction or rGOT treatment.
  • FIGs. 6A-B are graphs illustrating rGOT enzymatic levels.
  • CSF cerebrospinal fluid
  • FIGs. 6A-B are graphs illustrating rGOT enzymatic levels.
  • the present invention in some embodiments thereof, relates to methods of treating advanced or progressive multiple sclerosis using agents that reduce blood glutamate levels.
  • MS Multiple sclerosis
  • Glu glutamate
  • scavenging of excess brain glutamate can be carried out by intravenous administration of agents which are able to decrease blood glutamate levels (e.g. recombinant preparation of the enzyme, Glutamate Oxaloacetate Transaminase (GOT)).
  • GTO Glutamate Oxaloacetate Transaminase
  • GOT treatment of MS can be used as a neuroprotective drug which is effective when neuronal damage is apparent (e.g. to reverse, prevent or delay neuronal damage), such as in the advanced or progressive stages of disease.
  • a method of treating advanced or progressive multiple sclerosis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agent which reduces blood glutamate levels and enhances brain to blood glutamate efflux, to thereby treat the advanced or progressive multiple sclerosis in the subject.
  • a method of treating multiple sclerosis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an agent which reduces blood glutamate levels and enhances brain to blood glutamate efflux and an agent for the treatment of multiple sclerosis, to thereby treat the multiple sclerosis in the subject.
  • treating refers to abrogating, substantially inhibiting delaying, slowing or reversing the progression of multiple sclerosis, substantially ameliorating or alleviating the clinical symptoms and/or the neuronal damages of multiple sclerosis, substantially preventing the appearance of clinical symptoms and/or the neuronal damages of multiple sclerosis or halting the deleterious effects of multiple sclerosis.
  • subject or “subject in need thereof as used herein, includes mammals, preferably human beings, at any age or gender. Typically, the subject has been diagnosed with multiple sclerosis. The subject may or may not have received treatment for the multiple sclerosis.
  • any type of advanced or progressive multiple sclerosis may be treated according to the teachings of the present invention including advanced stages of relapsing-remitting MS, primary progressive MS (PPMS), secondary progressive MS (SPMS), progressive relapsing MS (also called relapsing-secondary progressive multiple sclerosis (RSPMS)), and advanced or progressive stages of special cases of MS with non-standard behavior (also referred to as borderline forms of MS), such as for example without limitation, Neuromyelitis optica (NMO), Balo concentric sclerosis, Schilder disease, Marburg multiple sclerosis, acute disseminated encephalomyelitis (ADEM) and autoimmune variants of peripheral neuropathies.
  • NMO Neuromyelitis optica
  • Schilder disease Seseminated encephalomyelitis
  • ADAM acute disseminated encephalomyelitis
  • autoimmune variants of peripheral neuropathies such as for example without limitation, Neuromyelitis optica (NMO), Balo concentric sclerosis, S
  • Advanced Multiple Sclerosis or “advanced MS” as used herein refers to the stage of Multiple Sclerosis in which neuronal damage (i.e. neurodegeneration) is evident and is accompanied by disability.
  • advanced MS is considered when the subject has an Expanded
  • EDSS Disability Status Scale
  • Advanced MS includes advanced stages of relapsing remitting MS (i.e. prior to transition into progressive MS).
  • RRMS Relapsing-remitting multiple sclerosis
  • RRMS relapsing form of multiple sclerosis characterized by clearly defined disease relapses (also known as attacks or exacerbations).
  • the defining elements of RRMS are episodes of acute worsening of neurologic function followed by a variable degree of recovery, with a stable course between attacks. In the advanced stages of RRMS, neurodegeneration is evident.
  • Progressive MS refers to the stage of the disease in which neuronal damage (i.e. neurodegeneration) is irreversible and/or progresses. According to one embodiment, progressive MS is considered when the subject has an EDSS score above 2 (e.g. when the subject has an EDSS score in the range of 2-9.5, as discussed in detail below and in Table 1 below).
  • Primary progressive multiple sclerosis or “PPMS” - In primary progressive MS (PPMS) symptoms gradually get worse without any obvious relapses or remissions.
  • SPMS Secondary progressive MS
  • SPMS secondary-progressive MS
  • Progressive-relapsing MS or “Relapsing-secondary progressive MS” or “RSPMS” - comprises those subjects during the early stages after transitioning to SPMS that still exhibit features of relapse activity and inflammation, as documented on neuroimaging studies as new Tl gadolinium enhancing lesions or new or newly enlarging T2 lesions on brain or spinal cord MRI.
  • An advanced or progressive form of MS can be determined by any method known in the art (or combinations thereof) such as, without being limited to, magnetic resonance imaging (MRI), Expanded Disability Status Scale (EDSS), Multiple Sclerosis Functional Composite (MSFC), Modified Fatigue Impact Scale (MFIS) or SF-36.
  • MRI magnetic resonance imaging
  • EDSS Expanded Disability Status Scale
  • MSFC Multiple Sclerosis Functional Composite
  • MFIS Modified Fatigue Impact Scale
  • EDSS Extended Disability Status Scale
  • FS Functional Systems
  • Table 1 Expanded Disability Status Scale
  • the EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist.
  • EDSS steps 1.0 to 3.5 refer to measures of impairment in eight functional systems (FS): pyramidal - weakness or difficulty moving limbs, cerebellar - ataxia, loss of coordination or tremor, brainstem - problems with speech, swallowing and nystagmus, sensory - numbness or loss of sensations, bowel and bladder function, visual function, cerebral (or mental) functions and other.
  • FS functional systems
  • MSFC Multiple Sclerosis Functional Composite
  • T25FW Timed 25 Foot Walk
  • SHPT 9 Hole Peg Test
  • PASAT Paced Auditory Serial Arithmetic Test
  • MFIS Modified Fatigue Impact Scale
  • SF-36 refers to the multi-purpose, short-form health survey with 36 questions which yields an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures and a preference -based health utility index. It is a generic measure, as opposed to one that targets a specific age, disease, or treatment group.
  • the survey is developed by and can be obtained from QualityMetric, Inc. of Buffalo, R.I.
  • An agent which is capable of reducing blood glutamate levels and enhancing brain to blood glutamate efflux according to this aspect of the present invention includes any glutamate modifying enzyme.
  • a glutamate modifying enzyme is an enzyme, which utilizes glutamate as a substrate and produces a glutamate reaction product.
  • a glutamate modifying enzyme can be a natural occurring enzyme or an enzyme which has been modified to obtain improved features, such as higher affinity to glutamate than to a modified glutamate, stability under physiological conditions, solubility, enhanced enantioselectivity, increased thermostability and the like as is further described hereinunder.
  • transaminases which play a central role in amino acid metabolism and generally funnel a-amino groups from a variety of amino acids via the coupled conversion of glutamate into a-ketoglutarate or of a- ketoglutarate into glutamate.
  • exemplary transaminases include, but are not limited to, glutamate oxaloacetate transaminases (GOT) and glutamate pyruvate transaminases (GPT). Additional exemplary transaminases are described in PCT publication no. WO/2009/144699, incorporated herein by reference in its entirety.
  • glutamate modifying enzymes include, but are not limited to, glutamate dehydrogenases, which generate ammonium ion from glutamate by oxidative deamination; decarboxylases such as glutamate decarboxylase; ligases such as glutamate-ethylamine ligase, glutamate-cysteine ligase; transferases such as glutamate N-acetyltransferase and N2-acetyl-L- ornithine, adenylyltransferase; aminomutases such as glutamate- 1-semialdehyde 2,1-aminomutase and glutamate racemase [Glavas and Tanner (2001) Biochemistry 40(21):6199-204)].
  • glutamate dehydrogenases which generate ammonium ion from glutamate by oxidative deamination
  • decarboxylases such as glutamate decarboxylase
  • ligases such as glutamate
  • modified glutamate i.e., glutamate reaction product
  • the agent preferably includes a modified glutamate converting enzyme which is incapable of converting the modified glutamate back into glutamate to thereby insuring continual metabolism of glutamate.
  • modified or modifiable glutamate converting enzymes include but are not limited to GPT, GOT, Glutamate decarboxylase and glutamate dehydrogenase.
  • Modified glutamate converting enzymes can also include glutamate modifying enzymes artificially modified to possess lower affinity for glutamate reaction product than for glutamate.
  • the E. coli GOT (GenBank Accession No. D90731.1) is characterized by an affinity for glutamate of about 8 mM and an affinity for 2-ketoglutarate of about 0.2 mM.
  • a human enzyme or a humanized enzyme characterized by such affinities is preferably used according to this aspect of the present invention such as described by Doyle et al. in Biochem J. 1990 270(3):651-7.
  • the glutamate modifying enzyme is a glutamate oxaloacetate transaminase (GOT) or a glutamate pyruvate transaminase (GPT).
  • GTT glutamate oxaloacetate transaminase
  • GPT glutamate pyruvate transaminase
  • the glutamate oxaloacetate transaminase is a Glutamate Oxaloacetate Transaminase 1 (GOT1), also referred to as serum-GOTl.
  • the agent which reduces blood glutamate levels according to this aspect of the present invention can include one or more co-substrates of glutamate modifying enzymes, which can accelerate activity of the latter (V max ). These can be administered in order to enhance the rate of endogenous glutamate modifying enzymes or in conjunction with glutamate modifying enzymes (described hereinabove).
  • Co-substrates of glutamate-modifying enzymes include, but are not limited to, oxaloacetate, pyruvate, NAD + , NADP + , 2-oxohexanedioic acid, 2-oxo-3-sulfopropionate, 2-oxo-3-sulfmopropionic acid, 2-oxo-3-phenylpropionic acid, 3-indole-2-oxopropionic acid, 3-(4-hydroxyphenyl)-2- oxopropionic acid, 4-methylsulfonyl-2-oxobutyric acid, 3-hydroxy-2-oxopropionic acid, 5- oxopentanoate, 6-oxo-hexanoate, glyoxalate, 4-oxobutanoate, a-ketoisocaproate, a-ketoisovalerate, a-keto-P-methyl valerate, succinic semialdehyde-(-4-o
  • the glutamate modifying enzyme comprises glutamate oxaloacetate transaminase (GOT) and the co-substrate comprises oxaloacetate.
  • the glutamate modifying enzyme comprises glutamate pyruvate transaminase (GPT) and the co-substrate thereof comprises pyruvate.
  • GPT glutamate pyruvate transaminase
  • co-factors of modified glutamate converting enzymes can be used according to some embodiments of the present invention.
  • co-factors of modified glutamate converting enzymes include, but are not limited, to lipoic acid and its precursors, thiamine pyrophosphate and its precursors, pyridoxal phosphate and its precursors and the like.
  • the glutamate modifying enzyme comprises glutamate oxaloacetate transaminase (GOT) and the co-factor thereof comprises pyridoxal phosphate.
  • the glutamate modifying enzyme comprises glutamate pyruvate transaminase (GPT) and the co-factor thereof comprises pyridoxal phosphate.
  • GPT glutamate pyruvate transaminase
  • the agent administered is modified in order to increase the therapeutic effect or reduce unwanted side effects.
  • the present invention also envisages repetitive administration of the enzyme (e.g., on a monthly basis), use of reagents which will increase the life-time in the circulation e.g. PEGylated enzyme, or the entrapment of the enzyme in suitable carriers that should cause a sustained increase of blood enzyme levels allowing an effective blood glutamate scavenging with lower concentrations of the co-factor.
  • repetitive administration of the enzyme e.g., on a monthly basis
  • reagents which will increase the life-time in the circulation e.g. PEGylated enzyme
  • suitable carriers that should cause a sustained increase of blood enzyme levels allowing an effective blood glutamate scavenging with lower concentrations of the co-factor.
  • heterologous polypeptide that increases the half-life of the enzyme in the serum.
  • heterologous amino acid sequences that may be used in accordance with the teachings of the present invention include, but are not limited to, immunoglobulin, galactosidase, glucuronidase, glutathione - S-transferase (GST), carboxy terminal peptide (CTP) from chorionic gonadotrophin (CG) and chloramphenicol acetyltransferase (CAT) (see for example U.S. Publication No. 20030171551, incorporated herein by reference).
  • the glutamate oxaloacetate transaminase is a recombinant GOT (rGOT).
  • the rGOT is rGOTl.
  • rGOTl chimeric protein is generated by fusing the human GOTl gene (without the first ATG codon) to the C-terminus of the gene encoding the Small Ubiquitin-like Modifier (SUMO) entity, as described in PCT publication no. WO/2017/157190, incorporated herein by reference in its entirety.
  • SUMO Small Ubiquitin-like Modifier
  • the SUMO-rGOT chimeric protein is expressed in a host cell (e.g. bacterial cell), after which the SUMO entity is cleaved from the fusion protein, by a SUMO protease and the rGOTl is isolated and purified, as described in PCT publication no. WO/2017/157190, incorporated herein by reference in its entirety.
  • a host cell e.g. bacterial cell
  • the rGOT is comprised in a protein preparation comprising Glutamate Oxaloacetate Transaminase 1 (GOT1) polypeptide molecules, wherein 100 % of the GOT1 polypeptide molecules have an alanine at position 1 of the GOT1 polypeptide, and wherein the GOT1 polypeptide molecules constitute at least 95% of the proteins in the preparation.
  • GOT1 Glutamate Oxaloacetate Transaminase 1
  • the protein constitutes at least 98 % of the molecules in the preparation.
  • the rGOT is comprised in a pharmaceutical composition comprising the protein preparation as the active agent and a pharmaceutically acceptable carrier.
  • the rGOTl comprises an amino acid sequence at least 90 % homologous to SEQ ID NO: 3.
  • the rGOTl comprises an amino acid sequence at least 95 % homologous to SEQ ID NO: 3.
  • the rGOTl comprises an amino acid sequence at least 99 % homologous to SEQ ID NO: 3.
  • the rGOTl comprises the amino acid sequence as set forth in SEQ ID NO: 3.
  • the rGOTl comprises the nucleic acid sequence as set forth in SEQ ID NO: 1 or 2.
  • rGOTl comprises an enzymatic activity of at least 500 U/L per 1 mg of purified rGOT. Determination of enzymatic activity can be carried out using any method known in the art, such as by a Reflotron strip assay (Roche, Basel, Switzerland).
  • the agent which reduces blood glutamate levels and enhances brain to blood glutamate efflux of some embodiments of the invention can be administered to a subject using any one of several suitable administration modes which are further described hereinbelow with respect to the pharmaceutical compositions of the present invention.
  • the agent utilized by the method of the present invention can be administered to an individual subject per se, or as part of a pharmaceutical composition where it is mixed with a pharmaceutically acceptable carrier.
  • a pharmaceutical composition refers to a preparation of one or more of the active ingredients described hereinabove along with other components such as physiologically suitable carriers and excipients, penetrants etc.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • active ingredient refers to the preparation accountable for the biological effect (e.g., the glutamate modifying enzyme).
  • physiologically acceptable carrier and pharmaceutically acceptable carrier
  • pharmaceutically acceptable carrier refers to a carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • An adjuvant is included under these phrases.
  • One of the ingredients included in the pharmaceutically acceptable carrier can be, for example, polyethylene glycol (PEG), a biocompatible polymer with a wide range of solubility in both organic and aqueous media (Mutter et al. (1979).
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate administration of an active ingredient.
  • excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • Suitable routes of administration of the pharmaceutical composition of the present invention may, for example, include oral, rectal, transmucosal, especially transnasal, intestinal or parenteral delivery, including intramuscular, subcutaneous and intramedullary injections as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraosseus and intraocular injections.
  • the route of administration is a peripheral route of administration.
  • the route of administration is a systemic mode of administration.
  • the route of administration is an intravenous (i.v.) route.
  • Pharmaceutical compositions of some embodiments of the invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • compositions for use in accordance with some embodiments of the invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • the active ingredients of the pharmaceutical composition may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological salt buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the pharmaceutical composition can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the pharmaceutical composition to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient.
  • Pharmacological preparations for oral use can be made using a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carbomethylcellulose; and/or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this purpose, concentrated sugar solutions may be used which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules may contain the active ingredients in admixture with filler such as lactose, binders such as starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active ingredients may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the active ingredients for use according to some embodiments of the invention are conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of, e.g., gelatin for use in a dispenser may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
  • compositions described herein may be formulated for parenteral administration, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multidose containers with optionally, an added preservative.
  • the compositions may be suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active preparation in water-soluble form. Additionally, suspensions of the active ingredients may be prepared as appropriate oily or water based injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acids esters such as ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the active ingredients to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water based solution, before use.
  • a suitable vehicle e.g., sterile, pyrogen-free water based solution
  • compositions of some embodiments of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, e.g., conventional suppository bases such as cocoa butter or other glycerides.
  • compositions suitable for use in context of some embodiments of the invention include compositions wherein the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount of active ingredients (i.e. agent which reduces blood glutamate levels) effective to prevent, alleviate or ameliorate symptoms of a disorder (e.g., advanced or progressive multiple sclerosis) or prolong the survival of the subject being treated.
  • active ingredients i.e. agent which reduces blood glutamate levels
  • a disorder e.g., advanced or progressive multiple sclerosis
  • the therapeutically effective amount or dose can be estimated initially from in vitro and cell culture assays.
  • a dose can be formulated in animal models to achieve a desired concentration or titer. Such information can be used to more accurately determine useful doses in humans.
  • an effective amount is an amount that reduces blood (e.g. plasma) glutamate levels and enhances brain-to-blood glutamate efflux.
  • blood e.g. plasma
  • an effective amount is an amount capable of reducing glutamate levels in the central nervous system (CNS) of the subject.
  • an effective amount is an amount capable of reducing glutamate levels in the cerebrospinal fluid (CSF) of the subject.
  • an effective amount reduces the glutamate levels in the CNS (e.g. CSF) by at least about 10 %, 20 %, 30 %, 40 %, 50 %, 60 %, 70 %, 80 %, 90 % or by 100 %.
  • CNS e.g. CSF
  • Obtaining a CSF sample may be effected using any method known in the art, e.g. by fine needle aspiration.
  • measuring the glutamate levels in the CSF may be effected using any method known in the art, e.g. using a UPLC/MS/MS system consisting of e.g. an Acquity UPLC chromatographic system and a Quattro Premier XE triple quad mass spectrometer; or using an ELISA kit e.g. Glutamate Assay Kit (such as the one commercially available from Abeam).
  • Toxicity and therapeutic efficacy of the active ingredients described herein can be determined by standard pharmaceutical procedures in vitro, in cell cultures or experimental animals.
  • the data obtained from these in vitro and cell culture assays and animal studies can be used in formulating a range of dosage for use in human.
  • the dosage may vary depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl, et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. l).
  • EAE experimental autoimmune encephalomyelitis
  • Dosage amount and interval may be adjusted individually to provide the active ingredient at a sufficient amount to induce or suppress the biological effect (minimal effective concentration, MEC).
  • MEC minimum effective concentration
  • the MEC will vary for each preparation, but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. Detection assays can be used to determine plasma concentrations.
  • dosing can be of a single or a plurality of administrations, with course of treatment lasting from several days to several weeks or until cure is effected or diminution of the disease state is achieved.
  • the glutamate modifying enzyme e.g. rGOTl
  • the glutamate modifying enzyme is administered in a single daily administration.
  • the glutamate modifying enzyme e.g. rGOTl
  • the glutamate modifying enzyme is administered in multiple daily administrations (e.g. two, three or more administrations per day).
  • the glutamate modifying enzyme e.g. rGOTl
  • the glutamate modifying enzyme is administered in a single weekly or monthly administration.
  • the glutamate modifying enzyme e.g. rGOTl
  • the glutamate modifying enzyme is administered in multiple weekly or monthly administrations (e.g. two, three or more administrations per week or month).
  • compositions to be administered will, of course, be dependent on the subject being treated, the severity of the affliction, the manner of administration, the judgment of the prescribing physician, etc.
  • compositions of some embodiments of the invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accommodated by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
  • Compositions comprising a preparation of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition, as is further detailed above.
  • compositions of the invention may comprise, in addition to the agents described above, other known medications for the treatment of multiple sclerosis such as, but not limited to, immunosuppressants, immunomodulatory drugs, neuroprotective drugs and cognitive enhancing drugs.
  • the agent which reduces blood glutamate levels is administered to the subject prior to, following to, or concomitantly with an agent for the treatment of multiple sclerosis.
  • the agent for the treatment of multiple sclerosis is administered to a subject at an early stage of the disease and the agent which reduces blood glutamate levels is administered to the subject at a later (e.g. at an advanced or progressive stage) of the disease.
  • the agent for the treatment of multiple sclerosis and the agent which reduces blood glutamate levels are co -administered to the subject at any stage of the disease.
  • Co-administration may be carried out on the same day, on consequent days, or even a week or few weeks apart.
  • the agent which reduces blood glutamate levels and the agent for the treatment of multiple sclerosis are be provided in a kit where each component is packed separately or in a co -formulation.
  • the agent for the treatment of multiple sclerosis comprises an immunosuppressant, an immunomodulatory drug, a neuroprotective drug, or cognitive enhancing drug, or a combination thereof.
  • the therapeutic agent for the treatment of multiple sclerosis is selected from the group consisting of a beta interferon, glatiramer acetate (GA, Copaxone ® ), fingolimod (Gilenya ® ), natalizumab (Tysabri ® ), mitoxantrone (Novantrone ® ), teriflunimide (Aubagio ® ), BG-12 (Tecfidera ® ), alemtuzumab (Lemtrada ® ), daclizumab (Zinbryta ® ), ocrelizumab (Ocrevus ® ), amantadine (Symmetrel ® ), amitriptyline (Elavil ® ), nortriptyline, modafinil (Provigil ® ), and dalfampridine (Ampyra ® ), or a combination thereof.
  • a beta interferon glatiramer acetate
  • the therapeutic agent for the treatment of multiple sclerosis is an anti-inflammatory drug.
  • anti-inflammatory agents include, but are not limited to, NSAIDs (Non- Steroidal NSAIDs (Non- Steroidal NSAIDs).
  • Anti-inflammatory Drugs include, but are not limited to, Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; De
  • Enlimomab Enolicam Sodium; Epirizole; Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen;
  • Fenclofenac Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacort; Flufenamic Acid;
  • Flumizole Flunisolide Acetate; Flunixin; Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate; Furaprofen; Furobufen;
  • Halcinonide Halobetasol Propionate; Halopredone Acetate; Ibufenac; Ibuprofen; Ibuprofen
  • Ibuprofen Piconol Inol
  • Ibuprofen Piconol Inonidap
  • Indomethacin Indomethacin Sodium
  • Indoprofen Indoxole
  • Intrazole Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen; Lofemizole Hydrochloride;
  • Talosalate Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Tetrydamine;
  • Tiopinac Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; Zidometacin;
  • immunosuppressants and immunomodulatory agents include, but are not limited to, interferons such as alpha or beta interferon (e.g., Avonex ® or Betaseron ® ), glatiramer acetate, corticosteroid (e.g. systemic corticosteroid such as methylprednisolone (Solu-Medrol ® )), prednisone (Deltasone ® ), azathioprine (AZA), cyclophosphamide, methotrexate and mitoxantrone, or a combination thereof.
  • interferons such as alpha or beta interferon (e.g., Avonex ® or Betaseron ® ), glatiramer acetate, corticosteroid (e.g. systemic corticosteroid such as methylprednisolone (Solu-Medrol ® )), prednisone (Deltasone ® ), aza
  • the cognitive enhancing drug comprises an acetylcholine receptor agonist, an acetylcholinesterase inhibitor, a butyrylcholinesterase inhibitor, an N-methyl-D- aspartate (NMDA) receptor antagonist, an activity-dependent neuroprotective protein (ADNP) agonist, a serotonin 5-HT1A receptor agonist, a 5-HT4 receptor agonist, a 5-HT6 receptor antagonist, a serotonin 1A receptor antagonist, a histamine H3 receptor antagonist, a calpain inhibitor, a vascular endothelial growth factor (VEGF) protein or agonist, a trophic growth factor, an anti-apoptotic compound, an AMPA-type glutamate receptor activator, a L-type or N-type calcium channel blocker or modulator, a potassium channel blocker, a hypoxia inducible factor (HIF) activator, a HIF prolyl 4-hydroxylase inhibitor, an anti-inflammatory agent, an inhibitor of amyloid A.beta
  • ADNP
  • Exemplary cognitive enhancing drug include, but are not limited to, donepezil (Aricept ® ), rivastigmine (Exelon ® ), galanthamine (Reminyl ® ), memantine (Namenda ® ), or a combination thereof.
  • compositions, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.
  • a compound or “at least one compound” may include a plurality of compounds, including mixtures thereof.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • any Sequence Identification Number can refer to either a DNA sequence or a RNA sequence, depending on the context where that SEQ ID NO is mentioned, even if that SEQ ID NO is expressed only in a DNA sequence format or a RNA sequence format.
  • SEQ ID NO: 1 is expressed in a DNA sequence format (e.g. , reciting T for thymine), but it can refer to either a DNA sequence that corresponds to an GOT1 nucleic acid sequence, or the RNA sequence of an RNA molecule nucleic acid sequence.
  • RNA sequence format e.g.
  • EAE Experimental autoimmune encephalomyelitis
  • mice were examined daily and scored as follows: 0 - no disease, 1 - loss of tail tonicity, 2 - hind leg weakness, 3 - hind leg complete paralysis, 3.5 hind leg complete paralysis with hind body paresis, 4 - hind and foreleg paralysis, 5 - moribund or dead animals. rGOT treatment
  • mice with apparent clinical manifestations scores 1-3 (termed suppression therapeutic treatment) starting at days 11-14 from disease induction, by daily intraperitoneal injections, 40 ⁇ g per mouse per day (2 mg/kg), in 0.1 ml phosphate Buffered saline (PBS).
  • PBS phosphate Buffered saline
  • rGOT treatment was applied to mice with apparent clinical manifestations, score 3.0 (termed suppression therapeutic treatment) starting at days 11-14 from disease induction, by twice daily intraperitoneal injections (morning and evening), 40 ⁇ g per mouse per injection (4 mg/kg/day), in 0.1 ml phosphate Buffered saline (PBS). Control mice with identical clinical scores were similarly injected with PBS (untreated controls).
  • Figures 3A-C or score 1-1.5 (for Figures 4A-C), starting 11-14 days from disease induction, by daily intraperitoneal injections, 20 ⁇ g per mouse per day (1 mg/kg), in 0.1 ml phosphate Buffered saline (PBS).
  • PBS 0.1 ml phosphate Buffered saline
  • Control mice with identical clinical scores were similarly injected by PBS (untreated controls).
  • rGOT is effective in both groups of mice, however, better results were obtained from the group with a more advanced disease stage.

Abstract

La présente invention concerne une méthode de traitement de la sclérose en plaques avancée ou progressive chez un sujet en ayant besoin. La méthode comprend l'administration au sujet d'une quantité thérapeutiquement efficace d'un agent qui réduit les taux de glutamate sanguin et améliore l'efflux de glutamate du cerveau vers le sang. Des méthodes de traitement de la sclérose en plaques comprenant une polythérapie comprenant une quantité thérapeutiquement efficace d'un agent qui réduit les taux de glutamate sanguin et améliore l'efflux de glutamate du cerveau vers le sang et un agent pour le traitement de la sclérose en plaques sont en outre décrites.
PCT/IL2018/050648 2017-06-13 2018-06-13 Traitement de la sclérose en plaques avancée ou progressive WO2018229764A1 (fr)

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