WO2013185187A1

WO2013185187A1 - Gastrin-releasing peptide receptor-based methods for the treatment of stereotypies, social behavior deficits, and compulsive behaviors associated with neuropsychiatry and neurodevelopmental disorders and pharmaceutical composition containing grp

Info

Publication number: WO2013185187A1
Application number: PCT/BR2012/000182
Authority: WO
Inventors: Gilberto Schwartsmann; Rafael Roesler; Michele MICHELIN BECKER; Rudimar DOS SANTOS RIESGO
Original assignee: Gilberto Schwartsmann; Rafael Roesler; Michelin Becker Michele; Dos Santos Riesgo Rudimar
Priority date: 2012-06-11
Filing date: 2012-06-11
Publication date: 2013-12-19
Also published as: BR112014031123A2

Abstract

The present invention provides methods for treating symptoms including stereotypies, social behavior deficits, and obsessive behaviors in a subject afflicted with a neuropsychiatric or neurodevelopmental disorder. The methods comprise administering to a subject a therapeutically effective amount of gastrin-releasing peptide (GRP) or other GRP receptor (GRPR) agonist.

Description

GASTRIN-RELEASING PEPTIDE RECEPTOR-BASED METHODS FOR THE TREATMENT OF STEREOTYPIES, SOCIAL BEHAVIOR DEFICITS, AND COMPULSIVE BEHAVIORS ASSOCIATED WITH NEUROPSYCHIATRY AND NEURODEVELOPMENTAL DISORDERS AND PHARMACEUTICAL COMPOSITION CONTAINING GRP

FIELD OF THE INVENTION

The invention is directed towards methods of treating symptoms associated with neuropsychiatric and neurodevelopmental disorders, in particular symptoms related to stereotyped behaviors, social behavior deficits, and obsessive behaviors.

BACKGROUND OF THE INVENTION

Stereotyped and obsessive behaviors and deficits in social behavior and attachment are features of neuropsychiatric and neurodevelopmental disorders including autism spectrum disorders (ASD), schizophrenia, and obsessivecompulsive disorder (OCD). Novel therapeutic targets and treatment strategies for the treatment of symptoms associated to these behavioral alterations are warranted (DiCicco-Bloom et al., 2006).

Neuropeptides released from nerve terminals regulate several aspects of behavior in mammals and have been increasingly implicated behavioral alterations assoctaed with neuropsychiatric, neurodevelopmental, and neurodegenerative disorders. Gastrin-releasing peptide (GRP; Ala-Pro-Val-Ser- Val-Gly-Gly-Gly-Thr-Val-Leu-Ala-Lys-Met-Tyr-Pro-Arg-Gly-Asn-His-Trp-Ala-Val- Gly-His-Leu-Met-NH2), a neuropeptide that is the mammalian analog of the amphibian peptide bombesin (Pyr-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly- His-Leu-Met NH2), acts by binding to the GRP receptor (GRPR, also called BB₂ receptor) on neuronal membranes (Jensen et al. 2008; Roesler et al. 2006).

Human studies have suggested that the GRPR may be a therapeutic target in neuropsychiatric and neurodevelopmental disorders, and the GRPR gene (GRPR) has emerged as a candidate locus for ASD. A translocation breakpoint on the X chromosome in the first intron of the GRPR gene was described in a patient with autism accompanied by mental retardation and epilepsy (Ishikawa-Brush et al. 1997). Another study analyzing mutations of the GRPR gene in Italian autistic patients identified a possible role of mutations of the GRPR gene in ASD in two patients (Seidita et al., 2008). The role of GRPR in the mammalian brain in regulating stereotypy, social behavior, emotional behavior, and cognition, revealed by animal studies, is strongly consistent with the view that altered GRPR signaling is involved in behavioral alterations associated with ASD and other neuropsychiatric and neurodevelopmental disorders (Roesler et al., 2006). Thus, pharmacological blockade of the GRPR by acute systemic administration of a selective antagonist to mice blocks stereotypy induced by the dopamine receptor agonist apomorphine (Meller et al., 2004). Moreover, pharmacological GRPR blockade during central nervous system development in rats results in long-lasting and profound deficits in aspects of social behavior including social interaction in adults and maternal odor preference in juvenile rats (Garcia et al. 2010; Presti- Torres et al., 2007; 2012).

Unites States Patent Application 20080051315 (Kandel et al.) describes the use of a GRPR agonist for treating fear-related disorders, including phobia, chronic anxiety, panic attack, post-traumatic stress disorder, and autism.

United States Patent 7,795,385 (WO 2006/063837 A2; Schwartsmann et al.) describes the use of GRPR antagonists for treating or preventing brain disorders, preferably bipolar disorder, and in particular the different forms and/or subforms of bipolar disorder, such as mania, acute mania, severe mania, hypomania, depression, moderate depression, dysthymia, severe depression, episodes of mania and/or depression, psychosis/psychotic symptoms (e.g. hallucinations, delusions), mixed bipolar state, bipolar I disorder, bipolar II disorder and/or rapid-cycling bipolar disorder.

In spite of the evidence from animal studies indicating that GRPR blockade can ameliorate stereotypy and produce social behavior impairment, there is no previous evidence that administration of GRP can improve stereotyped and obsessive behaviors or social behavior deficits. No previous scientific publication, patent, or patent application describes or claims the use of GRPR agonists for the treatment of stereotypy, obsessive behaviors, or social behavior impairment.

The present invention aims to address this need by providing a therapeutic method to ameliorate those symptoms.

SUMMARY OF THE INVENTION In one aspect, the present invention provides a method for treating symptoms associated with stereotyped behaviors, obsessive behaviors, and social behavior deficits, in a subject in need of intervention, by administering to the subject a therapeutically effective amount of a composition containing GRP or a comparable GRPR agonist, including bombesin.

Also, ir considers the neuropsychiatric or neurodevelopmental disorder being Rett syndrome, Angelman syndrome, cerebral palsy, schizophrenia, obsessive-compulsive disorder (OCD), mental retardation, mood disorder, preferentially major depressive disorder, tardive dyskinesia, stereotypic movement disorder and frontotemporal dementia.

In another aspect, the invention provides a pharmaceutical composition containing human recombinant GRP dissolved in saline solution (NaCI 0.9%) in an adequate amount that allows a dose of 160 pmol/kg to be administered to the subject subcutaneously (s.c.) or intravenously (i.v.).

In a further aspect of the invention, the composition is preferably administered for a defined period, preferably once a day during 3 days or once a day during 4 days.

In yet a further aspect, the compositions containing the GRPR agonist can be given to the subject in solid or liquid formulations through any therapeutically adequate administration route, including the oral, sublingual, nasal, ophthalmic, intradermic, anal, subcutaneous, or intravenous routes.

BRIEF DESCRIPTION OF THE TABLES

Table 1. Symptoms before and after one daily infusion of human recombinant gastrin-releasing peptide (160 pmol/kg, s.c.) over 4 days to a patient diagnosed with classical autism.

DETAILED DESCRIPTION

The inventors have found a consistent amelioration of symptoms including stereotyped and obsessive behaviors and social withdraw after administration over a defined period of GRP to subjects afflicted with autism.

All experimental protocols were approved by an accredited institutional

Research Ethics Committee at the university hospital where the study was conducted (CEP-HCPA, Hospital de Clinicas de Porto Alegre, Porto Alegre, RS, Brazil), and the procedures followed the appropriate clinical research and research ethics guidelines approved in Brazil (Resolugao 196/96 - Diretrizes e Normas Regulamentadoras de Pesquisas Envolvendo Seres Humanos; Resolugao 251/97 - Normas de Pesquisa com Novos Farmacos, Medicamentos, Vacinas e Testes Diagnosticos Envolvendo Seres Humanos).

The aim of the study was to examine the effects of systemic administration of GRP on symptoms related to social interaction, withdrawn, communication, and stereotyped and obsessive behaviors in three pediatric patients (all males, ages 5 (patient 1), 5 (patient 2), and 4 (patient 3) diagnosed with classical autism. The results presented here were obtained from the clinical assessment of three patients using standardized scales and tests in a pilot study.

The assessment of symptoms related to autism was performed one day before GRP administration. On four consecutive days after treatment, subjects were given a daily s.c. injection of GRP at the dose of 160 pmol/kg. After the 4^th GRP injection, the patients were again assessed for the symptoms using the same standardized tests and scales. The patients were evaluated for symptoms and monitored for vital signs and possible drug-related adverse effects by one researcher directly involved in the study.

Because of the possibility of GRP-induced increase in gastric acid secretion, the patients were given concomitant treatment with the gastric acid secretion inhibitor omeprazole. Based on the available published data, it is highly unlikely that omeprazole could interfere with the symptoms of autism examined.

Human recombinant GRP was synthesized by Biopeptide, Inc (San Diego, CA, USA; reference 0912085780; September 13, 2008; 2 g; > 95% purity by HPLC).

Symptom assessment and screening instruments

Autism Diagnostic Interview-Revised (ADI-R; version translated and validated in Brazil): The ADI-R is a widely used structured interview conducted with the parents of subjects under evaluation for possible ASD. The instrument measures behaviors related primarily to reciprocal social interaction, communication, and language.

Social Communication Questionnaire (SCQ): Thirty-five item questionnaire completed by parents regarding the behavior of their child, including communication, social interaction and stereotypy, used in parallel to the ADI-R.

Childhood Autism Rating Scale (CARS): This is a standardized behavior rating scale. The child is rated on a scale from one to four, ranging from normal to severe, and quantitative scores ranging from 15 to 60. The items rated are relationship to people, imitation, emotional response, body, object use, adaptation to change, visual response, listening response, taste-smell- touch response and use, fear and nervousness, verbal communication, nonverbal communication, activity level, level and consistency of intellectual response, and general impressions. The scale can be completed by the subject's clinician or parent, based on observations of the child's behavior.

Results

Parental report (for patient 1): Behavioral changes reported by the parents as positive during GRP treatment included: 1 ) a reduction in compulsive showering - before treatment the patient took 5-6 showers daily and asked to shower every time he felt anxious, dirty, sweating, or hurt - from the first day of infusion; 2) reduced stereotyped behavior - the patient displayed stereotyped hand movements pointing repeatedly the index finger to the nose; stereotypy ceased after the first day of GRP infusion; and returned, with other previously unobserved movements, after the last day of infusion; 3) a decrease in agitation, with a larger effect on the first day of treatment with GRP; 4) increased tolerance to frustration with reduced arguing and shouting at the parents; 5) improved mood at waking time, calm behavior after infusions, and better sleep pattern, without waking up during the night or requiring rituals before sleeping; 6) improvement in interest and pattern of playing; before the treatment, played only with toy cars in a stereotyped and limited way; lost interest for any other toys a few minutes after getting them. During the treatment, playing with cars became more sophisticated and the patient showed interest for other toys, including larger cars and stuffed toys; 7) after treatment, the patient started eating his meals at the table with his parents; before treatment, the patient always ate alone; 8) improvement in behavior in the bathroom, including getting dressed by himself, putting down the toilet seat, and turning off the light after using it; and 9) subtle improvement in affective behavior toward the parents, including longer visual contact and smiling back (although still not often), and 10) increased appetite.

The parents did not report any undesirable behavioral changes or probable adverse drug effects.

Social Communication Questionnaire (SCQ) scores:

Table 1 summarizes the symptoms assessed before and after the first and second administrations of GRP for patient 1. Improvements after GRP treatment were observed in body and hand stereotypies, use of objects, fear and anxiety, compulsive behaviors, facial expressions, using other person's hand, and social smiling.

Table 1. Symptoms before and after one daily infusion of human recombinant gastrin-releasing peptide (160 pmol/kg, s.c.) over 4 days to a patient diagnosed with classical autism

Interpersonal relationship deficits + + + +

Lack of imitation - - - -

Body stereotypy * - + -

Hand stereotypy + - ♦ -

Lack of emotional response - - - -

Inappropriate use of objects * - ⁺ -

Restricted interests + + + +

Difficulty adapting to changes + + + +

Abnormal auditory response + . + + +

Poor visual contact + + + +

Inappropriate use of touch, taste, and smell - - - ^■ -

Abnormal fear or increased anxiety ⁺ - ⁺ -

Verbal communication deficit + + + +

Non-verbal communication deficit + + + +

Agitation + + + + Aggression and self-aggression - - - -

Compulsive behaviors ⁺ + -

Rituals - - - -

Inappropriate facial expression - + -

Using other person's hand as a tool * * -

Regular interests + + + +

Narrow interests + + + +

Lack of social smiling + - + -

Inability to share with others + + + +

No imaginative play + + + +

Inability to comfort - - - -

Before 1^s' After 1^s' Before 2"" After 2"°

GRP GRP GRP GRP

injection injection injection injection

All the examples and references used in this description cannot be understand as limitations of the scope of the invention, since the invention is based on a new, non-obvious and useful composition including GRP and a method for treating of stereotypies, social behavior deficits, and compulsive behaviors associated with neuropsychiatric and neurodevelopmental disorders including GRP.

REFERENCES

DiCicco-Bloom, E., Lord, C, Zwaigenbaum, L, Courchesne, E., Dager, S.R., Schmitz, C, Schultz, R.T., Crawley, J., Young, L.J, 2006. The developmental neurobiology of autism spectrum disorder. Journal of Neuroscience, 26, 6897- 6906.

Garcia, V.A., Dornelles, A.S., Presti-Torres, J., Alcalde, L.A., Halmenschlager, L.H., Schwartsmann, G., Roesler, R., Lucion, A.B., Schroder, N. 2010. Neonatal gastrin-releasing peptide receptor blockade reduces maternal odor preference in rats. Behavioural Brain Research, 214, 456-459.

Ishikawa-Brush, Y., Powell, J.F., Bolton, P., Miller, A.P., Francis, F., Willard, H.F., Lehrach, H., Monaco, A.P. 1997. Autism and multiple exostoses associated with an X;8 translocation occurring within the GRPR gene and 30 to the SDC2 gene. Human Molecular Genetics, 6, 1241-1250.

Jensen, R.T., Battey, J.F., Spindel, E.R., Benya, R.V. 2008. International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharmacological Reviews, 60, 1-42. Meller, C.A., Henriques, J.A.P., Schwartsmann, G., Roesler, R. 2004. The bombesin/gastrin releasing peptide receptor antagonist RC-3095 blocks apomorphine but not MK-801 -induced stereotypy in mice. Peptides, 25, 585- 588.

Presti-Torres, J., de Lima, M.N., Scalco, F.S., Caldana, F., Garcia, V.A., Guimaraes, M.R., Schwartsmann, G., Roesler, R., Schroder, N. 2007. Impairments of social behavior and memory after neonatal gastrin-releasing peptide receptor blockade in rats: Implications for an animal model of neurodevelopmental disorders. Neuropharmacology, 52, 724-732.

Presti-Torres, J., Garcia, V.A., Dornelles, A., Halmenschlager, L.H., Alcalde, L.A., Vedana, G., Rico, E.P., Bogo, M.R., Schwartsmann, G., Roesler, R., Schroder N. 2012. Rescue of social behavior impairment by clozapine and alterations in the expression of neuronal receptors in a rat model of neurodevelopmental impairment induced by GRPR blockade. Journal of Neural Transmission, 119, 319-327.

Roesler, R., Henriques, J.A.P., Schwartsmann, G., 2006. Gastrin-releasing peptide receptor as a molecular target for psychiatric and neurological disorders. CNS and Neurological Disorders Drug Targets, 5, 197-204.

Seidita, G., Mirisola, M., D'Anna, R.P., Gallo, A., Jensen, R.T., Mantey, S.A., Gonzalez, N., Falco, M., Zingale, M., Elia, M., Cucina, L, Chiavetta, V., Romano, V., Cali, F. 2008. Analysis of the gastrin-releasing peptide receptor gene in Italian patients with autism spectrum disorders. American Journal of Medical Genetics. Part B, 147B, 807-813.

Claims

1. A method for treating symptoms in a subject afflicted by a neuropsychiatric or neurodevelopmental disorder, characterized by administering to the subject a therapeutically effective amount of a gastrin-releasing peptide receptor (GRPR) agonist.

2. The method of claim 1 , wherein the subject is a human.

3. The method of claim 1 , wherein the symptom is a stereotyped behavior.

4. The method of claim 1 , wherein the symptom is an impairment of social behavior.

5. The method of claim 1 , wherein the symptom is an obsessive behavior.

6. The method of claim 1 , wherein the neuropsychiatric or neurodevelopmental disorder is an autism spectrum disorder (ASD), preferentially classic autism, Asperger syndrome, or Pervasive Developmental Disorder - Not Otherwise Specified ("atypical" autism).

7. The method of claim 1 , wherein the neuropsychiatric or neurodevelopmental disorder is Rett syndrome.

8. The method of claim 1 , wherein the neuropsychiatric or neurodevelopmental disorder is Angelman syndrome.

9. The method of claim 1 , wherein the neuropsychiatric or neurodevelopmental disorder is cerebral palsy. Z

10. The method of claim 1, wherein the neuropsychiatric or neurodevelopmental disorder is schizophrenia.

11. The method of claim 1 , wherein the neuropsychiatric or neurodevelopmental disorder is obsessive-compulsive disorder (OCD).

12. The method of claim 1 , wherein the neuropsychiatric or neurodevelopmental disorder is mental retardation.

13. The method of claim 1 , wherein the neuropsychiatric or neurodevelopmental disorder is a mood disorder, preferentially major depressive disorder.

14. The method of claim 1 , wherein the neuropsychiatric or neurodevelopmental disorder is tardive dyskinesia.

15. The method of claim 1 , wherein the neuropsychiatric or neurodevelopmental disorder is stereotypic movement disorder.

16. The method of claim 1 , wherein the neuropsychiatric or neurodevelopmental disorder is frontotemporal dementia.

17. The method of claim 1 , wherein the GRPR agonist is gastrin-releasing peptide (GRP; Ala-Pro-Val-Ser-Val-Gly-Gly-Gly-Thr-Val-Leu-Ala-Lys-Met-Tyr- Pro-Arg-Gly-Asn-His-Trp-Ala-Val-Gly-His-Leu-Met-NH2).

18. The method of claim 1 , wherein the GRPR agonist is bombesin (Pyr-Gln- Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met NH2).

19. Pharmaceutical compositions characterized by containing human recombinant GRP dissolved in saline solution (NaCI 0.9%).