Methods for the prophylaxis and treatment of autism related disorders

Abstract

The present invention recognizes that there is a need for the prophylaxis or treatment of Autism Related Disorders, which includes but is not limited to Autism Spectrum Disorder, Autism, Autistic Disorder, Asperger Syndrome, Rett Syndrome Fragile X syndrome, Phelan-McDermid Syndrome, Angelman Syndrome, Pitt Hopkins Syndrome, Prader-Willi Syndrome, or combinations thereof. A first aspect of the present invention generally relates to methods of prophylaxis or treatment of Autism Related Disorders using various pharmaceutical compositions. A second aspect of the present invention generally relates to pharmaceutical compositions used for the prophylaxis or treatment of Autism Related Disorders.

Description

[0001] Title METHODS FOR THE PROPHYLAXIS AND TREATMENT OF AUTISM RELATED DISORDERS Cross Reference to Related Applications The present application: claims benefit of priority to United States Provisional Application Serial No.63 / 557,559, filed February 25, 2024; each of which is incorporated by reference herein in its entirety. Technical Field The present invention relates generally to the fields of treatment and prophylaxis of Autism Related Disorders, which includes but is not limited to Autism Spectrum Disorder, Autism, Autistic Disorder, Asperger Syndrome, Rett Syndrome Fragile X syndrome, Phelan-McDermid Syndrome, Angelman Syndrome, Pitt Hopkins Syndrome, Prader-Willi Syndrome, or combinations thereof. Background Autism Related Disorders, a term that is utilized and possibly originates in the present application, refers to disorders that have at least some symptoms of the various forms of Autism. Autism Related Disorders includes but is not limited to Autism Spectrum Disorder, Autism, Autistic Disorder, Asperger Syndrome, Rett Syndrome, Fragile X syndrome, Phelan-McDermid Syndrome, Angelman Syndrome, Pitt Hopkins Syndrome, Prader-Willi Syndrome, or combinations thereof. Autism Spectrum Disorders (ASD), a subset of Autism Related Disorder, is a developmental disability caused by differences in the brain. Some people with ASD have a known difference, such as a genetic condition. Other causes are not yet known. Autism spectrum disorders (ASD) are a collection of linked developmental disorders, characterized by abnormalities in social interaction and communication, and repetitive behaviors. Current classification of ASD recognizes various forms: classical autism or Autistic Disorder, Asperger syndrome, Rett syndrome, and related disorders including but not limited to Fragile X Syndrome, Phelan-McDermid Syndrome, Angelman Syndrome, Pitt Hopkins Syndrome, Prader-Willi Syndrome, and combinations thereof. Diagnosing ASD can be difficult since there is no medical test, like a blood test, to diagnose the disorder. ASD can sometimes be detected at 18 months of age or younger. By age two, a diagnosis by an experienced professional can be considered reliable. However, many children do not receive a final diagnosis until they are much older. Some people are not diagnosed until they are adolescents or adults. This delay means that people with ASD might not get the early help they need. There is currently no effective treatment for Autism Spectrum Disorders (ASD), and patient care is limited to managing symptoms. Trofinetide (DAYBUE) was recently approved by the U.S. FDA for the treatment of patients with Rett Syndrome. Its chemical name is glycyl-L-2-methylprolyl-L-glutamic acid. It is a synthetic analog of glycine-proline-glutamate (GPE), a tripeptide produced by the enzymatic cleavage of Insulin-like Growth Factor 1 (IGF-1). (https: / / go.drugbank.com / drugs / DB05633) The structure of Trofinetide differs from that of GPE as to a CH₃ group. The chemical formula of GPE is C₁₂H₁₉N₃O₆, with an average molecular weight of 301.299 g / mol. The chemical of Trofinetide is chemical formula is C13H21N3O6with an average molecular weight of 315.326. (https: / / go.drugbank.com / drugs / DB06045) GPE has lower stability than cPG, which is counted in minutes of half-life in the plasma and around half an hour in the brain and cerebrospinal fluid. As shown in Tran’s US Patent 7,232,798 , glycine-proline-glutamate is metabolized to cyclo prolyl glycine. Thus, Trofinetide is thought to be a prodrug of cyclo prolyl glycine. The risks associated with Trofinetide use did not preclude approval. The most common adverse events were of gastrointestinal nature, including serious diarrhea and vomiting. According to the FDA’s prescription information of Trofinetide, https: / / www.accessdata.fda.gov / drugsatfda_docs / label / 2023 / 217026s000lbl.pdf. In the Phase 3 clinical study and in long-term studies, 85% of patients treated with DAYBUE experienced diarrhea. In those treated with DAYBUE, 49% either had persistent diarrhea or recurrence after resolution despite dose interruptions, reductions, or concomitant antidiarrheal therapy. Diarrhea severity was of mild or moderate severity in 96% of cases. This is a clinically meaningful risk in a pediatric population. The FDA recommended that warnings for the clinical significance of diarrhea and weight loss were to be added to the product label. (Camillo L, Pozzi M, Bernardo P, Pisano S, Nobile M. Profile of Trofinetide in the Treatment of Rett Syndrome: Design, Development and Potential Place in Therapy. Drug Des Devel Ther.2024 Nov 6;18:5023-5040. doi: 10.2147 / DDDT.S383133. PMID: 39525048; PMCID: PMC11550706.). GPE and its analog Trofinetide are believed to be metabolized to cyclo prolyl glycine as described in the US patent 7,232,798 (Tran). In the present invention, it is postulated that the adverse effects of Trofinetide is due to the fact that it is metabolized to cyclic Prolyl Glycine (cPG) and Glutamic Acid, the latter is the main cause of gastrointestinal disturbance. Glutamic acid is the main excitatory neurotransmitter in the body, and multiple glutamate receptors and transporters have been found in the gastrointestinal tract and enteric nervous system. High doses of glutamate can induce neurotoxicity (Annette L Kirchgessner (2001). Glutamate in the enteric nervous system. , 1(6), 0–596. doi:10.1016 / s1471-4892(01)00101-1 ) (Olney, J. W.; Sharpe, L. G. (1969). Brain Lesions in an Infant Rhesus Monkey Treated with Monosodium Glutamate. Science, 166(3903), 386–388. doi:10.1126 / science.166.3903.386) The present invention relates to synthetic analogs and peptidomimetics of cyclic Prolyl Glycine (cPG). In particular, this invention relates to cPG analogs and peptidomimetics, to methods of making them, to pharmaceutical compositions containing them, and to their use for the treatment of neurodegenerative diseases. In the present invention, we present clinical trial results demonstrating the unexpected efficacy of cPG in treating Rett Syndrome, achieving significantly better outcomes than Trofinetide without serious adverse effects. Summary The present invention recognizes that there is a need for the prophylaxis or treatment of Autism Related Disorders, which includes but is not limited to Autism Spectrum Disorder, Autism, Autistic Disorder, Asperger Syndrome, Rett Syndrome Fragile X syndrome, Phelan-McDermid Syndrome, Angelman Syndrome, Pitt Hopkins Syndrome, Prader-Willi Syndrome, or combinations thereof. A first aspect of the present invention generally relates to methods of prophylaxis or treatment of Autism Related Disorders using various pharmaceutical compositions. A second aspect of the present invention generally relates to pharmaceutical compositions used for the prophylaxis or treatment of Autism Related Disorders. Brief Description of the Figures FIG.1 generally depicts in graphic form Glutamate toxicity in cerebellar microexplants (P4) and rescue effect by cyclic GP. FIG.2 generally depicts in graphic form prevention of glutamate toxicity by cyclic GP monitored within P4-cerebellar microexplants. FIG.3 generally depicts in graphic form effects of cPG on functional recovery after 6- OHDA lesion. FIG.4 generally depicts the time to reach platform. Morris Water Maze (MWM) Model of Learning and Memory Used to Assess Effects of cyclic Prolyl Glycine on Cognitive Function. FIG.5 generally depicts the impact of BrdU + Cells / 300 micrometer at sub ventricular zone for cPG, cGMeP and c(PG)3 drug solutions. FIG.6 generally depicts the impact of BrdU + Cells / 300 micrometer at dentate gyrus for cPG, c(PG)3 cGMeP and drug solutions. FIG.7 generally depicts the Mean (s.e.m) Change From Baseline in RSBQ Total Score vs. Time. FIG.8 generally depicts the Clinical Global Impression–Improvement-Scale Score vs. Time Detailed Description of the Invention Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, chemistry, microbiology, molecular biology, cell science and cell culture described below are well known and commonly employed in the art. Conventional methods are used for these procedures, such as those provided in the art and various general references. Where a term is provided in the singular, the plural of that term is contemplated; and where a term is provided in the plural, the singular of that term is contemplated. The nomenclature used herein and the laboratory procedures described below are those well-known and commonly employed in the art. As employed throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings: “Directly” refers to direct causation of a process that does not require intermediate steps. “Indirectly” refers to indirect causation that requires intermediate steps. “About” refers to plus or minus 10% of the indicated value. Autism Related Disorders, a term that is utilized and possibly originates in the present application, refers to disorders that have at least some symptoms of the various forms of Autism. Autism Related Disorders includes but is not limited to Autism Spectrum Disorder, Autism, Autistic Disorder, Asperger Syndrome, Rett Syndrome, Fragile X syndrome, Phelan-McDermid Syndrome, Angelman Syndrome, Pitt Hopkins Syndrome, Prader-Willi Syndrome, or combinations thereof. Autism Spectrum Disorders (ASD), a subset of Autism Related Disorder, is a developmental disability caused by differences in the brain. Some people with ASD have a known difference, such as a genetic condition. Other causes are not yet known. Autism spectrum disorders (ASD) are a collection of linked developmental disorders, characterized by abnormalities in social interaction and communication, and repetitive behaviors. Current classification of ASD recognizes various forms: classical autism or Autistic Disorder, Asperger syndrome, Rett syndrome, and related disorders including but not limited to Fragile X Syndrome, Phelan-McDermid Syndrome, Angelman Syndrome, Pitt Hopkins Syndrome, Prader-Willi Syndrome, and combinations thereof. Other technical terms used herein have their ordinary meaning in the art that they are used, as exemplified by a variety of technical dictionaries. Introduction The present invention recognizes that there is a need for the prophylaxis or treatment of Autism Related Disorders, which includes but is not limited to Autism Spectrum Disorder, Autism, Autistic Disorder, Asperger Syndrome, Rett Syndrome Fragile X syndrome, Phelan-McDermid Syndrome, Angelman Syndrome, Pitt Hopkins Syndrome, Prader-Willi Syndrome, or combinations thereof. As a non-limiting introduction to the breath of the present invention, the present invention includes several general and useful aspects, including: 1) methods of prophylaxis or treatment of Autism Related Disorders using various pharmaceutical compositions. 2) pharmaceutical compositions used for the prophylaxis or treatment of Autism Related Disorders. These aspects of the invention, as well as others described herein, can be achieved by using the methods, articles of manufacture and compositions of matter described herein. To gain a full appreciation of the scope of the present invention, it will be further recognized that various aspects of the present invention can be combined to make desirable embodiments of the invention. I. METHODS OF TREATMENT OF AT LEAST ONE AUTISM RELATED DISORDERS A first aspect of the present invention includes a method of prophylaxis or treatment of at least one Autism Related Disorder, including: (a) providing a subject in need of the prophylaxis or treatment of at least one Autism Related Disorder; (b) providing at least one pharmaceutical composition including: 1) at least one cPG compound, optionally in combination with one or more of the following components; a. at least one IGF-1 compound; b. at least one Des-(1-3) IGF-1 compound; or combinations thereof; wherein the components are administered together or separately; further wherein the components are provided together or separately; c. administering a pharmaceutically effective amount of the at least one pharmaceutical composition to the subject; wherein the subject is provided prophylaxis or treatment of the at least one Autism Related Disorder. A. COMPONENTS An aspect of the present invention includes wherein the components are provided in a pharmaceutically acceptable diluent, adjuvant, excipient, or combinations thereof. Another aspect of the present invention includes wherein the components, individually or combinations thereof, are provided as or in a pharmaceutically acceptable salt. A further aspect of the present invention includes wherein the components are administered separately. An additional aspect of the present invention includes wherein the components are administered together. B. PROPHYLAXIS / TREATMENT OF RETT SYNDROME An aspect of the present invention includes wherein the prophylaxis or treatment of the at least one Autism Related Disorder includes Rett Syndrome, Autism Spectrum Disorder, Autism, Autistic Disorder, Asperger Syndrome, Fragile X syndrome, Phelan-McDermid Syndrome, Angelman Syndrome, Pitt Hopkins Syndrome, Prader-Willi Syndrome, or combinations thereof. Another aspect of the present invention includes wherein the prophylaxis or treatment of the at least one Autism Related Disorder includes developmental delays, learning disabilities, social problems, behavior problems, anxiety, depression, obsessive-compulsive behaviors or combinations thereof. C. cPG COMPOUND A further aspect of the present invention includes wherein the at least one cPG compound includes at least one of Cyclic Prolyl Glycine, Cyclic Glycyl-2-Allyl Proline, Cyclic (glycyl-L- prolylglycyl-L-prolylglycyl-L-prolyl), or combinations thereof. An additional aspect of the present invention includes wherein the at least one cPG compound includes Cyclic Prolyl Glycine. An aspect of the present invention includes wherein the Cyclic Prolyl Glycine is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg. Another aspect of the present invention includes wherein the Cyclic Prolyl Glycine is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg. A further aspect of the present invention includes the Cyclic Prolyl Glycine is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg. An additional aspect of the present invention includes wherein the Cyclic Prolyl Glycine is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg. An aspect of the present invention includes wherein the at least one pharmaceutical composition comprising Cyclic Prolyl Glycine is administered about once a day, about twice a day, or combinations thereof. Another aspect of the present invention includes wherein the at least one pharmaceutical composition comprising Cyclic Prolyl Glycine is administered orally, intranasally, or combinations thereof. A further aspect of the present invention includes wherein the at least one cPG compound includes Cyclic Glycyl-2-Allyl Proline. An additional aspect of the present invention includes wherein the Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 0.5 mg to 10.0 mg / kg. An aspect of the present invention includes wherein the Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg. Another aspect of the present invention includes wherein the Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg. A further aspect of the present invention includes wherein the Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg. An additional aspect of the present invention includes wherein the at least one pharmaceutical composition comprising Cyclic Glycyl-2-Allyl Proline is administered about once a day, about twice a day, or combinations thereof. An aspect of the present invention includes wherein the at least one pharmaceutical composition comprising Cyclic Glycyl-2-Allyl Proline is administered orally, intranasally, or combinations thereof. Another aspect of the present invention includes wherein the at least one cPG compound includes Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl). A further aspect of the present invention includes wherein the Cyclic (glycyl-L-prolylglycyl- L-prolylglycyl-L-prolyl) is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg. An additional aspect of the present invention includes wherein the Cyclic (glycyl-L- prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg. An aspect of the present invention includes wherein the Cyclic (glycyl-L-prolylglycyl-L- prolylglycyl-L-prolyl) is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg. Another aspect of the present invention includes wherein the Cyclic (glycyl-L-prolylglycyl- L-prolylglycyl-L-prolyl) is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg. A further aspect of the present invention includes wherein the at least one pharmaceutical composition comprising Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is administered about once a day, about twice a day, or combinations thereof. An additional aspect of the present invention includes wherein the at least one pharmaceutical composition comprising Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is administered orally, intranasally, or combinations thereof. D. IGF-1 COMPOUND An aspect of the present invention includes wherein the at least one IGF-1 compound includes at least one of: a) at lest one IGF-1; b) at least one IGF-2; c) at least one IGF receptor (IGF- 1R); d) at least one IGF binding proteins (IGFBP);ve) or combinations thereof. Another aspect of the present invention includes wherein the at least one IGF-1 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously; c) administered about twice daily; d) administered for about six months; d) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof. A further aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-1 compound is administered subcutaneously, orally, intranasally, or combinations thereof. An additional aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-1 compound is administered about once a day, about twice a day, about once a week, or about twice a week, or combinations thereof. An aspect of the present invention includes wherein the at least one IGF-1 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously; c) administered about twice daily; d) administered for about six months; d) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof. Another aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-1 compound is administered subcutaneously, orally, intranasally, or combinations thereof. A further aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-1 compound is administered about once a day, about twice a day, about once a week, or about twice a week or combinations thereof. An additional aspect of the present invention includes wherein the at least one IGF-2 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously; c) administered about twice daily; d) administered for about six months; c) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof. An aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-2 compound is administered subcutaneously, orally, intranasally, or combinations thereof. Another aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-2 compound is administered once a week, twice a week or combinations thereof. A further aspect of the present invention includes wherein the at least one IGF-2 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously; c) administered about twice daily; d) administered for about six months; e) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; f) or combinations thereof. An additional aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-2 compound is administered subcutaneously, orally, intranasally, or combinations thereof. An aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-2 compound is administered about once a day, about twice a day, about once a week, or about twice a week, or combinations thereof. E. DES (1-3)-IGF-1 COMPOUND Another aspect of the present invention includes wherein the at least one des-(1-3)-IGF-1 compound includes at least one of: a) Des-(1-3)IGF-1 which is truncated for the N-terminal tripeptide; b) R3IGF-1 that is substituted by arginine for glutamic acid at position 3; c) LONGTMR3IGF-1 whose N-terminus is prolonged by additional 13 residues compared with R3IGF-1; d) or combinations thereof. A further aspect of the present invention includes wherein the at least one pharmaceutical composition including at least one Des-(1-3) IGF-1 compound is: a) provided in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) is administered subcutaneously; c) is administered about twice / day; d) is administered for about six months; e) is administered for the first and the last weeks at a dose of about 0.05 mg / Kg and during the remaining periods administered at a dose of about 0.1mg / Kg; f) or combinations thereof. An additional aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one Des-IGF-1 compound is administered subcutaneously, orally, intranasally, or combinations thereof. An aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one Des-IGF-1 compound is administered about once a day, about twice a day, about once a week, or about twice a week, or combinations thereof. F. OUTCOMES Another aspect of the present invention includes wherein the prophylaxis or treatment of the at least one Autism Related Disorder results in global improvement in symptoms related thereto, including language, communication, ambulation, hand movements, social (eye contact), autonomic features, seizures, and attentiveness, and improvement of common Rett symptoms, such as breathing, nighttime behaviors, eye gaze, vocalizations, mood, repetitive behaviors, facial expressions, or combinations thereof. A further aspect of the present invention includes wherein the prophylaxis or treatment of the at least one Autism Related Disorder is prophylaxis. An additional aspect of the present invention includes wherein the prophylaxis or treatment of the at least one Autism Related Disorder is treatment. G. SUBJECT An aspect of the present invention includes wherein the subject is a human. H. ADMINSTERED TOGETHER OR SEPARATELY Another aspect of the present invention includes wherein the components are administered together in a single or multiple doses. A further aspect of the present invention includes wherein the components are administered separately in a single or multiple doses. I. PROVIDED TOGETHER OR SEPARATELY An additional aspect of the present invention includes wherein the components are provided together in a single or multiple containers. An aspect of the present invention includes wherein the components are provided separately in a single or multiple containers. J. GENERAL AND PREFERRED ASPECTS OF THE PRESENT INVENTION Another aspect of the present invention includes wherein the at least one cPG compound is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg. A further aspect of the present invention includes wherein the at least one cPG compound is provided by a route of administration of injection, orally, intranasally, intraperitoneal, intravenous, subcutaneous, or combinations thereof. An additional aspect of the present invention includes wherein the at least one cPG compound is provided in a regime of between once per hour to about once per three months. II. PHARMACEUTICAL COMPOSITIONS A second aspect of the present invention includes a pharmaceutical composition for the prophylaxis or treatment of at least one Autism Related Disorder, including at least one of: a) at least one cPG compound, optionally in combination with; b) at least one IGF-1 compound; c) at least one IGF-2 compound; d) at least one Des (1-3) IGF-1 compound; e) combinations thereof; wherein the components are provided together or separately; further wherein the pharmaceutical composition when administered to a subject in need of prophylaxis or treatment of obesity is so prevented from or treated for the at least one Autism Related Disorder. Any of the components disclosed and described herein can be used as components in this aspect of the present invention, including but not limited to the cPG compounds, the additional compounds such as but not limited to IGF-1 compounds, Des-(1-3) IGF-1 compounds, or combinations thereof. III. DETAILED DESCRIPTION OF CERTAIN ASPECTS AND EMBODIMENTS OF THE PRESENT INVENTION The present invention is directed in part towards compounds that are effective in preventing and treating Autism Related Disorders, which includes but is not limited to Autism Spectrum Disorder, Autism, Autistic Disorder, Asperger Syndrome, Rett Syndrome, Fragile X syndrome, Phelan-McDermid Syndrome, Angelman Syndrome, Pitt Hopkins Syndrome, Prader-Willi Syndrome, or combinations thereof. Autism Spectrum Disorders (ADSs): Autism Spectrum Disorders (ADSs) are a collection of linked developmental disorders, characterized by abnormalities in social interaction and communication, restricted interests and repetitive behaviors. Current classification of ASDs recognizes various distinct forms: classical autism or Autistic Disorder, Asperger syndrome, Rett syndrome, and related disorders including but not limited to Fragile X Syndrome, Phelan-McDermid Syndrome, Angelman Syndrome, Pitt Hopkins Syndrome, Prader-Willi Syndrome, and combinations thereof. Autism: Autism is a neurodevelopmental disorder "characterized by persistent deficits in social communication and social interaction across multiple contexts" and "restricted, repetitive patterns of behavior, interests, or activities". (Diagnostic and Statistical Manual of Mental Disorders(5th ed.) (DSM-5). American Psychiatric Association.2013. p.31.). Common symptoms of Autism Spectrum Disorder include: a) Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history (examples are illustrative, not exhaustive): b) Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at least two of the following, currently or by history (examples are illustrative, not exhaustive): c). Symptoms must be present in the early developmental period (but may not become fully manifest until social demands exceed limited capacities or may be masked by learned strategies in later life). d) Symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning. e) These disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur; to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication should be below that expected for general developmental level. The precise causes of autism are unknown in most individual cases. Research shows that the disorder is highly heritable and polygenic, and neurobiological risks from the environment are also relevant. There is no known cure for autism. Asperger Syndrome: Asperger syndrome (AS), also known as Asperger's syndrome or Asperger's, is a diagnostic label that has historically been used to describe a neurodevelopmental disorder characterized by significant difficulties in social interaction and nonverbal communication, along with restricted, repetitive patterns of behavior and interests. Asperger syndrome has been merged with other conditions into autism spectrum disorder (ASD) and is no longer a diagnosis in the WHO's ICD-11 or the APA's DSM-5-TR. It was considered milder than other diagnoses which were merged into ASD due to relatively unimpaired spoken language and intelligence. Rett Syndrome: Rett Syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects females (1 in 10:000 live births). Approximately 16,000 patients are currently affected by it in the U.S.A. (Rett Syndrome Research Trust data). Rett syndrome (RTT), first described by Andreas Rett in 1966, is a neurological disorder that predominantly affects girls. [Hagberg, B., and Hagberg, G. (1997). Rett syndrome: epidemiology and geographical variability. Eur. Child Adolesc. Psychiatry 6 (Suppl 1), 5–7). RTT is classified as an autism spectrum disorder (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition—Revised (DSM-IV-R). The onset of RTT usually begins between 6-18 months of age with a slowing of development and growth rates. The outcome of the Rett Syndrome occurs through different clinical stages: the onset corresponds to an interruption of growth and a decrease in the head circumference growth (stage 1) followed by a second stage with autistic features and regression of acquired skills (language, motor abilities, and purposeful use of hands), appearance of seizures, hand stereotypes, alteration in the cardiorespiratory function, and problems with the autonomic system. The third stage is characterized by a reduction of autistic symptoms, appearance of scoliosis and seizures, followed by a late regression (stage 4). There are several pathologies associated with RTT, one of which is breathing difficulties. Most RTT patients survive into adulthood with severe disabilities and require 24-hour-a-day care. (B. Hagberg and I. Witt- Engerstrom, “Rett syndrome: a suggested staging system for describing impairment profile with increasing age towards adolescence,” American Journal of Medical Genetics, vol.24, no.1, pp.47– 59, 1986.). Between 85% and 95% cases of RTT are reported to be caused by a mutation of the MeCP2 gene. MeCP2 maps to the X-chromosome (location Xq28) and for this reason, mutations to the gene in males are usually lethal. While RTT is a genetic disorder, less than 1% of recorded cases are inherited; almost all mutations of Mecp2 occur de novo, with two thirds caused by mutations at 8 CPG dinucleotides (R106, R133, T158, R168, R255, R270, R294 and R306) located on the third and fourth exons. Rett syndrome cases are caused by a mutation within the Methylcytosine-binding protein 2 (MECP2) gene. The MECP2gene is located on the X chromosome. Other Diseases related to Rett Syndrome • Fragile X syndrome • Phelan-McDermid syndrome • Angelman syndrome • Pitt Hopkins syndrome • Prader-Willi syndrome Fragile X syndrome Fragile X syndrome (FXS) is a genetic disorder caused by changes in a gene called fragile X messenger ribonucleoprotein 1 (FMR1). FMR1 usually makes a protein called FMRP that is needed for brain development. People who have FXS do not make this protein. Those with fragile X- associated disorders have changes in the FMR1 gene but usually still make some of the protein. FXS affects both males and females. However, females often have milder symptoms than males. The exact number of people who have FXS is unknown, but a review of research studies estimated that about 1 in 7,000 males and about 1 in 11,000 females have been diagnosed with FXS. Signs that a child might have FXS include • Developmental delays (not sitting, walking, or talking at the same time as other children the same age); • Learning disabilities (trouble learning new skills); and • Social and behavior problems (such as not making eye contact, anxiety, trouble paying attention, hand flapping, acting and speaking without thinking, and being very active). • Anxiety. • Depression. • Obsessive-compulsive behaviors. Males who have FXS usually have some degree of intellectual disability that can range from mild to severe. Females with FXS can have normal intelligence or some degree of intellectual disability. Autism spectrum disorder (ASD) also occurs more frequently in people with FXS. There is no cure for FXS. However, treatment services can help people learn important skills. Phelan-McDermid syndrome (caused by mutations in SHANK3) SHANK3 and MECP2 are genes linked to neurological development and are considered related because they both play crucial roles in the function of synapses within the brain, with mutations in either gene being associated with autism spectrum disorders (ASDs) like Rett syndrome; mutations in MECP2 primarily cause Rett syndrome, while mutations in SHANK3 are associated with Phelan-McDermid syndrome and can also contribute to ASDs. Phelan-McDermid syndrome (PMS) is a rare genetic disorder caused by a deletion or mutation in the SHANK3 gene on chromosome 22. It is characterized by a range of developmental and behavioral symptoms, including: Developmental Delays: • Significant delays in acquiring motor skills, such as crawling, walking, and talking • Intellectual disability • Regression in previously acquired skills Behavioral Issues: Autism spectrum disorder (ASD), Social and communication difficulties, Repetitive behaviors, and Seizures. Physical Features: • Dysmorphic features, such as a long face, prominent ears, and a small chin • Muscle weakness and hypotonia (low muscle tone) • Joint stiffness • Scoliosis Other Symptoms: • Gastrointestinal problems, such as reflux and vomiting • Heat intolerance • Reduced pain sensation There is currently no cure for PMS. Angelman Syndrome (caused by mutations in UBE3A) MECP2 and UBE3A are related, as both genes play a significant role in neurodevelopment, and mutations in either can lead to neurological disorders; specifically, mutations in MECP2 cause Rett syndrome, while mutations in UBE3A cause Angelman syndrome, and studies have shown that MECP2 deficiency can impact the expression of UBE3A, indicating a functional link between the two genes. Overview Angelman syndrome is caused by changes in a gene, called a genetic change. It's most often caused by changes in a gene on chromosome 15 called the ubiquitin protein ligase E3A (UBE3A) gene. Angelman syndrome causes delayed development, problems with speech and balance, mental disability, and, sometimes, seizures. Many people with Angelman syndrome smile and laugh often. They tend to be happy and easy to excite. Delays in maturing, called developmental delays, begin between about 6 and 12 months of age. The delays often are the first signs of Angelman syndrome. Seizures may begin between the ages of 2 and 3 years old. People with Angelman syndrome tend to live close to a typical life span. But the condition can't be cured. Treatment focuses on managing medical, sleep and developmental issues. Symptoms Angelman syndrome symptoms include: • Developmental delays, including no crawling or babbling at 6 to 12 months. • Mental disability, also called intellectual disability. • No speech or little speech. • Trouble walking, moving or balancing. • Smiling and laughing often and seeming happy. • Being easy to excite. • Trouble sucking or feeding. • Trouble going to sleep and staying asleep. Pitt-Hopkins syndrome (caused by mutations in MECP2) MECP2 and TCF4 are related in that they both play significant roles in brain development and function, and research has shown that their interactions can impact neurodevelopmental disorders like Rett syndrome (associated with MECP2 mutations) and Pitt-Hopkins syndrome (associated with TCF4 mutations); essentially, while they are distinct genes, their pathways can overlap and influence each other's function at the molecular level. Pitt-Hopkins syndrome is a rare genetic disorder characterized by intellectual disability, developmental delays, and distinctive facial features. Causes: Pitt-Hopkins syndrome is caused by mutations in the TCF4 gene, which plays a role in brain development. Symptoms: • Intellectual disability • Developmental delays • Seizures • Breathing problems, such as hyperventilation and apneic spells • Distinctive facial features, including a small head (microcephaly), wide eyes, and a prominent lower lip • Poor coordination • Delayed speech or lack of speech • Gastrointestinal problems, such as constipation There is no cure for Pitt-Hopkins syndrome. Prader-Willi syndrome (caused by abnormalities on chromosome 15q11-q13) MECP2 is related to the 15q11-q13 region on chromosome 15, as research suggests that mutations in MECP2 can affect the expression of genes located within this region, particularly the GABRB3 gene, which is implicated in neurodevelopmental disorders like autism and is often associated with abnormalities on chromosome 15q11-q13; essentially, MECP2 dysfunction can lead to dysregulation of gene expression within this region. Prader-Willi syndrome (PWS) is a rare genetic disorder that affects multiple body systems. It is caused by a deletion or mutation of genes on chromosome 15. PWS affects between 1 in 10,000 to 30,000 people worldwide. The condition is named after Swiss physicians Andrea Prader and Heinrich Willi who, together with Alexis Labhart, described it in detail in 1956. An earlier description was made in 1887 by British physician John Langdon Dow Symptoms: • Infancy: • Weak muscle tone (hypotonia) • Feeding difficulties • Slow growth • Delayed development • Childhood: • Insatiable appetite, leading to obesity • Intellectual disability • Behavioral problems, such as tantrums, stubbornness, and obsessive-compulsive behaviors • Sleep disturbances • Adolescence and Adulthood: • Short stature • Endocrine problems, such as hypothyroidism and diabetes • Osteoporosis • Skin picking and other compulsive behaviors • Delayed puberty • Infertility Treatment: There is no cure for PWS, but management can improve symptoms and quality of life. The present invention relates to an improved use of cPG Compound in therapy for Autism Related Disorders. In one aspect of the present invention certain dosage regimes of cPG Compounds are indicated which provide improved effect in diseases or conditions, such as prevention and / or treatment of Autism Related Disorder. Treatment of Clinical Autism Related Disorders (ASD) and ASD Animal Models With cPG A conserved pathology is observed in ASDs that include impaired neurite development, impaired synaptic connectivity and a corresponding impairment in social and cognitive functioning as a result. Such synaptic dysfunctions result from genetically altered functions of postsynaptic density proteins. Normal neurite growth and postsynaptic development may be regulated and augmented by growth factors such as brain derived neurotrophic factor (BDNF; Chapleau et al, 2009) and insulin-like growth factor-1 (IGF-1; Riikonen et al, 2006; Tropea et al, 2009). One MeCP2 target is a neuronal activity-dependent gene, brain-derived neurotrophic factor (BDNF) which plays an important role in neuronal survival and growth, serves as a neurotransmitter modulator, and participates in neuronal plasticity, which is essential for learning and memory. In cultured neonatal cortical neurons, basal BDNF transcription is repressed by MeCP2 in the absence of neuronal activity, but activity-dependent upregulation of BDNF is unaffected by MeCP2 deletion. Chang et al reported that BDNF protein level in the whole-brain lysate in MeCP2 mutant mice is decreased to about 70% of the wild-type level. They discovered that deleting BDNF from the MeCP2 mutant brain resulted in an earlier onset / accelerated disease progression, whereas over- expressing BDNF in the MeCP2 mutant brain led to later onset / slower disease progression. It was suggested that that manipulating the BDNF level or the BDNF signaling pathways may present therapeutic opportunities for RTT patients. (Q. Chang, G. Khare, V. Dani, S. Nelson, and R. Jaenisch, “The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression,” Neuron, vol.49, no.3, pp.341–348, 2006.). In addition, IGF-1 is essential for normal dendritic spine growth and synapse formation (Cheng et al., 2003J Neurosci Res.73:1-9). Drugs that promote growth factor function are therefore of use in the treatment of progressive developmental disorders such as ASDs. Autism, Rett Syndrome and Fragile X Syndrome are characterized by defects in synaptic function and neuronal connectivity. This is reflected in animal models which are based on genetic changes known to be pathological in these disorders. In these animal models, neuronal connectivity defects are revealed morphologically, and also as a failure of Long Term Potentiation (LTP). It has been demonstrated that IGF-1increases synapse formation. Cyclic Prolyl Glycine (cPG) is a small molecule drug, which is a metabolite of analog of the terminal tripeptide of IGF-1, IGF1(1-3). As an IGF-1 mimetic analog, cPG exerts trophic and neuroprotective effects in various animal models. (Lloyd Tran-US Patent # US7232798 US and 11,090,303). In the present invention, methods of using cPG as a viable effective at treating Rett Syndrome or other symptoms relating to synaptic dysfunctions such as but not limited to those resulting from the gene mutations described above are provided. In one aspect of the present invention an "effective amount" or “pharmaceutically effective amount” refers to an amount sufficient to cure, alleviate, or partially arrest the clinical manifestations of a given disease or state and its complications. An amount adequate to accomplish this is defined as "effective amount" or “pharmaceutically effective amount.” Effective amounts or pharmaceutically effective amounts for each purpose will depend on the severity of the disease or injury. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician or veterinary. A. cPG COMPOUNDS The present invention relates to a composition comprising of cyclic Prolyl Glycine (cPG) and its analogues collective referred herein as cPG Compound or at least one cPG Compound, for the treatment and prevention of Autism Related Disorders. The present invention relates to a composition comprising a metabolite of IGF-1, known a cyclic Prolyl Glycine (cPG) and its analogues collective referred herein as cPG Compound, for the treatment and prevention of Autism Related Disorders. Cyclic Glycine-Proline (cGP) regulates the homeostasis of insulin-like growth factor (IGF)-1 function and cGP / IGF-1 ratio determines IGF-1 bioactivity in vitro and in vivo. Cyclic Prolyl Glycine (“cyclic PG” or “cPG”) has the following structure: Prolyl Glycine The present invention includes novel diketopiperazines that are structurally related to cPG. One aspect of this invention provides novel cyclic compounds having the structural formula and substituents described below. cyclic Glycyl-2-Allyl Proline, or cyclic Glycyl-Alkyl Proline referred herein as “cGAL”. Where R can be an Alkyl” which refers to a saturated branched, straight chain or cyclic hydrocarbon radical. Exemplary alkyl groups include methyl, ethyl, isopropyl, cyclopropyl, tert- butyl, cyclopropylmethyl, hexyl and the like. Where R can be an Ally, which refer to a group is a substituent with the structural formula H2C=CH−CH2R, where R is the rest of the molecule. With R is a methyl, an aspect of the present invention that includes Cyclic Glycyl-2-Alkyl Proline is (8aS)-Methyl-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione, which is referred to as Cyclic Glycyl-2- Methyl-Proline or cyclicGMeP or cGMeP.

[0002] Structure 3: Cyclic G-2MeP (which is available for purchase from polypeptide suppliers such as Bachem Americas, Inc. (Torrance, California, USA)). In general, c(PG)3 and cGAL can be prepared by methods such as are already well-known to persons of ordinary skill in the art of peptide and modified peptide synthesis. See for example, Bodanzsky: Principles of Peptide Synthesis, Berlin, New York: Springer-Verlag 1993. Synthesis of the diketopiperazine compounds of this invention may be by solution-phase synthesis as discussed in the Examples or via the solid-phase synthesis method exemplified by Merrifield et al.1963 J. Amer. Chem. Soc.: 85, 2149-2156. Specific examples of diketopiperazine synthesis can be found in Fischer, 2003, J. Peptide Science: 9: 9-35 and references therein. A person of ordinary skill in the art will have no difficulty, taking account of that skill and the knowledge available, and of this disclosure, in developing one or more suitable synthetic methods for compounds of this invention. In the present application, notably but not limited to this section where compound names and structures and abbreviations are provided, the various compounds can all be used in all aspects of the present invention included herein. For example, should cPG be indicted in the specification, then all other compounds of this section (and the application as a whole) that are cPG compounds and related derivatives such as but not limited to cGAL are included in that and other descriptions, notably but not limited to methods of treatment of a variety of conditions described herein.

[0003] re for cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) The chemical synthesis of cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) was carried out as published in Israel Journal of Chemistry, Vol.12, Nos.1-2, 1974, pp.15-29 “CYCLIC Peptides VII: The Synthesis and Characterization of Cyclic Peptides with Repeating Pro-Gly Sequences- by Charles M. Deber and Elkan R. Blout. Synthesis of Cyclic (glycyl-L -prolyl-glycyl-L -prolyl-glycyl-L -prolyl) A solution of p-nitrophenyl ester hydrochloride (500 mg) dissolved in dimethyl-formamide (DMF) (20 ml, dried over sodium sulfate) was added dropwise with stirring over 6 hours to 500 ml of reagent-grade pyridine, at room temperature. The bright yellow mixture was constantly stirred over 48 hours at room temperature. Solvents were removed by rotary-evaporator-high vacuum pump system at 45°. The residue was washed with 20 ml of acetone which dissolved the p-nitrophenol and pyridine hydrochloride, but left the peptidic fraction insoluble. The insoluble materials and acetone were transferred to a flask and allow acetone to evaporate at 45°. The material was then dissolved in a minimum of DMF. The white microcrystalline precipitate was shown to be Cyc / o(glycyl-L -prolyl- glycyl-L -prolyl-glycyl-L -prolyl) (155 mg, with 28% yield), formed complexed with DMF. Crystallization from methanol-ether of 100 mg of this material gave crystalline cyclo(Pro-Gly)3(55 mg) free of DMF. Chemical analysis: Calculated for C2IH30N606H20 : C, 52.49; H, 6.71; N, 17.49. Elemental analysis found C, 52.60; H, 6.81; N, 17.38. In still other aspects, present invention provides pharmaceutical compositions including a pharmaceutically acceptable excipient or carrier and a therapeutically effective amount of cyclic GP or its analogues with structural formulas given above to treat a disease, disorder, or condition, including but not limited to Alzheimer’s disease and its related conditions such an impairment of cognitive function. Pharmacology and Utility Cyclic Prolyl Glycine (cPG) compounds of this invention can be administered in therapeutically effective amounts by any of the usual modes known in the art, either singly or in combination with at least one other compound of this invention and / or at least one other conventional therapeutic agent for the disease being treated. A therapeutically effective amount may vary widely depending on the disease or injury, the severity of the disease, the age and relative health of the animal being treated, the potency of the compound(s), and other factors. As anti- inflammatory, anti-apoptotic, anti-necrotic, anti-neurodegenerative, therapeutically effective amounts of compounds of this invention can range from about 0.001 milligrams per kilogram (mg / kg) to about 100 (mg / kg) mass of the animal, for example, about 0.1 to about 10 mg / kg, with lower doses such as about 0.001 to about 0.1 mg / Kg, e.g. about 0.01 mg / Kg, being appropriate for administration through the cerebrospinal fluid, such as by intracerebroventricular administration, and higher doses such as about 1 to about 100 mg / Kg, e.g. about 10 mg / Kg, being appropriate for administration by methods such as oral, systemic (e.g. transdermal), or parenteral (e.g. intravenous) administration. A person of ordinary skill in the art will be able without undue experimentation, having regard to that skill and this disclosure, to determine a therapeutically effective amount of a compound of this invention for a given disease or injury. In general, compounds of this invention can be administered as pharmaceutical compositions by one of the following routes: oral, topical, systemic (for example transdermal, intranasal, or by suppository), or parenteral (for example intramuscular, subcutaneous, or intravenous injection), by administration to the CNS (for example by intraspinal or intercisternal injection); by implantation, and by infusion through such devices as osmotic pumps, implantable pumps, transdermal patches, and the like. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulation, solutions, suspensions, elixirs, aerosols, soluble gels or any other appropriate compositions; and comprise at least one compound of this invention in combination with at least one pharmaceutically acceptable or physiological acceptable excipient. Suitable excipients are well known to persons of ordinary skill in the art, and they, and the methods of formulating the compositions. Suitable liquid carriers, especially for injectable solutions, include water, aqueous saline solution, aqueous dextrose solution, glycols, and the like, with isotonic solutions being preferred for intravenous, intraspinal, and intracisternal administration and vehicles such as artificial cerebrospinal fluid being also especially suitable for administration of the compound to the CNS. The above text is expressly incorporated herein fully by reference. Compounds of this invention can be administered orally, in tablets or capsules. In some embodiments, compounds of this invention can be prepared in water-in-oil emulsions in the form of microemulsions, coarse emulsions, liquid crystals, or nanoparticle formulations. Compounds of this invention can also be suitably administered by a sustained-release system or gel material with CPG incorporated therein. A composition may optionally contain, in addition to a compound of this invention, at least one agent selected from, for example, growth factors and associated derivatives (insulin-like growth factor-I (IGF-I), insulin-like growth factor-II (IGF-II), transforming growth factor-β1, activin, growth hormone, nerve growth factor, brain-derived neurotrophic factor (BDNF), growth hormone binding protein, IGF-binding proteins (especially IGFBP-3), basic fibroblast growth factor, acidic fibroblast growth factor, the hst / Kfgk gene product, FGF-3, FGF-4, FGF-6, keratinocyte growth factor, androgen-induced growth factor. Additional members of the FGF family include, for example, int-2, fibroblast growth factor homologous factor-1 (FHF-1), FHF-2, FHF-3 and FHF- 4, karatinocyte growth factor 2, glial-activating factor, FGF-10 and FGF-16, ciliary neurotrophic factor, brain derived growth factor, neurotrophin3, neurotrophin 4, bone morphogenetic protein 2 (BMP-2), glial-cell line derived neurotrophic factor, activity-dependant neurotrophic factor, cytokine leukaemia inhibiting factor, oncostatin M, interleukin), α-, β-, γ-, or consensus interferon, and TNF- α. Other forms of neuroprotective therapeutic agents include, for example, clomethiazole; kynurenic acid, Semax, tacrolimus, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, and renocorticotropin-(4-9) analog [ORG 2766] and dizolcipine (MK-801), selegiline; glutamate antagonists such as mematine (Namenda) NPS1506, GV1505260, MK-801, GV150526; AMPA antagonists such as 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(f)quinoxaline (NBQX), LY303070 and LY300164; anti-inflammatory agents directed against MAdCAM-1 and / or its integrin α4 receptors (α4β1 and α4β7), such as anti-MAdCAM-1 mAb MECA-367 (ATCC accession no. HB-9478). Combination therapy with metabotropic glutamate receptor antagonists such as fenobam may also be useful. Also, in addition to a compound of this invention, a composition may include a selective serotonin reuptake inhibitor such as fluoxetine, a selective norepinephine reuptake inhibitor such as viloxazine, or an atypical anti-psychotic such as risperidone. Most of these agents, especially the peptides such as the growth factors, etc., are not orally active, and will require administration by injection or infusion. Preparation of Compositions Cyclic Prolyl Glycine compounds are either available from commercial suppliers such as Sigma-Aldrich, Inc. (St. Louis, Missouri , USA) and Bachem (Torrance, California USA) ), Sigma (St. Louis, Mo.). Starting materials, intermediates, and compounds of this invention may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, and the like. They may be characterized using conventional methods, including physical constants and spectral data. Compounds of this invention may be prepared by the methods described below and or are prepared by methods well known to the person of ordinary skill in the art following procedures described in such references as Fieser and Fieser's Reagents for Organic Synthesis, vols 1-17, John Wiley and Sons, New York, N.Y., 1991. B. IGF-1 COMOUNDS IGF-1 is a protein that in humans is encoded by the IGF1 gene. IGF-1 consists of 70 amino acids in a single chain with three intramolecular disulfide bridges. IGF-1 has a molecular weight of 7,649 daltons. C71H119N17O19S IGF-1 is produced primarily by the liver. Production is stimulated by growth hormone (GH). Most of IGF-1 is bound to one of 6 binding proteins (IGF-BP). IGFBP-1 is regulated by insulin. IGF-1 is produced throughout life; the highest rates of IGF-1 production occur during the pubertal growth spurt. IGF-1 is a hormone that is structurally very similar to insulin and mediates the effects of growth hormone (GH) thus affecting metabolism, regeneration, and overall development. The GH- IGF-1 signaling pathway is crucial in the process of vascular remodeling and angiogenesis, i.e., the process of building new blood vessels and thus, helps in maintaining blood circulation in the body. In the brain, IGF-1 is abundant in various cells and regions and research over the years, suggest an imperative role of IGF-1 activity in neurodevelopment making it critical in learning and memory. A synthetic analog of IGF-1, mecasermin, is used for the treatment of growth failure in children with severe IGF-1 deficiency. Cyclic glycine-proline (cGP) is a metabolite of hormone insulin-like growth factor-1 (IGF-1). It has a cyclic structure, lipophilic nature, and is enzymatically stable which makes it a more favorable candidate for manipulating the binding-release process between IGF-1 and its binding protein, thereby normalizing IGF-1 function. As a major growth factor, IGF-1 is responsible for stimulating growth of all cell types, and causing significant metabolic effects One important metabolic effect of IGF-1 is signaling cells that sufficient nutrients are available for them to undergo hypertrophy and cell division. Its effects also include inhibiting cell apoptosis and increasing the production of cellular proteins. IGF-1 receptors are ubiquitous, which allows for metabolic changes caused by IGF-1 to occur in all cell types. IGF- 1's metabolic effects are far-reaching and can coordinate protein, carbohydrate, and fat metabolism in a variety of different cell types. The regulation of IGF-1's metabolic effects on target tissues is also coordinated with other hormones such as growth hormone and insulin. (Suwa S, Katsumata N, Maesaka H, Tokuhiro E, Yokoya S (December 1988). "Serum insulin-like growth factor I (somatomedin-C) level in normal subjects from infancy to adulthood, pituitary dwarfs and normal variant short children". Endocrinologia Japonica.35 (6): 857– 864. doi:10.1507 / endocrj1954.35.857. ) (Keating GM (2008). "Mecasermin". BioDrugs.22 (3): 177–188. doi:10.2165 / 00063030- 200822030-00004. PMID 18481900) IGF-1 is part of the insulin-like growth factor (IGF) system. This system consists of three ligands (insulin, IGF-1 and IGF-2), two tyrosine kinase receptors (insulin receptor and IGF-1R receptor) and six ligand binding proteins (IGFBP 1–6). Together they play an essential role in proliferation, survival, regulation of cell growth and affect almost every organ system in the body. (García-Mato Á, Cervantes B, Murillo-Cuesta S, Rodríguez-de la Rosa L, Varela-Nieto I. "Insulin- like Growth Factor 1 Signaling in Mammalian Hearing". Genes.12 (10): 1553. doi:10.3390 / genes12101553. PMC 8535591. PMID 34680948.) Similarly to IGF-1, IGF-2 is mainly produced in the liver and after it is released into circulation, it stimulates growth and cell proliferation. IGF-2 is thought to be a fetal growth factor, as it is essential for a normal embryonic development and is highly expressed in embryonic and neonatal tissues The IGF-1 family includes but is not limited to: • IGF-1, • IGF-2 • IGF receptors (IGF-1R) and • IGF binding proteins (IGFBP). The therapeutic applications of IGF-1 are limited due to its poor central uptake and potential side-effects. IGF-1 that is not bound to its binding protein bares a very short half-life and is cleaved by enzymes to form the tripeptide glycine-proline-glutamate (GPE). However, the enzymatic instability of GPE, with a plasma half-life of less than 4 minutes, is further cleaved to produce the final product, cyclic-Glycine-Proline (cGP) IGF1 (Mecasermin-Increlex∗) was administered subcutaneously twice / day for six months. The caretakers were trained to perform the injections at home. For the first and the last weeks the drug dosage was 0.05 mg / Kg; during the remaining periods the dosage was 0.1mg / Kg. The dosage is the same used in the IGF1- deficiency treatment. The maintaining dosage is the one approved for treating IGF deficiencies in children. C. DES(1-3)IGF-1 COMPOUNDS des(1-3)IGF-1 is a naturally occurring, endogenous protein, as well as drug, and truncated analogue of insulin-like growth factor 1 (IGF-1). des(1-3)IGF-1 lacks the first three amino acids at the N-terminus of IGF-1 (for a total of 67 amino acids, relative to the 70 of IGF-1). As a result of this difference, it has considerably reduced binding to the insulin-like growth factor-binding proteins (IGFBPs) and enhanced potency (about 10-fold in vivo) relative to IGF-1. Des( l-3)IGF-I is a 67 amino acid protein that is identical to human IGF-I but with the tripeptide Gly-Pro-Glu omitted from the N-terminal (see Fig.1). The molecule is maintained in relatively tight conformation by three di-sulphide bridges, Cys6-Cys48, Cys18-Cys61and Cys47-Cys52, the amino acid numbers being those in full length IGF-I. Primary structures of (a) human IGF-1 (MW 7648.7); (b) des(1-3)IGF-1 (MW 7365.5), which is truncated for the N-terminal tripeptide; (c) R3IGF-1 (MW 7675.8), that is substituted by arginine for glutamic acid at position 3; and (d) LONGTMR3IGF-1 (MW 9111.6), whose N- terminus is prolonged by additional 13 residues compared with R3IGF-1. Removal of the three amino-terminal amino acids of insulin-like growth factor-I (IGF-1) produces des(l-3)IGF-1, a growth factor that is more potent in several cell culture assays than the full-length peptide. This increased potency is most likely a consequence of the relatively poor association of des(l-3)IGF-I with IGF-binding proteins secreted by the cultured cells. See, for example, Ballard, F. J., Francis, G. L., Ross, M., Bagley, C. J., May, B. & Wallace, J.C. (1987). Natural and synthetic forms of insulin-like growth factor-1 (IGF-1) and the potent derivative, des- tripeptide IGF-1: Biological activities and receptor binding. Biochemical and Biophysical Research Communications 149, 398-404. D. PHARMACEUTICAL DOSAGES - VARIOUS EMBODIMENTS An administered dose may contain from 0.5mg to 1.5 mg / kg or between 30 mg to 150 mg for a typical adult of 70 kg weight, or between 60 mg to 150 mg for obese person normally weighing 80 -120 kg An administered dose may range from 0.5 mg to 1.5 mg / kg, which corresponds to 30 mg to 90 mg for a typical 70 kg adult, or 60 mg to 180 mg for an obese individual weighing between 80 kg and 120 kg. Pharmaceutical compositions comprising a pharmaceutically acceptable salt, amide, or ester thereof, and a pharmaceutically acceptable excipient may be prepared as is known in the art. A composition may be administered in several dosage forms, for example as a solution; a suspension; emulsion; a microemulsion; multiple emulsions; a foam; a salve; a paste; a plaster; an ointment; a tablet; a coated tablet; a chewing gum; a rinse; a capsule such as hard or soft gelatin capsules; a suppositories; a rectal capsule; drops; a gel; a spray; a powder; an aerosol; an inhalant; eye drops; an ophthalmic ointment; an ophthalmic rinse; a vaginal pessary; a vaginal ring; a vaginal ointment; an injection solution; an in situ transforming solution such as in situ gelling, setting, precipitating, and in situ crystallization; an infusion solution; or as an implant. A composition may further be compounded in a drug carrier or drug delivery system, e.g. in order to improve stability, bioavailability, and / or solubility. In a particular embodiment a composition may be attached to such system through covalent, hydrophobic, and / or electrostatic interactions. The purpose of such compounding may be, e.g., to decrease adverse effects, achieve chronotherapy, and / or increase patient compliance. A composition may also be used in the formulation of controlled, sustained, protracting, retarded, and / or controlled release drug delivery systems. The composition may be administered by parenteral administration. Parenteral administration may be performed by subcutaneous, intramuscular, intraperitoneal, or intravenous injection by means of a syringe, optionally a pen-like syringe, or by means of an infusion pump. Pharmaceutical compositions are well known in the medical arts and can include formulations in solid form such as a tablet to be administered orally. Formulations of the present invention can also include liquid, gel, semisolid, colloidal, vapor and gas phase formulations capable of oral, nasal, bronchial, intestinal, or colonic (anal and perianal) delivery. In one embodiment, the compositions of the present invention are administered mucosally (for example, to the mucosa of the subject). By mucosa is meant anybody mucosa including oral, nasal, bronchial, esophageal, intestinal, and anal or perianal. It will be recognized to the skilled clinician, choice of a carrier, including a physiologically acceptable compound, depends, for example, on the manner in which the peptide or encoding polynucleotide is to be administered, as well as on the route of administration of the composition and its dose. Where the composition is administered under immunizing conditions, for example, as a vaccine, it generally is administered intramuscularly, intradermally, or subcutaneously, but also can be administered parenterally such as intravenously, and can be administered by injection, intubation, or other such method known in the art. Where the desired modulation of the immune system is tolerization, the composition preferably is administered orally, or can be administered as above. The term "therapeutically effective amount" or "effective amount" means the amount of a compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician. Thus, the total amount of a composition to be administered in practicing a method of the present invention can be administered to a subject as a single dose, either as a bolus or by infusion over a relatively short period of time, and can be followed up with one or more booster doses over a period of time. The amount of the composition to stimulate an immune response in a subject depends on various factors including the age and general health of the subject, as well as the route of administration and the number of treatments to be administered. In view of these factors, the skilled clinician will know to adjust the particular dosage as necessary. The total amount of a compound or composition to be administered in practicing a method of the present invention can be administered to a subject as a single dose, either as a bolus or by infusion over a relatively short period of time, or can be administered using a fractionated treatment protocol, in which multiple doses are administered over a prolonged period of time. One skilled in the art would know that the amount of the compositions of the present invention to treat SARS in a subject depends on many factors including the age and general health of the subject as well as the route of administration and the number of treatments to be administered. In view of these factors, the skilled artisan would adjust the particular dose as necessary. In general, the formulation of the pharmaceutical composition and the routes and frequency of administration are determined, initially, using Phase I and Phase II clinical trials. All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the spirit and scope of the present invention. More specifically, the described embodiments are to be considered in all respects only as illustrative and not restrictive. All similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit and scope of the present invention as defined by the appended claims. Alternatively, or additionally, additional antiviral agent may optionally be unsuitable for the frequency of administration of the composition, for example, wherein the composition is formulated for administration once per day, and the additional antiviral agent is more suitable for administration once per week (for example., a PEGylated interferon-alpha). The composition may be, for example, in the form of a liquid, a semi-solid (for example, gel), or solid. In some embodiments of the present invention, the composition is in a solid form. Examples of solid forms for a composition include, without limitation, a tablet, a capsule (for example, comprising an encapsulated solid), a caplet, a powder, microspheroids, and granules. The composition is preferably formulated in accordance with the intended frequency of administration of the composition. This, in turn, will depend on the properties of the active agents. As discussed herein, artemether and atazanavir may be administered, for example, once per day, but also at other frequencies (for example, twice or thrice a day). It is to be appreciated that an active agent can be made more suitable for less frequent administration (for example, once per day, as is particularly convenient, instead of twice or more per day) by formulating a composition appropriately, for example, by formulating the composition for slow release of the active agents therein. Slow release preparations typically include slow release biodegradable carriers. Slow release biodegradable carriers are well known in the art. These are materials that may form particles that may capture therein an active compound(s) and slowly degrade / dissolve under a suitable environment (for example, aqueous, acidic, basic, etc.) and thereby degrade / dissolve in body fluids and release the active compound(s) therein. The particles are preferably nanoparticles (for example, in the nanometer range, for example, in the range of about 1 to about 500 nm in diameter, preferably about 50 to about 200 nm in diameter, most preferably about 100 nm in diameter). Oral slow-release forms are often designed to maintain therapeutic drug concentrations for greater than 12 hours. The absorption rate can be controlled by coating drug particles with wax or other water-insoluble material, by embedding the drug in a matrix from which it is released slowly during transit through the GI tract, or by complexing the drug with ion-exchange resins. Thus, for example, a slow-release formulation in tablet form, can be based on the use of a hydrophilic polymer which swells in contact with gastrointestinal fluids, to form a gel, which creates a barrier that enrobes the tablet. The barrier limits physical exchanges between the inside of the tablet and the surrounding medium. As a consequence, intrusion of water towards the tablet matrix and diffusion of drug are slowed down, allowing a controlled slow release of the drug. Various types of polymers may be used as a matrix for the slow-release of drugs, such as polyvinyl chloride, polyethylene polyamides, ethylcellulose, silicone, poly (hydroxyethyl methacrylate), other acrylic co-polymers, and polyvinylacetate-polyvinyl chloride copolymers. In some embodiments of the present invention, the composition is a unit dosage form (for example, a unit dosage form formulated for oral administration). Pharmaceutical compositions can be administered by an appropriate route of administration at an appropriate dose and an appropriate regime. Pharmaceutical compositions for use in accordance with embodiments of the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients (artemether and antiviral agents described herein) into preparations which, can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. For injection, the active ingredient(s) of embodiments of the present invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer with or without organic solvents such as propylene glycol, polyethylene glycol. For oral administration, the active ingredients can be formulated readily by combining the active ingredients described herein with pharmaceutically acceptable carriers well known in the art. Such carriers enable the active ingredient(s) to be formulated as tablets, pills, 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. 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, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Pharmaceutical 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. In soft capsules, the active ingredients described herein may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for the chosen route of administration. The active ingredients described herein can be formulated for parenteral administration, for example, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, 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. Pharmaceutical compositions for parenteral administration include aqueous solutions of the active ingredients. Additionally, suspensions of the active ingredients may be prepared as appropriate oily injection suspensions and emulsions (for example, water-in-oil, oil-in-water or water-in-oil in oil emulsions). 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. Alternatively, the active ingredients may be in powder form for constitution with a suitable vehicle, for example, sterile, pyrogen-free water, before use. The active ingredients of embodiments of the present invention may also be formulated in rectal compositions such as suppositories or retention enemas, using, for example, conventional suppository. For administration by inhalation, the active ingredient(s) for use according to embodiments of the present invention are conveniently delivered in the form of an aerosol spray presentation (which typically includes powdered, liquefied and / or gaseous carriers) from a pressurized pack or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichloro-tetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the active ingredient(s) and a suitable powder base such as, but not limited to, lactose or starch. The choice of drug delivery methods requires understanding of tissue distribution, metabolism and cellular effects as well as an understanding of the interaction of the drug with the specific underlying pathological processes of the disease under treatment, for which general and specific teaching are available in the art. Because the route of drug administration determines bioavailability and tissue levels and distribution, change in delivery may modify fundamentally the location, nature, extent and duration of disease condition, as well as alter dosing requirements and toxicities. However, it was observed that when artemether is administered locally via nasal delivery system in vivo, the drug was adsorbed quickly with more bioavailability and short duration of action in treating the fever very quickly than when administered systemically. For pulmonary delivery, a therapeutic composition of the invention can be formulated and administered to the patient in solid or liquid particulate form by direct administration for example, inhalation into the respiratory system. Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. In general, particles ranging from about 1 to about 10 microns in size are within the general respirable range. The therapeutic composition containing the anti-malarial and antiviral compounds are preferably administered by direct inhalation into the respiratory system for delivery as a mist or other aerosol or dry powder. The dosage of active compound via this route may vary depending on the condition being treated and the state of the subject, but generally may be an amount sufficient to achieve dissolved concentrations of anti-malarial and antiviral compound on the airway surfaces of the subject. Depending upon the solubility of the particular formulation of active compound administered, the daily dose may be divided among one or several unit dose administrations. The daily dose administered via direct inhalation is normally much less than oral dose. For example, a daily dose of artemether administered via direct inhalation ranges from 20 to 40 mg per day and Atazanavir from about 25 mg to about 100 mg per day. The doses of the active compounds can be provided as one or several prepackaged units. Aerosols of liquid particles can be produced by any suitable means, such as inhalatory delivery systems. One is a traditional nebulizer which works in a mechanism similar to the familiar perfume atomizer. The airborne particles are generated by a jet of air from either a compressor or compressed gas cylinder-passing through the device (pressure driven aerosol nebulizer) (U.S. Pat. No.4,501,729- “Aerosolized amiloride treatment of retained pulmonary secretions”). All headings are for the convenience of the reader and should not be used to limit the meaning of the text that follows the heading, unless so specified. EXAMPLES Experiment 1: Cyclic Prolyl Glycine prevents glutamate induced neuronal death in vitro in a dose related manner. Methods: Cerebellar Cell Culture Preparing and coating of cover slips Ten coverslips were placed into a large petri dish and washed in 70% alcohol for 5 minutes, then washed with Millipore H2O. The coverslips were air dried, then coated with Poly-D-Lysine (1 mg / ml stock solution in PBS, 90-100 μl) and incubated for 2 hours at 34˚ C. Extraction Postnatal day 4 Wistar rats were used for the study. Rats were placed in ice for 1 minute, the heads were decapitated, and the cerebellum removed on ice. Cerebellum tissue was placed in 1 ml of 0.65% glucose supplemented PBS (10 μl 65% stock D (+) glucose / 1 ml PBS) in a large petri dish, chopped up into smaller sections and triturate with a 1 ml insulin syringe via a 23 G (0.4 mm) needle, and then squirted back into the glucose solution on the large petri dish. The tissue was sieved through (125 μm pore size gaze) and centrifuged (2 minutes at 60 g) two times for a medium exchange into serum-free BSA-supplemented START V medium (Biochrom). The second centrifugation step was done with 1 ml of START V medium. The microexplants were reconstituted into 500 μl of START V medium and put on ice. Cultivation and fixation of cerebellar cells Two hours after PDL-coating, the slides were washed with Millipore H2O and air dried. Each slide was placed into a small 35 mm petri dish and 40 μl of START V / cell suspension added. The tissue was incubated for 2 hours at 34˚ C (settlement period). START V-medium (1 ml) was then added to the petri dish and cultivated at 34˚ C / 5% CO2 / 100% humidity for 48 hours. Cells were rinsed in PBS and then fixed for 2-3 minutes in increasing concentrations of paraformaldehyde (500 μl of 0.4% PFA was applied; then 1.2% PFA; then 3% PFA and finally 4% PFA - all fixation solutions contain 0.2% glutardialdehyde). Finally, the microexplants were rinsed in PBS. Drug Application 10 µl of toxin (L-glutamate-100 mM in Millipore water) was applied simultaneously with Cyclic Prolyl Glycine (cPG) (from Bachem, 10 mM stock prepared in PBS and diluted to final concentrations between 1-100 nM) for Study 1. A delay in administration of cPG at 6 hours after glutamate treatment was performed for Study 2. Results: Study 1: Glutamate treatment resulted in 85% loss of cerebellum neurons. Cyclic Prolyl Glycine G significantly reduced the glutamate induced neuronal death in a dose response manner when administered simultaneously with glutamate (FIG.1). The treatments with lower doses of cPG (10-100 nM) showed significant recovery from glutamate-induced neurotoxicity. Study 2: Cyclic Prolyl Glycine showed a significantly recovery from glutamate induced neurotoxicity in a dose range of 1-100 nM when given 6 hours after the glutamate treatment compared to the vehicle treated group (FIG.2). A further lower dose of cPG also showed a significant increase in neuron number compared to the normal control group, suggest a role for cPG in neuronal proliferation and differentiation. Conclusions Excessive glutamate can cause neuronal excitotoxicity by active NMDA receptors. cPG completely prevented the glutamate-induced neurotoxicity, when given either immediately or 6 hours after the glutamate treatment by acting as a direct or indirect NMDA agonist. Given that cPG can agonize mGlu2 / 3 receptor, which can inhibit NMDA activity. cPG can be involved in preventing neurons undergoing apoptosis because cPG can be effective as a delayed treatment and promoted the neuronal proliferation. Experiment 2: Cyclic (tri(prolylglycyl)) or c(PG)3 prevents glutamate induced neuronal death in vitro in a dose related manner. Methods: (see above for Experiment 1, which is incorporated by reference herein.) 10 µl of toxin (L-glutamate-100 mM in Millipore water) was applied simultaneously with cyclic(tri(prolylglycyl)) (which was obtained from NeuroActiva, San Jose, California), 10 mM stock prepared in PBS and diluted to final concentrations between 1-100 nM) for Study 1. A delay in administration of cyclic(tri(prolylglycyl)) at 6 hours after glutamate treatment was performed for Study 2. Result: Study 1: Glutamate treatment resulted in 85% loss of cerebellum neurons. cyclic(tri(prolylglycyl)) significantly reduced the glutamate induced neuronal death by 57% in a dose response manner when administered simultaneously with glutamate. The treatments with lower doses of cyclic(tri(prolylglycyl)) (10-100nM) showed significant recovery from glutamate-induced neurotoxicity. Study 2: cyclic(tri(prolylglycyl)) showed an improvement of approximately 43% significantly recovery from glutamate induced neurotoxicity in a dose range of 1-100nM when given 6 hours after the glutamate treatment compared to the vehicle treated group. A further lower dose of cyclic(tri(prolylglycyl)) also showed a significant increase in neuron number compared to the normal control group, suggest a role for cPG in neuronal proliferation and differentiation. Experiment 3: Cyclic Glycyl-2-Methyl Proline prevents glutamate induced neuronal death in vitro in a dose related manner. Methods: (see above for Experiment 1 and Experiment 2, which is incorporated by reference herein) 10 µl of toxin (L-glutamate-100 mM in Millipore water) was applied simultaneously with cyclic Glycyl-2-Methyl Proline (obtained from NeuroActiva, San Jose California), 10 mM stock prepared in PBS and diluted to final concentrations between 1-100 nM) for Study 1. A delay in administration of cPG at 6 hours after glutamate treatment was performed for Study 2. Result: Study 1: Glutamate treatment resulted in 85% loss of cerebellum neurons. cyclic Glycyl-2- Methyl Proline significantly reduced the glutamate induced neuronal death by 63% in a dose response manner when administered simultaneously with glutamate. The treatments with lower doses of cyclic Glycyl-2-Methyl Proline (10-100 nM) showed significant recovery from glutamate- induced neurotoxicity. Study 2: cyclic Glycyl-2-Methyl Proline showed an improvement of approximately 58% significantly recovery from glutamate induced neurotoxicity in a dose range of 1-100nM when given 6 hours after the glutamate treatment compared to the vehicle treated group. A further lower dose of cyclic Glycyl-2-Methyl Proline also showed a significant increase in neuron number compared to the normal control group, suggest a role for cPG in neuronal proliferation and differentiation. Conclusions Excessive glutamate can cause neuronal excitotoxicity by active NMDA receptors. Cyclic Prolyl Glycine analogues, cyclic(tri(prolylglycyl)) and cyclic Glycyl-2-Methyl Proline significantly prevented the glutamate-induced neurotoxicity, when given either immediately or 6 hours after the glutamate treatment by acting as a direct or indirect NMDA agonist. Cyclic Prolyl Glycine and its analogues, such as but not limited to cyclic(tri(prolylglycyl)) and cyclic Glycyl-2-Methyl Proline can be used in preventing neurons undergoing apoptosis because cPG compounds can be effective as a delayed treatment, and promoted the neuronal proliferation. Experiment 4: Effects of cPG after 6-OHDA induced nigral-striatal lesion. Methods Twenty male Wistar rats (280-310 g) were used. After exposing the skull, 6-OHDA (8 µg in a base of 2 µl 0.9% saline containing 1% ascorbic acid) was administered into the right medial forebrain bundle (MFB) using co-ordinates AP +4.7 mm, R 1.6 mmv –8 mm under 3% halothane anesthesia. 6-OHDA was injected through a 25G needle connected via a polyethylene catheter to a 100 µl Hamilton syringe. The 6-OHDA was infused by a microdialysis infusion pump at a rate of 0.5µl / min. The needle was left in the brain for a further 3 minutes before being slowly withdrawn. The skin was sutured with 2.0 silk and the rats were allowed to recover from anesthesia. The rats were housed in a holding room with free access to food and water at all times except during behavioral testing. Cyclic PG was dissolved in saline. Four different doses of cPG (0, 0.1, 0.5, 1 mg / kg, Bachem) were administered intraperitoneally 2 hours post lesion. At 7 days post-lesion, rats were injected with 0.1 mg / kg apomorphine and the number of contralateral rotations / hour was recorded and calculated using a computerized Rotameter (St Diego Instruments). Experimenter was blinded from the treatment groups. Results: The group treated with 1 mg cPG (n=5, 154 ±64) showed a trend toward a reduction in the number of rotations compared to the vehicle treated group (n=5, 290 ±18) indicating that cPG in improves functional recovery in 6-OHDA induced nigrostriatal injury. (FIG.3). Experiment 5: Effects of cyclic(tri(prolylglycyl)) after 6-OHDA induced nigral-striatal lesion. Materials and Methods: (see above for Experiment 1, Experiment 2, Experiment 3, and Experiment 4, which is incorporated by reference herein) Cyclic(tri(prolylglycyl)) was dissolved in saline solution. Four different doses of Cyclic(tri(prolylglycyl)) (0, 0.1, 0.5, 1 mg / kg, NeuroActiva) were administered intraperitoneally 2 hours post lesion. The group treated with 1 mg cyclic (tri(prolylglycyl)) (n=5, 172±69) showed a trend toward a reduction in the number of rotations compared to the vehicle treated group (n=5, 290 ±18) indicating a role for cyclic(tri(prolylglycyl)) in improving functional recovery in 6-OHDA induced nigrostriatal injury. Conclusions Cyclic (tri(prolylglycyl)) improved the functional recovery after 6-OHDA induced nigral- striatal lesions in a dose related manner. This data indicates cyclic (tri(prolylglycyl)) can be used as a treatment for Parkinson’s disease and other neurological disorders. Experiment 6: Effects of Cyclic Glycyl-2-Methyl Proline after 6-OHDA induced nigral-striatal lesion. Materials and Methods (see above for Experiment 5 which are incorporated by reference herein) Cyclic Glycyl-2-Methyl Proline (cGMeP) was dissolved in saline solution. Four different doses of cGMeP (0, 0.1, 0.5, 1 mg / kg, NeuroActiva) were administered intraperitoneally 2 hours post lesion. The group treated with 1mg cGMeP (n=5, 134±69) showed a trend toward a significant reduction in the number of rotations compared to the vehicle treated group (n=5, 292±21) indicating a role for cGMeP in improving functional recovery in 6-OHDA induced nigrostriatal injury. Conclusions Cyclic Glycyl-2-Methyl Proline improved the functional recovery after 6-OHDA induced nigral-striatal lesions in a dose related manner. This data indicated that Cyclic Glycyl-2-Methyl Proline has efficacy as a treatment for Parkinson’s disease. Experiment 7: Morris Water Maze (MWM) Model of Learning and Memory Used to Assess Effects of cyclic Prolyl Glycine on Cognitive Function. Cyclic Prolyl Glycine (cPG) administered to animals treated with scopolamine-induced cognitive dysfunction produces clinical improvement in those animals, similar to the therapeutic improvement observed in people suffering from cholinergic hypofunction. Scopolamine is commonly used in animal models of cholinergic hypofunction associated with Alzheimer's disease. The functional deficits observed after scopolamine treatment include those found in human patients with Alzheimer's disease. Thus, scopolamine treatment is reasonably predictive of cognitive impairment found in human diseases. Additionally, scopolamine treatment mimics cognitive disfunctions in humans who do not have neurodegenerative disorders. The purpose of the study was to investigate cyclic Prolyl Glycine to evaluate its impact cognitive deficit and affective state (anxiety). Methods The first part of the study involved acute testing of the cyclic Prolyl Glycine in the Morris Water Maze memory model. The MWM test is one of the most frequently used tests for assessing spatial memory in rats and is well recognized to accurately predict effects of disease and treatment on spatial memory generally. Therefore, the MWM test reflects effects of disease and treatment in human subjects. The standard procedure for MWM was followed. We used a circular swimming pool (80 cm depth × 150 cm diameter) filled with opaque water, with the temperature maintained at 20°C. A platform was hidden 1 cm below the water surface, with a white flag (10 cm×10 cm) located either 20 cm above the platform for the visual cue and at 3 o'clock position in relation to the starting location for a spatial cue. On days 1-4 of the experiment rats underwent memory acquisition trials with 6 trials (60 seconds each) in each day of testing (habituation phase). Latency to reach the platform was recorded and the daily reduction of average latency was used to measure the capability to learn where the hidden platform was. On day 5 of the experiment normal, non-aged Wistar rats were split into groups to receive either saline (N=12) or scopolamine (0.5 mg / kg, i.p., N=12) to induce memory deficit. Scopolamine was administered half an hour before the probe test commenced. 10 min following the scopolamine treatment, the cyclic Prolyl Glycine was administered orally at 10 mg / kg (N=16) with vehicle-treated animals administered the diluent by oral gavage using an identical treatment protocol (n=15). TABLE 1: Animals Used to Test Effects of cPG on Memory Scopolamine Vehicle Vehicle N = 12 N = 12 impairment and in age-matched control animals with no memory impairment to determine any direct pharmacological effect on memory processing. Experimental groups are detailed in TABLE 1. On day 5, the probe MWM test was performed with the platform removed. There were 6 trials, each of maximum duration of 60 s, at least 5 min rest between trials). The amount of time the rats spend swimming near the platform provided a measure of how much they relied on visual and spatial cue to locate the platform, as opposed to using a non-spatial strategy. Data was collected and analyzed using Any-maze (v4.2) software. The data generated from behavioral tests was analyzed using one-way ANOVA for determining the difference between the aged-groups. Two-way ANOVA was used for examining the progress of behavioral results with the time points treated as dependent factors. GraphPad Prism version 3.02 was used for data analysis. Results Treatment with scopolamine significantly impaired acquisition of spatial memory in treated animals (time to platform approximately 208% of control on day 4). Cyclic Prolyl Glycine (20 mg / kg; daily) significantly reversed the cognitive impairment induced by scopolamine. (FIG.4) These results confirmed the presence of choline-positive effect in cPG on retrieval of learned skill of finding a submerged platform (spatial memory) and that this drug can be effective in patients with mild cognitive impairment. Experiment 8: Determination of neurogenesis by testing cPG and its analogues c(PG)3 and cGMeP with Bromodeoxyuridine The objective of this experiment is to study the impact of intra-peritoneal infusion of cPG and its analogues c(PG)3 and cGMeP in rats, which were co-administrated with BrdU in highly neurogenic regions including the sub ventricular zone and the dentate gyrus in the hippocampus. Method: Male Wistar rats weighing about 250-270 g (not newborn) were used. All animal experiments were conducted in agreement with national and international guidelines. Care was taken to minimize suffering for the animals. Animals were allowed to acclimatize for 1 week before start of the studies. Animals were housed under standardized conditions with normal light–dark periods and in groups of five animals per cage. Animals had access to food and water ad libitum during the studies. Three neurogenesis modulating agents, cPG, c(PG)3 and cGMeP were separately administered intraperitoneally to Male Wistar rats (N=10) at 10 mg / kg in 0.1% Rat Serum Albumin (RSA). The negative control (n=12), the vehicle group was injected with saline (in 0.1% RSA). Bromodeoxyuridine (BrdU; 50 mg / kg) was co-administrated together with the compounds. The intraperitoneally injections were given with a 12 hour interval for 7 days. Animals were perfused on day 8. The rats were kept at 12 hours light / dark regime. In perfusion, animals were perfused transcranially with 50 ml of ice cold phosphate buffered saline (PBS) and then 100 ml of 4% paraformaldehyde in PBS. Brains were fixed after removal in 4% paraformaldehyde in PBS for 24 hours at 4° C., at least 3 days before sectioning. The procedures of transcranial infusion consist the following steps: The animals were weighed to the nearest 0.1 grams and were administered with sodium pentobarbital and ketamine / xylazine. The animals were placed in a heated cage for 10-15 minutes. The rats were secured in the supine position (lying on the back with face upward) with its forepaws and hind paws pinned to a Styrofoam work surface inside a chemical fume hood. An incision was made through the skin with surgical scissors along the thoracic midline from just beneath the xiphoid process to the clavicle. Two additional skin incisions were made from the xiphoid process along the base of the ventral rib cage laterally. Gently reflect the two flaps of skin rostrally and laterally making sure to expose the thoracic field completely. The cartilage of the xiphoid process was grasped with blunt forceps and it was raised slightly to insert pointed scissors. The thoracic musculature and ribcage were cut through between the breastbone and medial rib insertion points and the incision was extended rostrally to the level of the clavicles. The diaphragm from the chest wall on both sides was separated with scissor cuts. The reflected ribcage was taped or pinned with 18G needles laterally to expose the heart and other thoracic organs. The pericardial sac was gently grasped with blunt forceps and was torn open fully. The beating heart was secured with blunt forceps and a 1-2 mm incision was made in the left ventricle. A 24G X 25.4 mm animal feeding needle with a bulnous tip (Harvard apparatus Cat. #52-4009) was inserted. The feeding needle was thread into the base of the aortic arch using a dissecting microscope. The needle base was clamped to the left ventricle above the incision site using a hemostat. The right atrium was cut immediately with scissors and at the first sign of blood flow, the infusion of heparinized saline was started (stage 1 perfusate) and continued until the fluid exiting the right atrium is entirely clear. The saline perfusate was changed to aldehyde-based fixative (stage 2 perfusate) to a total of 20-30 ml of fixative as infused to an animal. The animal was decapitated with large surgical scissors. The brains were removed and embedded in paraffin. Sections were prepared using a freezing microtome and stored in cryoprotectant at −20° C. before immunostaining for BrdU. Sections were immune-stained for BrdU with mouse anti-BrdU paired with a biotinylated goat anti mouse IgG and visualized using ABC Elite kit (Vectorlabs. using manufactures directions). Standard light microscope techniques were used to count the total number of BrdU positive cells in each section and in relevant region of the brain. Analysis and quantification were performed for proliferative brain regions, subventricular zone, and the dentate gyros in hippocampus. Other experimental details not listed here are known to one of skill in the art and may be found for example in Pencea V et al. J. Neurosci Sep.1 (2001).21(17):6706-17. Results Notably, it was found that rats given intra-peritoneal infusion of cPG, c(PG)3 and cGMeP at 10 mg / kg in 0.1% RSA, co-administrated with BrdU twice daily showed a significant increase (nonparametric One-way ANOVA) in the number of newborn cells (BrdU positive compared to sham injected) in highly neurogenic regions including the sub ventricular zone and the dentate gyrus in the hippocampus (FIG.5 and FIG.6). Conclusion In summary, the experiments demonstrated that cPG, c(PG)3 and cGMeP exhibit neural stem cell proliferative effect pointing to neurogenesis. Experiment 9: Determination of the regeneration of damaged nerve tissue with cPG Postnatal day 4 Wistar 10 rats were used for the study. The rats were divided in 2 groups: one group of 5 animals treated with drug solution, and the other group of 5 animals treated with 0.9% sodium chloride (saline) solution. A drug solution containing cPG (from Bachem, 10 mM solution prepared in 0.9% sodium chloride (saline) solution) was administered four times a day in volumes of 0.75 ml to thoroughly flood the site of injury. Two days after crushing the spinal cord, the dura of a rat was opened and a polyethylene tube was sutured to the vertebral spines and adjacent soft tissues so that the opening in one end lay directly over the injured part of the spinal cord. The tubing was brought through a subcutaneous tunnel so that its other end emerged at the base of the skull. A syringe adapter was attached to the external opening for injecting the drugs. All experiments were on a double-blind basis on 2 groups: one group of 5 animals treated with drug solution of 10 mM cPG in saline solution, and the other group of 5 animals treated with 0.9% sodium chloride (saline) solution. Treatment of every animal was continued for 14 days, after which the animals were killed and histological sections prepared. Results The drug treated animals showed greater invasion of the lesion by nerve fibers than did the vehicle treated with saline solution. In the drug-treated animals, the nerve fibers grew into the lesion site in such profusion that they were no longer oriented longitudinally, but grew rather haphazardly in all directions. Fibers were frequently undulating and varicose and were often arranged in small bundles containing 3-6 axons. The axons were very fine in calibers, most of them being 3-7 microns in diameter. When the slides were coded and randomized, there was no difficulty in distinguishing between the specimens from the drug-treated and the saline treated animals. The most prolific nerve growth occurred in the animals treated with cPG. Conclusion This Example showed that nerve regeneration is promoted by thoroughly bathing or otherwise contacting the injury site with the foregoing composition. The foregoing composition promotes regeneration of damaged nerve tissue when administered directly to the site of the injury. Experiment 10: Regeneration of damaged nerve tissue of cyclic (glycyl-L-prolylglycyl-L- prolylglycyl-L-prolyl) Postnatal day 4 Wistar 10 rats were used for the study. The rats were divided in 2 groups: one group of 5 animals treated with drug solution, and the other group of 5 animals treated with 0.9% sodium chloride (saline) solution. A drug solution containing 10 mM of cyclic (glycyl-L- prolylglycyl-L- prolylglycyl-L-prolyl) or c(PG)3, (obtained from NeuroActiva, San Jose, California). 10 mM solution prepared in 0.9% sodium chloride (saline) solution was administered four times a day in volumes of 0.75 ml to thoroughly flood the site of injury. Two days after crushing the spinal cord, the dura of a rat was opened and a polyethylene tube was sutured to the vertebral spines and adjacent soft tissues so that the opening in one end lay directly over the injured part of the spinal cord. The tubing was brought through a subcutaneous tunnel so that its other end emerged at the base of the skull. A syringe adapter was attached to the external opening for injecting the drugs. All experiments were on a double-blind basis on 2 groups: one group of 5 animals treated with drug solution of 10 mM c(PG)3 in saline solution, and the other group of 5 animals treated with 0.9% sodium chloride (saline) solution. Treatment of every animal was continued for 14 days, after which the animals were killed and histological sections prepared. Results The results are similar to the above experiment with cPG. In the c(PG) treated animals, the nerve fibers grew into the lesion site in such profusion that they were no longer oriented longitudinally, but grew rather haphazardly in all directions. Fibers were frequently undulating and varicose and were often arranged in small bundles containing 3-6 axons. The axons were very fine in caliber, most of them being 3-7 microns in diameter. When the slides were coded and randomized, there was no difficulty in distinguishing between the specimens from the drug-treated and the saline treated animals. The most prolific nerve growth occurred in the animals treated with c(PG)3. Nerve regeneration is promoted by thoroughly bathing the injury site with the foregoing composition. The foregoing composition promotes regeneration of damaged nerve tissue when administered to the site of the injury, including direct administration to the site of injury. Experiment 11: Regeneration of damaged nerve tissue of cyclic Glycyl-2-Methyl Proline Postnatal day 4 Wistar 10 rats were used for the study. The rats were divided in 2 groups: one group of 5 animals treated with drug solution, and the other group of 5 animals treated with 0.9% sodium chloride (saline) solution. A drug solution containing 10 mM of cyclic Glycyl-2-Methyl Proline, or cGMeP (from NeuroActiva, 10 mM solution prepared in 0.9% sodium chloride (saline) solution) was administered four times a day in volumes of 0.75 ml to thoroughly flood the site of injury. Two days after crushing the spinal cord, the dura of a rat was opened and a polyethylene tube was sutured to the vertebral spines and adjacent soft tissues so that the opening in one end lay directly over the injured part of the spinal cord. The tubing was brought through a subcutaneous tunnel so that its other end emerged at the base of the skull. A syringe adapter was attached to the external opening for injecting the drugs. All experiments were on a double-blind basis on 2 groups: one group of 5 animals treated with drug solution of 10 mM cGMeP in saline solution, and the other group of 5 animals treated with 0.9% sodium chloride (saline) solution. Treatment of every animal was continued for 14 days, after which the animals were killed and histological sections prepared. Results The results are similar to the above experiment with cPG. In the cGMeP treated animals, the nerve fibers grew into the lesion site in such profusion that they were no longer oriented longitudinally, but grew rather haphazardly in all directions. Fibers were frequently undulating and varicose and were often arranged in small bundles containing 3-6 axons. The axons were very fine in caliber, most of them being 3-7 microns in diameter. When the slides were coded and randomized, there was no difficulty in distinguishing between the specimens from the drug-treated and the saline treated animals. The most prolific nerve growth occurred in the animals treated with cGMeP. Nerve regeneration is promoted by contacting, such as but limited to bathing the injury site with the foregoing composition. The foregoing composition promotes regeneration of damaged nerve tissue when administered directly to the site of the injury. Example 12: Effects of Cyclic Prolyl Glycine on Lifespan and Long-Term Potentiation in Rett Syndrome (RTT) Model Rett syndrome is an X-linked dominant disorder caused by loss-of-function mutations in the gene encoding methyl CpG binding protein 2 (MeCP2). To determine whether cPG treatment can impact the development and progression of Rett Syndrome in a murine model of the disorder, we used hemizygous MeCP2(1lox) male mice. The MeCP2 knock-out (MeCP2-KO) mouse system is widely accepted in the art as closely mimicking the range and the severity of physiological and neurological abnormalities characteristic of the human disorder, Rett Syndrome. Methods Hemizygous MeCP2(1lox) male mice were treated with 5mg / kg / day of cPG or saline, (0.01% BSA, n=15 per group in survival experiment and n=24 in the LTP experiment). The treatments were administered intraperitoneally from 4 weeks after birth. For the survival experiments the treatment was maintained through the course of the experiment. For the LTP experiment the mice were treated until week9 when they were used for slice preparation. MeCP2 deficient mutant mice develop RTT symptoms at about 4-6 weeks of age and die between 10-12 weeks (Chen et al., 2001. Nat Genet 27: 327-331). MeCP2 deficient mice have been previously reported to suffer from functional and ultrastructural synaptic dysfunction, significant impairment of hippocampus-dependent memory and hippocampal long-term potentiation (LTP) (Moretti P, el al Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J Neurosci.2006 Jan 4;26(1):319-2). To test the effects of the cPG treatment on synaptic function in the RTT model we compared hippocampal LTP in both vehicle and cPG treated animals at 9 weeks of age. Results: Wild-type mice (top line) are control animals, and therefore their survival was 100% at each time point. MeCP2 deficient mice treated with saline only died much more rapidly (dotted line) than wild-type mice, such that by about 11 weeks, only 50% of the MeCP deficient mice survived. We found that MeCP2 deficient mice treated with cPG survived substantially longer than saline-treated mice. At about 15 weeks, 70% of the animals survived. cPG treated animals showed improved survival, with 30 percent having died at 16 weeks. No safety concerns were raised by CPG treatment of MeCP2 mice. These results demonstrated that cPG can substantially increase survival of MeCP2 deficient mice. Because MeCP2 deficient mice are predictive of the pathology and therapeutic efficacy in human beings with Rett Syndrome, we conclude that cPG can increase life span of human beings with Rett Syndrome. Example 13: Effect of Oral cyclic Prolyl Glycine on Survival in Rett Syndrome in Mice Cyclic Prolyl Glycine (5mg / kg) was administered orally to MeCP2 deficient mice. Briefly, an aqueous solution, a water-in-oil emulsion (micro-emulsion, coarse emulsion or liquid crystal), or a gel composition containing a pharmaceutically effective amount of cPG (5 mg / kg per animal) is administered daily. The wild-type animals were administered saline only to obtain baseline data similar to the design of studies described above. In wild-type animals, survival is defined to be 100% at each time point. In MeCP2 deficient animals, survival is decreased substantially. It was observed after oral administration of cPG to MeCP2 deficient mice, survival is increased substantially. Example 14: Effect of Cyclic Prolyl Glycine on Seizure Activity in Rett Syndrome in Mice The effects of cPG has been tested on seizure activity in MeCP2 deficient animals, as seizures are a prominent, hazardous and a difficult to treat aspect of Rett Syndrome. Electroencephalographic recordings of wild-type mice and MeCP2 deficient mice treated with either saline or cPG. It was found that cPG can be effective in decreasing both motor seizures and non-convulsive seizures. Conclusions Based on our in vivo and in vitro studies in MeCP2 deficient animals, we conclude that cPG can be an effective therapy for treating human beings with Rett Syndrome. As cPG can be easily administered orally and has shown effective in treating neurodegenerative disorders, including Rett Syndrome, we conclude that cPG can be convenient and beneficial for long-term therapy of patients with Rett Syndrome and other autism spectrum disorders. Example 15: Effects of Cyclic Prolyl Glycine in Human Beings with Rett Syndrome The study is a randomized double-blind placebo controlled parallel study with three doses of either placebo, 5 mg / kg T.I.D oral cPG for five days. Methods Thirty six subjects with Rett Syndrome are recruited. Subjects are female and aged between 16 and 29 years (Mean=19.1 SD=4.7). All subjects have an IQ<60 and mutations of the MECP2 gene. Subjects also show ether spike activity in the EEG or an increase in lower frequency bands of the EEG as detected by Fast Fourier Transform (FFT). Subjects are instructed that concomitant medications are to be stable for at least six weeks prior to study. Subjects receiving medication to treat signs of inattention are tested in the morning and instructed to take their medication in the afternoon. Subjects with QTc interval >451 msec are excluded. Subjects are tested at baseline using the following instruments: The Rett Syndrome Natural History / Clinical Severity Scale, Aberrant Behavior Checklist Community Edition (ABC), Vinelands, Clinical Global Impression of Severity (CGI-S) and their careers completed the Caregiver Strain Questionnaire (CSQ). ECG and respiratory rate were monitored continuously for 24 hours using polysomnography technology. Hand movements are also recorded using the Q-Sensor™. Derived EEG measures include: spikes per unit time in the EEG, overall power of frequency bands of the EEG, QTc and heart rate variability (HRV), and respiratory irregularities. Statistically, the effect of treatment with is analyzed by conducting a repeated analysis of covariance (ANCOVA) on the effect of treatment on change from baseline scores. Results Treatment with cPG produces no more adverse events than are present during treatment with placebo, with all adverse events being of short duration and mild severity. No Serious Adverse Events are reported. No instances of increases in QTC are reported. No effects are seen on respiratory rate or heart rate variability. Treatment with cPG produces a significant overall reduction of spikes per unit time in the EEG. Treatment with 5 mg / kg T.I.D. oral cPG decreases spike activity compared to placebo. This dose of cPG also decreases the power of the delta band of the EEG compared to placebo. Treatment with cPG also reduces total hand movements per twenty-four hour period as counted using the Q-Sensor™ device. This effect is significant for the 5 mg / kg T.I.D. dose compared to placebo. Conclusions Treatment with CPG produces significant improvements in Central Nervous System function in the present study. Despite relatively short-term treatment, abnormalities in the electrical activity of the brain were significantly reduced. This effect is dose dependent, seen after treatment 5 mg / kg T.I.D. oral cPG . These effects mirror the improvements in CNS function seen in the MeCP2 knockout transgenic mouse model of Rett Syndrome after administration of. The Non-verbal communication rating of the Rett Syndrome Natural History / Clinical Severity Scale is improved by treatment. This measure primarily assesses eye contact. This raises the prospect that longer term treatment with cPG may improve social relatedness in the population. cPG is well tolerated in this population. No effects are seen in either standard measures or areas of specific concern in the patient population, such as QTc interval prolongation or apnea. Example 16: Effects of CPG on Human Beings with Autism Spectrum Disorders Methods To determine whether cPG can treat symptoms of ASD, we conducted a double-blind placebo-controlled clinical study in human beings with ASD. Twenty six patients with an Autism Spectrum Disorder were recruited. Subjects were male and aged between 16 and 65 years (Mean=19.71 SD=4.2). All subjects had an IQ>60 and strict DSM-IV-TR diagnosis of Autistic Disorder or Asperger Disorder. Subjects also met criteria for an Autism Spectrum Disorder according the ADI-R and ADOS-G instruments, and fulfill the proposed DSM-V criteria for and Autism Spectrum Disorder. Subjects better treated with atypical anti-psychotic medications indicated for autism were excluded. Subjects were screened for known genetic disorders including and those with Fragile X Syndrome or tuberous sclerosis excluded. Subjects with uncontrolled epilepsy were excluded. Concomitant medications were required to be stable for at least eight weeks prior to study. Subjects receiving medication to treat signs of inattention were tested in the morning and instructed to take their medication in the afternoon. The study was a crossover study with three phases. Subjects entered each phase of the crossover in a randomized order. In the test phases, subjects received either placebo, or 5 mg / kg T.I.D oral cPG for five days. Each phase of the crossover was separated by a washout period of fourteen days. Subjects were tested at baseline using the following instruments: Wechsler IQ, Aberrant Behavior Checklist Community Edition (ABC), Vinelands, Yale-Brown Obsessive Compulsive Scale (YBOCS) compulsion subscale, Social Responsiveness Scale (SRS), Clinical Global Impression of Severity (CGI-S) and their care givers complete the Caregiver Strain Questionnaire (CSQ). The Aberrant Behavior Checklist-Community is a rating scale that measures the severity of a range of problem behaviors commonly observed in individuals with intellectual and developmental disabilities (IDD). The Aberrant Behavior Checklist (ABC) is designed to measure psychiatric symptoms and behavioral disturbance exhibited by individuals with IDD across 5 domains: Irritability, Agitation, & Crying; Lethargy / Social Withdrawal; Stereotypic Behavior; Hyperactivity / Noncompliance; and Inappropriate Speech Subjects were administered two tasks—the Reading the Mind in the Eyes Test-Revised (RMET) and an Eye Tracking (ET) task, as well as Clinical Global Impression of Improvement (CGI-I). Tasks commenced two hours following administration of placebo or either dose of G-2- MePE. The Revised Eyes Test was administered to a group of adults with AS and again compared these from a large number of normal controls drawn from different samples. In both the clinical and control groups the Eyes Test was inversely correlated with the Autism Spectrum Quotient (the AQ), a measure of autistic traits in adults of normal intelligence. The RMET is capable of detecting improvement with even a single dose of a pharmacological agent. Eye tracking issues are characteristic of patients with autism who spend less time looking at the eyes of photographs of human faces. Adverse events are also recorded using standard safety measures. Statistically, the effect of treatment with cPG is analyzed by conducting a repeated analysis of covariance (ANCOVA) on the effect of treatment on change from baseline scores. Results Treatment with cPG produces no more adverse events than were present during treatment with placebo, with all adverse events being of short duration and mild severity. No Serious Adverse Events were reported. Treatment with cPG produced a significant overall improvement in performance of the RMET test. Treatment with 5 mg / kg T.I.D. oral cPG increases the percent correct responses on the RMET. Treatment with cPG produces a significant overall improvement in time spent looking at the eye region in the ET test. Conclusions Treatment with cPG produces significant improvements in performance in the Reading the Mind in the Eyes Test—Revised, and in performance of an Eye Tracking task. This effect is dose dependent, seen after treatment 5 mg / kg T.I.D. oral cPG. Improvement in these measures is reflective of an improvement in processing of social information processing. Social interaction deficits are a core symptom diagnostic for autism spectrum disorders, and this is therefore a key finding. Cyclic Prolyl Glycine also produces an overall improvement in function as indexed by the Clinical Global Impression of Improvement. The case report from the study indicated this effect related to an improvement in social skills of the subjects. relatedness. The changes seen in the RMET and ET task may have relevance to social activity in daily life. cPG is well tolerated in this population with no serious adverse effects.

[0004] Experiment 17: Clinical Study of CPG Compound for the Treatment of Girls and Women with Rett Syndrome The primary objective of the clinical study is to investigate the efficacy of treatment with oral CPG Compound versus placebo in girls and women with Rett syndrome. The key secondary objective of the clinical study is to investigate the efficacy of treatment with oral CPG Compound versus placebo on ability to communicate in girls and women with Rett syndrome. This was a 12-week randomized, double-blind, placebo-controlled, parallel group study. The study will compare one active treatment group receiving weight-banded doses of CPG Compound with a placebo group. Subjects will be stratified according to age stratum (5-10 years old, 11-15 years old, and 16-20 years old) and Baseline RSBQ severity (<35 total score and ≥35 total score). 198 participants screened and 184 participants randomized to cPG.173 participants (94.0%) completed the study (cPG n=86; placebo, n =87). Treatment groups were well balanced for demographic and baseline characteristics as given in TABLE 2.

[0005] TABLE 2: Demographic and Baseline Characteristics Randomized analysis set In the respective cPG and placebo groups, 42% and 44% of participants were administered study medication via gastrostomy tube. The Sponsor, subjects, caregivers, and Investigators were blinded to treatment assignment. The study had 3 periods: • Screening period: up to 3 weeks • Double-blind Treatment period: 12 weeks • Safety follow-up period: 30 days A total of 178 subjects were randomized (with a minimum of 12 subjects randomized for three age ranges [5-10 years old, 11-15 years old, and 16-20 years old]) with a total of 89 subjects per treatment arm. Subjects received an oral dose of CPG Compound or placebo, for up to 12 weeks. Dose was based on the subject’s weight at Baseline, as outlined below in TABLE 3. cPG was dissolved in sterile solution at 0.200 gram per ml. Doses was administered orally or by gastrostomy (G) tube (doses administered via gastrojejunal [GJ] tubes administered through the G-port), twice a day (BID) once in the morning and once in the evening. TABLE 3: Dosing Schedule Based on Weight at Baseline WeightDose Total Daily Dose12-20 kg 10 mL (2 g) BID 20 mL (4 g) >20-35 kg 15 mL (3 g) BID 30 mL (6 g) >35-50 kg 20 mL (4 g) BID 40 mL (8 g) >50 kg 30 mL (6 g) BID 60 mL (12 g) Abbreviations: BID=twice daily Inclusion Criteria: 1. Female subjects 5 to 20 years of age, inclusive, at Screening 2. Body weight ≥12 kg at Screening 3. Can swallow the study medication provided as a liquid solution or can take it by gastrostomy tube 4. Has classic / typical Rett syndrome (RTT) 5. Has a documented disease-causing mutation in the MECP2 gene 6. Has a stable pattern of seizures, or has had no seizures, within 8 weeks of Screening 7. Subjects of childbearing potential must abstain from sexual activity for the duration of the study and for at least 30 days thereafter or must agree to use acceptable methods of contraception. Subject must not be pregnant or breastfeeding. 8. The subject's caregiver is English-speaking and has sufficient language skills to complete the caregiver assessments 9. Subject and caregiver(s) must reside at a location to which study drug can be delivered and have been at their present residence for at least 3 months prior to Screening Exclusion Criteria: 1. Has been treated with insulin within 12 weeks of Baseline 2. Has current clinically significant cardiovascular, endocrine (such as hypo- or hyperthyroidism, Type 1 diabetes mellitus, or uncontrolled Type 2 diabetes mellitus), renal, hepatic, respiratory or gastrointestinal disease (such as celiac disease or inflammatory bowel disease) or has major surgery planned during the study 3. Has a history of, or current, cerebrovascular disease or brain trauma 4. Has significant, uncorrected visual or uncorrected hearing impairment 5. Has a history of, or current, malignancy 6. Has a known history or symptoms of long QT syndrome Additional inclusion / exclusion criteria apply. Patients will be evaluated at screening to ensure that all criteria for study participation are met. Patients may be excluded from the study based on these assessments (and specifically, if it is determined that their baseline health and condition do not meet all pre-specified entry criteria). Outcome Measures Rett Syndrome Behavior Questionnaire (RSBQ) Total Score - Change from Baseline to Week 12. The RSBQ is a 45-item caregiver-completed rating scale that includes 45 items, 39 of them grouped into 8 subscales, whose ratings reflect the severity and frequency of symptoms. Items are rated as 0 (not true), 1 (somewhat or sometimes true), or 2 (very true). The 8 subscales are general mood, breathing problems, hand behavior, face movements, body rocking / expressionless face, night- time behaviors, fear / anxiety, and walking / standing. Scores for item 31 are reversed in the calculation of the total score. The total score ranges from 0 to 90 and is calculated as the sum of the item scores. Higher scores mean worse behavior. Clinical Global Impression-Improvement (CGI-I) Score at Week 12 Clinical global impression (CGI) rating scales are measures of symptom severity, treatment response and the efficacy of treatments in treatment studies of patients with mental disorders. It is a brief 3-item observer-rated scale that can be used in clinical practice as well as in researches to track symptom changes. Its 3 items assess, 1) Severity of Illness (CGI-S), 2) Global Improvement (CGI-I), and 3) Efficacy Index (CGI-E, which is a measure of treatment effect and side effects specific to drugs that were administered). To rate how much the subject's illness has improved or worsened relative to a baseline state, a 7-point scale is used from 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse. Results In this clinical study females with Rett syndrome received twice-daily oral cPG or placebo for 12 weeks. For the co-primary efficacy endpoints, least squares mean (LSM) change from baseline to week 12 in the Rett Syndrome Behavior Questionnaire (RSBQ) for cPG was -5.5 versus - 1.6 for placebo (p = 0.001), n= 86 for cPG and n= 87 for placebo (FIG.7). Clinical Global Impression–Improvement at week 12 for cPG was 3.60 versus 3.83 for placebo (P = 0.0020, effect size, 0.42 ), n= 86 for cPG and n=87 for placebo. (FIG.8). The comparison the adverse reactions in the clinical trials of DAYBLUE and cPG is given in TABLE 4.

[0006] TABLE 4: Comparison of Adverse Reactions of in Clinical Trials of DAYBUE and cPG The adverse reactions of participants treated with DAYBUE is given in the publication of “Treatment Management Guide for Healthcare Professionals” published by Acadia Pharmaceuticals. (https: / / www.daybuehcp.com / treatment-management-guide.pdf). Conclusion: The results showed that cPG had comparable efficacy to DAYBLUE and significantly fewer adverse reactions, suggesting that cPG is beneficial in treating the core symptoms of Rett syndrome. While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of examples only, and not limitation. It will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the present invention as defined in the appended claims. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined in accordance with the following claims and their equivalents. The present invention is described with reference to specific embodiments thereof. Other features and embodiments of the present invention can be produced by those of skill in the art without undue experimentation and a reasonably likelihood of success. All of those and other embodiments are considered to be part of the present invention. All publication, including patent documents and scientific articles, referred to in this application, including any bibliography, are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference.

Claims

Claims What is claimed is:

1. A method of prophylaxis or treatment of at least one Autism Related Disorder, comprising: a. providing a subject in need of said prophylaxis or treatment of at least one Autism Related Disorder; b. providing at least one pharmaceutical composition comprising: 1) at least one cPG compound, optionally in combination with one or more of the following components; a. at least one IGF-1 compound; b. at least one Des-(1-3) IGF-1 compound; or combinations thereof; wherein said components are administered together or separately; further wherein said components are provided together or separately; c. administering a pharmaceutically effective amount of said at least one pharmaceutical composition to said subject; wherein said subject is provided prophylaxis or treatment of said at least one Autism Related Disorder.

2. The method of claim 1, wherein said components are provided in a pharmaceutically acceptable diluent, adjuvant, excipient, or combinations thereof.

3. The method of claim 1, wherein said components, individually or combinations thereof, are provided as or in a pharmaceutically acceptable salt.

4. The method of claim 1, wherein said components are administered separately.

5. The method of claim 1, wherein said components are administered together.

6. The method of claim 1, wherein said prophylaxis or treatment of said at least one Autism Related Disorder comprises Rett Syndrome, Autism Spectrum Disorder, Autism, Autistic Disorder, Asperger Syndrome, Fragile X syndrome, Phelan- McDermid Syndrome, Angelman Syndrome, Pitt Hopkins Syndrome, Prader- Willi Syndrome, or combinations thereof.

7. The method of claim 1, wherein said prophylaxis or treatment of said at least one Autism Related Disorder comprises developmental delays, learning disabilities, social problems, behavior problems, anxiety, depression, obsessive-compulsive behaviors or combinations thereof.

8. The method of claim 1, wherein said at least one cPG compound comprises at least one of Cyclic Prolyl Glycine, Cyclic Glycyl-2-Allyl Proline, Cyclic (glycyl-L-prolylglycyl- L-prolylglycyl-L-prolyl), or combinations thereof.

9. The method of claim 8, wherein said at least one cPG compound comprises Cyclic Prolyl Glycine.

10. The method of claim 9, wherein said Cyclic Prolyl Glycine is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg.

11. The method of claim 9, wherein said Cyclic Prolyl Glycine is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg.

12. The method of claim 9, wherein said Cyclic Prolyl Glycine is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg.

13. The method of claim 9, wherein said Cyclic Prolyl Glycine is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg.

14. The method of claim 9, wherein said at least one pharmaceutical composition comprising Cyclic Prolyl Glycine is administered about once a day, about twice a day, or combinations thereof.

15. The method of claim 9, wherein said at least one pharmaceutical composition comprising Cyclic Prolyl Glycine is administered orally, intravenously, intranasally, or combinations thereof.

16. The method of claim 8, wherein said at least one cPG compound comprises Cyclic Glycyl-2-Allyl Proline.

17. The method of claim 16, wherein said Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 0.5 mg to 10.0 mg / kg.

18. The method of claim 16, wherein said Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg.

19. The method of claim 16, wherein said Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg.

20. The method of claim 16, wherein said Cyclic Glycyl-2-Allyl Proline is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg.

21. The method of claim 16, wherein said at least one pharmaceutical composition comprising Cyclic Glycyl-2-Allyl Proline is administered about once a day, about twice a day, or combinations thereof.

22. The method of claim 16, wherein said at least one pharmaceutical composition comprising Cyclic Glycyl-2-Allyl Proline is administered orally, intravenously, intranasally, or combinations thereof.

23. The method of claim 8, wherein said at least one cPG compound comprises Cyclic (glycyl-L- prolylglycyl-L-prolylglycyl-L-prolyl).

24. The method of claim 23, wherein said Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg.

25. The method of claim 23, wherein said Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 1.0 mg / kg to about 3.0 mg / kg.

26. The method of claim 23, wherein said Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 3.0 mg / kg to about 7.0 mg / kg.

27. The method of claim 23, wherein said Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is provided in a dose between about 7.0 mg / kg to about 10.0 mg / kg.

28. The method of claim 23, wherein said at least one pharmaceutical composition comprising Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is administered about once a day, about twice a day, or combinations thereof.

29. The method of claim 23, wherein said at least one pharmaceutical composition comprising Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl) is administered orally, intravenously, intranasally, or combinations thereof.

30. The method of claim 1, wherein said at least one IGF-1 compound comprises at least one of: a) at lest one IGF-1; b) at least one IGF-2; c) at least one IGF receptor (IGF-1R); d) at least one IGF binding proteins (IGFBP); e) or combinations thereof.

31. The method of claim 30, wherein said at least one IGF-1 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously; c) administered about twice daily; d) administered for about six months; c) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof.

32. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-1 compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof.

33. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-1 compound is administered about once a day, about twice a day, about once a week, about twice a week, or combinations thereof.

34. The method of claim 30, wherein said at least one IGF-1 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously; c) administered about twice daily; d) administered for about six months; c) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof.

35. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-1 compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof.

36. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-1 compound is administered about once a day, about twice a day, about once a week, about twice a week, or combinations thereof.

37. The method of claim 30, wherein said at least one IGF-2 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously; c) administered about twice daily; d) administered for about six months; c) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof.

38. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-2 compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof.

39. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-2 compound is administered once a week, twice a week or combinations thereof.

40. The method of claim 30, wherein said at least one IGF-2 compound is: a) administered in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) administered subcutaneously; c) administered about twice daily; d) administered for about six months; c) administered for the first and the last weeks at a dose of about 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1mg / Kg; e) or combinations thereof.

41. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-2 compound is administered subcutaneously, orally, intravenously, intranasally, or combinations thereof.

42. The method of claim 30, wherein said at least one pharmaceutical composition comprising at least one IGF-2 compound is administered once a week, twice a week or combinations thereof.

43. The method of claim 1, wherein said at least one des-(1-3)-IGF-1 compound comprises at least one of: a) Des-(1-3)IGF-1 which is truncated for the N-terminal tripeptide; b) b) R3IGF-1 that is substituted by arginine for glutamic acid at position 3; c) c) LONGTMR3IGF-1 whose N-terminus is prolonged by additional 13 residues compared with R3IGF-1; d) or combinations thereof.

44. The method of claim 43, wherein said at least one pharmaceutical composition comprising at least one Des-(1-3) IGF-1 compound is: a) provided in a dose between about 0.05 mg / Kg and about 1.00 mg / Kg; b) is administered subcutaneously; c) is administered about twice / day; d) is administered for about six months; e) is administered for the first and the last weeks at a dose of about 0.05 mg / Kg and during the remaining periods administered at a dose of about 0.1mg / Kg; f) or combinations thereof.

45. The method of claim 43, wherein said at least one pharmaceutical composition comprising at least one Des-IGF-1 compound is administered subcutaneously, orally, intravenously intranasally, or combinations thereof.

46. The method of claim 43, wherein said at least one pharmaceutical composition comprising at least one Des-IGF-1 compound is administered about once a day, about twice a day, about once a week, about twice a week, or combinations thereof.

47. The method of claim 1, wherein said prophylaxis or treatment of said at least one Autism Related Disorder results in global improvement in symptoms related thereto, including language, communication, ambulation, hand movements, social (eye contact), autonomic features, seizures, and attentiveness, and improvement of common Rett symptoms, such as breathing, nighttime behaviors, eye gaze, vocalizations, mood, repetitive behaviors, facial expressions, or combinations thereof.

48. The method of claim 1, wherein said prophylaxis or treatment of said at least one Autism Related Disorder is prophylaxis.

49. The method of claim 1, wherein said prophylaxis or treatment of said at least one Autism Related Disorder is treatment.

50. The method of claim 1, wherein said subject is a human.

51. The method of claim 1, wherein said components are administered together in a single or multiple doses.

52. The method of claim 1, wherein said components are administered separately in a single or multiple doses.

53. The method of claim 1, wherein said components are provided together in a single or multiple containers.

54. The method of claim 1, wherein said components are provided separately in a single or multiple containers.

55. The method of claim 1, wherein said at least one cPG compound is provided in a dose between about 0.5 mg / kg to about 10.0 mg / kg.

56. The method of claim 1, wherein said at least one cPG compound is provided by a route of administration of injection, orally, intranasally, intraperitoneal, intravenously, subcutaneously, or combinations thereof.

57. The method of claim 1, wherein said at least one cPG compound is provided in a regime of between once per hour to about once per three months.

58. A pharmaceutical composition for the prophylaxis or treatment of at least one Autism Related Disorder, comprising at least one of: a) at least one cPG compound, optionally in combination with; b) at least one IGF-1 compound; c) at least one IGF-2 compound; d) at least one Des (1-3) IGF-1 compound; e) combinations thereof; wherein said components are provided together or separately; further wherein said pharmaceutical composition when administered to a subject in need of prophylaxis or treatment of obesity is so prevented from or treated for said at least one Autism Related Disorder.

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