Methods for the prophylaxis and treatment of friedreich's ataxia disorders

Abstract

The present invention recognizes that there is a need for the prophylaxis or treatment of Friedreich's Ataxia Related Disorders, which includes Friedreich's Ataxia, Spinocerebellar Ataxia as (SCAs), Ataxia-Telangiectasia (AT), Dentatorubral-Pallidoluysian Atrophy (DRPLA), Charcot-Marie-Tooth (CMT) Disease or combinations thereof. A first aspect of the present invention generally relates to methods of prophylaxis or treatment of Friedreich's Ataxia 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 Friedreich's Ataxia Related Disorders.

Description

PATENT BI1-003WOMETHODS FOR THE PROPHYLAXIS AND TREATMENT OF FRIEDREICH’S ATAXIA DISORDERSRELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Application No. 63 / 773,451 filed March 18, 2025, the contents of which are incorporated by reference.FIELD OF THE INVENTION

[0002] The present invention relates generally to the fields of treatment and prophylaxis of Friedreich’s Ataxia Related Disorder or combinations thereof.BACKGROUND

[0003] Friedreich’s Ataxia Related Disorders (FARD), 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 Friedreich’s Ataxia. Friedreich’s Ataxia Related Disorders includes but is not limited to Spinocerebellar Ataxia as (SCAs), Ataxia-Telangiectasia (AT), Dentatorubral-Pallidoluysian Atrophy (DRPLA), Charcot-Marie-Tooth (CMT) Disease, or combinations thereof.

[0004] Friedreich’s Ataxia is caused by mutations in the FXN gene, is a genetic disorder that can be differentiated from other Ataxia as and related conditions by its specific symptoms and genetic basis, including cardiomyopathy, scoliosis, and diabetes. Friedreich’s Ataxia (FA) is the most common hereditary Ataxia a accounting for approximately 50% of all Ataxia a cases. (Cook A, Giunti P. Friedreich’s Ataxia a: clinical features, pathogenesis and management. Br Med Bull. 2017 Dec 01;124(1):19-30.) (Delatycki MB, Bidichandani SI. Friedreich’s Ataxia - pathogenesis and implications for therapies. Neurobiol Dis. 2019 Dec; 132:104606).

[0005] The disease causes neurodegeneration and manifests as a combination of difficulty in ambulation, muscle weakness, loss of sensation and proprioception, andPATENT BI1-003WOimpaired speech. (Strawser CJ, Schadt KA, Lynch DR. Therapeutic approaches for the treatment of Friedreich’s Ataxia a. Expert Rev Neurother. 2014 Aug;14(8):949-57.)

[0006] Below is a breakdown of conditions that may have overlapping features with Friedreich’s Ataxia:1. Other Genetic Ataxia as:• Spinocerebellar Ataxia as (SCAs):While both FA and SCAs cause Ataxia a, SCAs are characterized by different genetic mutations and varying clinical presentations, including different ages of onset and progression rates.• Ataxia-Telangiectasia (AT):AT is a clinically complex disorder characterized by Ataxia, telangiectasia (spider veins), and immunodeficiency, which differs from FA in the absence of scoliosis and cardiomyopathy.• Dentatorubral-Pallidoluysian Atrophy (DRPLA):DRPLA is a form of Ataxia a with a different genetic basis and clinical presentation, including seizures and movement disorders.2. Neuropathy and Peripheral Nerve Disorders:• Charcot-Marie-Tooth (CMT) Disease:CMT is a group of disorders that affect the peripheral nerves, leading to muscle weakness and sensory loss, and can mimic some symptoms of FA, particularly in children.CIDP is an autoimmune disorder that causes nerve damage, leading to weakness and numbness, which can be differentiated from FRDA based on its underlying cause and response to treatment.

[0007] Friedreich’s Ataxia (FA) is a rare, inherited disorder that causes progressive damage to the nervous system. This can cause movement and sensory symptoms and trouble with walking and gait.PATENT BI1-003WO

[0008] In FA, nerve fibers in the spinal cord and peripheral nerves break down, becoming thinner. In the brain, the cerebellum, part of the brain that coordinates balance and movement, is most affected.

[0009] FA affects a person’s peripheral nerves, which carry information back and forth from the brain to the body using sensory and motor signals. This is why a person with FA develops motor weakness and sensory loss. Symptoms typically begin between the ages of five and 15, although they sometimes appear after age 25. Symptoms of FA may include:• Awkward, unsteady movements and impaired muscle coordination (Ataxia a) that worsens over time• Difficulty walking and poor balance• Impaired sensory functions, such as loss of sensation in the arms and legs, which may spread to the trunk and other parts of the body• Loss of normal reflexes, especially in the knees and ankles• Slowness and slurring of speech (dysarthria)• Increased muscle tone (spasticity)• Curving of the spine to one side (scoliosis)• Difficulty swallowing• Hearing and vision loss• Fatigue

[0010] Friedreich’s Ataxia causes neurodegeneration and manifests as a combination of difficulty in ambulation, muscle weakness, loss of sensation and proprioception, and impaired speech. (Strawser CJ, Schadt KA, Lynch DR. Therapeutic approaches for the treatment of Friedreich’s's ataxia. Expert Rev Neurother. 2014 Aug;14(8):949-57.) It has an autosomal recessive inheritance pattern, and symptom onset is usually in childhood. Unfortunately, symptoms worsen as time progresses, so most people affected by this disease end up requiring mobility aids such as wheelchairs, lose their vision and hearing, and develop other medical complications such as diabetes mellitus and scoliosis.

[0011] The most common cause of death in patients with FA is hypertrophic cardiomyopathy. (Lynch DR, Regner SR, Schadt KA, Friedman LS, Lin KY, St JohnPATENT BI1-003WOSutton MG. Management and therapy for cardiomyopathy in Friedreich’s's ataxia.Expert Rev CardiovascTher. 2012 Jun;10(6):767-77.) Patients with FA have an abnormal amount of trinucleotide repeats on the frataxin (FXN) gene on chromosome 9. The frataxin gene is responsible for producing frataxin, a protein that helps form enzymes needed for mitochondrial adenosine triphosphate (ATP) production and management of iron stores. In FA, the pathological trinucleotide repeats result in gene silencing and a decrease in frataxin. Highly active cells depending on ATP production, such as neurons, cardiomyocytes, and pancreatic beta cells, are adversely affected. (Lodi R, Rajagopalan B, Bradley JL, Taylor DJ, Crilley JG, Hart PE, Blamire AM, Manners D, Styles P, Schapira AH, Cooper JM. Mitochondrial dysfunction in Friedreich’s's ataxia: from pathogenesis to treatment perspectives. Free Radic Res. 2002 Apr;36(4):461 -6)

[0012] The cells most susceptible to damage are the ones that produce the most frataxin, which mainly includes the neurons and cardiomyocytes. There is a “dying back phenomena” with the progressive axonal loss of myelinated peripheral neurons and secondary gliosis in the spinal cord and spinal roots in patients with FA. The posterior columns, corticospinal tract, and ventral / dorsal spinocerebellar tracts display demyelination. This is due to the loss of large myelinated nerve fibers. The lost neurons are replaced by fibrosis, and the spinal cord becomes thin. This is evidenced by a reduction in the anteroposterior and transverse diameter of the thoracic spinal cord. The dorsal spinal ganglia are also affected. (Koeppen AH, Becker AB, Qian J, Feustel PJ. Friedreich’s Ataxia: Hypoplasia of Spinal Cord and Dorsal Root Ganglia. J Neuropathol Exp Neurol. 2017 Feb 01;76(2):101 -108)

[0013] Eventually, neurons in this area, particularly lumbosacral and nerve cells in the Clarke column, are lost and are replaced by capsular cells. Of note, corticospinal tracts are relatively spared down to the level of the cervicomedullary junction. Degeneration of the posterior column correlates with the loss of proprioception and sensory ataxia.Likewise, the loss of the sensory ganglia is responsible for the loss of tendon reflexes. The complication of kyphoscoliosis is a result of spinal muscular imbalance.PATENT BI1-003WO

[0014] Other affected areas include the dentate nucleus, which typically has mild to moderate neuronal loss, and the middle and superior cerebellar peduncles, which show atrophy. There is a patchy loss of Purkinje cells in the superior vermis of the cerebellum, and neuronal loss in the inferior olivary, pontine and medullary nuclei, along with the optic tracts. The cerebellar ataxia is caused by the loss of the lateral and ventral spinocerebellar tracts, Clarke column, dentate nucleus, superior vermis, and dentatorubral pathways. Cranial nerves VII, X, and XII are also commonly affected. Facial weakness, slurred speech, and dysphagia are also present due to the affected aforementioned cranial nerves. (Palau F. Friedreich’s's ataxia and frataxin: molecular genetics, evolution and pathogenesis (Review). Int J Mol Med. 2001 Jun;7(6):581-9.)

[0015] Friedreich’s's ataxia is a predominantly neurodegenerative disease caused by recessive mutations that produce a deficiency of frataxin (FXN). A herpesviral amplicon vector carrying a gene encoding for brain-derived neurotrophic factor (BDNF) was used to drive its overexpression in neuronal cells and test for its effect on FXN -deficient neurons both in culture and in the mouse cerebellum in vivo. Gene transfer of BDNF to primary cultures of mouse neurons prevents the apoptosis which is triggered by the knockdown of FXN gene expression. This neuroprotective effect of BDNF is also observed in vivo in a viral vector-based knockdown mouse cerebellar model. The injection of a lentiviral vector carrying a minigene encoding for an FXN-specific short hairpin ribonucleic acid (shRNA) into the mouse cerebellar cortex triggers a FXN deficit which is accompanied by significant apoptosis of granule neurons as well as loss of calbindin in Purkinje cells. These data demonstrate the potential therapeutic usefulness of neurotrophins like BDNF to protect FXN-deficient neurons from degeneration.(Katsu-Jimenez Y, Loria F, Corona JC, Diaz-Nido J. Gene Transfer of Brain-derived Neurotrophic Factor (BDNF) Prevents Neurodegeneration Triggered by FXN Deficiency. Mol Ther. 2016 May;24(5):877-89. doi: 10.1038 / mt.2016.32. Epub 2016 Feb 5. PMID: 26849417; PMCID: PMC4881769.)

[0016] In addition, Friedreich’s ataxia (FRDA) is an autosomal recessive, severelyPATENT BI1-003WOincapacitating disorder. Abnormalities in the insulin / insulin-like growth factor 1 (IGF-1) system (IIS) signaling pathway were thought to play a role in the physiopathological processes of various neurodegenerative disorders, including spinocerebellar ataxias. Cyclic Prolyl Glycine is a metabolite of IGF-1.

[0017] 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.

[0018] In the present invention, we present clinical trial results demonstrating the unexpected efficacy of cPG in treating Friedreich’s Ataxia, achieving significantly better outcomes than omaveloxolone without serious adverse effects.SUMMARY OF THE INVENTION

[0019] The inventions described and claimed herein have many attributes and embodiments including, but not limited to, those set forth or described or referenced in this brief summary. The inventions described and claimed herein are not limited to, or by, the features or embodiments identified in this summary, which is included for purposes of illustration only and not restriction.

[0020] The invention recognizes that there is a need for the prophylaxis or treatment of Friedreich’s Ataxia Related Disorders (FARD), which refers to disorders that have at least some symptoms of the various forms of Friedreich’s Ataxia.Friedreich’s Ataxia Related Disorders includes but is not limited to Spinocerebellar Ataxia as (SCAs), Ataxia a-Telangiectasia (AT), Dentatorubral- Pallidoluysian Atrophy (DRPLA), Charcot-Marie-Tooth (CMT) Disease, or combinations thereof.

[0021] A first aspect of the invention generally relates to methods of prophylaxis or treatment of Friedreich’s Ataxia Related Disorders using various pharmaceutical compositions.PATENT BI1-003WO

[0022] A second aspect of the invention generally relates to pharmaceutical compositions used for the prophylaxis or treatment of Friedreich’s Ataxia Related Disorders.

[0023] Embodiments also include methods of treating a Friedreich’s Ataxia Related Disorder in a subject. The methods can include administering a therapeutic amount of cPG compound to the subject. In aspects, the cPG compound is administered in combination with an IGF-1 compound and / or a Des-(1-3) IGF-1 compound. The individual compounds can be administered together or separately.

[0024] In aspects, the Friedreich’s Ataxia Related Disorder is Spinocerebellar Ataxia as (SCAs), Ataxia-Telangiectasia (AT), Dentatorubral-Pallidoluysian Atrophy (DRPLA), Charcot-Marie-Tooth (CMT) Disease or combinations thereof.

[0025] In aspects, the treatment improves one or more symptoms: difficulty in ambulation, muscle weakness, loss of sensation and proprioception, and impaired speech, social problems, behavior problems and anxiety.

[0026] In aspects, the cPG compound is Cyclic Prolyl Glycine, Cyclic Glycyl-2-Allyl Proline, Cyclic (glycyl-L-prolylglycyl- L-prolylglycyl-L-prolyl), or combinations thereof.

[0027] Embodiments also include a pharmaceutical composition for the treating a Friedreich’s Ataxia Related Disorder. The composition can include:a) a cPG compound, optionally in combination with;b) a IGF-1 compound;c) a IGF-2 compound;d) a Des (1-3) IGF-1 compound;as well as combinations thereof. The components can be provided together or separately.

[0028] In still another aspect, the present specification provides a use of the therapeutic small molecule or the pharmaceutical composition including the same in the preparation of drugs for the prevention or treatment of a Friedreich’s Ataxia Related Disorder.PATENT BI1-003WO

[0029] Embodiments also include use of a compound in the manufacture of a medicament for the treatment or prophylaxes of a Friedreich’s Ataxia Related Disorder. The compound can be Cyclic Prolyl Glycine, Cyclic Glycyl-2-Allyl Proline or Cyclic (glycyl-L-prolylglycyl- L-prolylglycyl-L-prolyl). Preferably, the compound is a cyclo prolyl glycine (CpG).

[0030] Preferably, the compound is administered orally to the subject. Preferably, the compound is administered in a dose between about 0.5 mg / kg to about 10.0 mg / kg.

[0031] In aspects, the medicament also includes an IGF-1 compound and / or a Des-(1-3) IGF-1 compound.

[0032] In aspects, the cPG compound is administered in combination with an IGF-1 compound and / or a Des-(1-3) IGF-1 compound.

[0033] Embodiments also include a pharmaceutical composition for use in the treatment or prophylaxes of a Friedreich’s Ataxia Related Disorder. Preferably, the compound is a cyclo prolyl glycine (CpG).

[0034] Other features and advantages of aspects of the present invention will become apparent from the following more detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of aspects of the invention.BRIEF DESCRIPTION OF THE DRAWINGS

[0035] The accompanying drawings illustrate aspects of the present invention. In such drawings:

[0036] FIG. 1 generally depicts in graphic form Glutamate toxicity in cerebellar microexplants (P4) and rescue effect by cyclic GP.

[0037] FIG. 2 generally depicts prevention of glutamate toxicity by cyclic GP monitored within P4-cerebellar microexplants.PATENT BI1-003WO

[0038] FIG. 3 generally depicts effects of cPG on functional recovery after 6- OHDA lesion.

[0039] 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.

[0040] FIG. 5 generally depicts the impact of BrdU + Cells / 300 micrometer at sub ventricular zone for cPG, cGMeP and c(PG)3 drug solutions.

[0041] FIG. 6 generally depicts the impact of BrdU + Cells / 300 micrometer at dentate gyrus for cPG, c(PG)3 cGMeP and drug solutions.DEFINITIONS

[0042] Reference in this specification to “one embodiment / aspect” or “an embodiment / aspect” means that a particular feature, structure, or characteristic described in connection with the embodiment / aspect is included in at least one embodiment / aspect of the disclosure. The use of the phrase “in one embodiment / aspect” or “in another embodiment / aspect” in various places in the specification are not necessarily all referring to the same embodiment / aspect, nor are separate or alternative embodiments / aspects mutually exclusive of other embodiments / aspects. Moreover, various features are described which may be exhibited by some embodiments / aspects and not by others. Similarly, various requirements are described which may be requirements for some embodiments / aspects but not other embodiments / aspects. Embodiment and aspect can in certain instances be used interchangeably.

[0043] The terms used in this specification generally have their ordinary meanings in the art, within the context of the disclosure, and in the specific context where each term is used. Certain terms that are used to describe the disclosure are discussed below, or elsewhere in the specification, to provide additional guidance to thePATENT BI1-003WOpractitioner regarding the description of the disclosure. It will be appreciated that the same thing can be said in more than one way.

[0044] Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein. Nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and is not intended to further limit the scope and meaning of the disclosure or of any exemplified term. Likewise, the disclosure is not limited to various embodiments given in this specification.

[0045] Without intent to further limit the scope of the disclosure, examples of instruments, apparatus, methods and their related results according to the embodiments of the present disclosure are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the disclosure. Unless otherwise defined, 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 disclosure pertains. In the case of conflict, the present document, including definitions, will control.

[0046] 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:PATENT BI1-003WO

[0047] “Directly” refers to direct causation of a process that does not require intermediate steps. “Indirectly” refers to indirect causation that requires intermediate steps.

[0048] “About” refers to plus or minus 10% of the indicated value.

[0049] Friedreich’s Ataxia Related Disorders (FARD), 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 Friedreich’s Ataxia. Friedreich’s Ataxia Related Disorders includes but is not limited to Spinocerebellar Ataxia as (SCAs), Ataxia-Telangiectasia (AT), Dentatorubral-Pallidoluysian Atrophy (DRPLA), Charcot-Marie-Tooth (CMT) Disease, or combinations thereof.

[0050] The term “formulation” as used herein refers to the antibodies disclosed herein and excipients combined together which can be administered and has the ability to bind to the corresponding receptors and initiate a signal transduction pathway resulting in the desired activity. The formulation can optionally comprise other agents.

[0051] The term “pharmaceutical composition” is intended to include the combination of an active agent (i.e., a prodrug therapeutic) with a carrier, inert or active, in a sterile composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo. In one aspect, the pharmaceutical composition is substantially free of endotoxins or is non-toxic to recipients at the dosage or concentration employed.

[0052] The term "administration" refers to the introduction of an amount of a predetermined substance into a patient by a certain suitable method. The composition disclosed herein may be administered via any of the common routes, as long as it is able to reach a desired tissue, for example, but is not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrapulmonary, or intrarectal administration. However, since peptides are digested upon oral administration, active ingredients of a composition for oral administration should be coated or formulated for protection against degradation in the stomach.PATENT BI1-003WO

[0053] The term “medicament,” “active agent” or “active ingredient” refers to a substance, compound, or molecule, which is biologically active or otherwise, induces a biological or physiological effect on a subject to which it is administered to. In other words, “active agent” or “active ingredient” refers to a component or components of a composition to which the whole or part of the effect of the composition is attributed. An active agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. An active agent can be a secondary agent, or in other words, the component(s) of a composition to which an additional part and / or other effect of the composition is attributed.

[0054] The terms “treating,” “treatment” and the like are used herein, without limitation, to mean obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disorder or sign or symptom thereof, and / or may be therapeutic in terms of amelioration of the symptoms of the disease or infection, or a partial or complete cure for a disorder and / or adverse effect attributable to the disorder.

[0055] Other technical terms used herein have their ordinary meaning in the art that they are used, as exemplified by a variety of technical dictionaries. The particular values and configurations discussed in these non-limiting examples can be varied and are cited merely to illustrate at least one embodiment and are not intended to limit the scope thereof.DETAILED DESCRIPTION

[0056] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the subject technology as claimed. Additional features and advantages of the subject technology are set forth in the description below, and in part will be apparent from the description, or may be learned by practice of the subjectPATENT BI1-003WOtechnology. The advantages of the subject technology will be realized and attained by the structure particularly pointed out in the written description and claims hereof.

[0057] The present invention recognizes that there is a need for the prophylaxis or treatment of Friedreich’s Ataxia Related Disorders (FARD), 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 Friedreich’s Ataxia. Friedreich’s Ataxia Related Disorders includes but is not limited to Spinocerebellar Ataxia as (SCAs), Ataxia-Telangiectasia (AT), Dentatorubral-Pallidoluysian Atrophy (DRPLA), Charcot-Marie-Tooth (CMT) Disease, or combinations thereof.

[0058] 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 Friedreich’s AtaxiaRelated Disorders using various pharmaceutical compositions.2) pharmaceutical compositions used for the prophylaxis or treatment of Friedreich’s Ataxia Related Disorders.

[0059] 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.METHODS OF TREATMENT OF FRIEDREICH’S ATAXIA RELATED DISORDERS

[0060] A first aspect of the present invention includes a method of prophylaxis or treatment of at least one Friedreich’s Ataxia Related Disorder, including: (a) providing a subject in need of the prophylaxis or treatment of at least one Friedreich’s Ataxia 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 administeredPATENT BI1-003WOtogether 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 Friedreich’s Ataxia Related Disorder.A. COMPONENTS

[0061] An aspect of the present invention includes wherein the components are provided in a pharmaceutically acceptable diluent, adjuvant, excipient, or combinations thereof.

[0062] Another aspect of the present invention includes wherein the components, individually or combinations thereof, are provided as or in a pharmaceutically acceptable salt.

[0063] A further aspect of the present invention includes wherein the components are administered separately.

[0064] An additional aspect of the present invention includes wherein the components are administered together.B. PROPHYLAXIS / TREATMENT OF FRIEDREICH’S ATAXIA

[0065] An aspect of the present invention includes wherein the prophylaxis or treatment of the at least one Friedreich’s Ataxia Related Disorder includes but is not limited to Friedreich’s Ataxia (FA), Spinocerebellar Ataxia as (SCAs), Ataxia -Telangiectasia (AT), Dentatorubral-Pallidoluysian Atrophy (DRPLA), Charcot-Marie-Tooth (CMT) Disease, or combinations thereof.

[0066] Another aspect of the present invention includes wherein the prophylaxis or treatment of Friedreich’s Ataxia in which the disease causes neurodegeneration and manifests as a combination of difficulty in ambulation, muscle weakness, loss ofPATENT BI1-003WOsensation and proprioception, and impaired speech, social problems, behavior problems, anxiety, depression, or combinations thereof.C. cPG COMPOUND

[0067] 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.

[0068] An additional aspect of the present invention includes wherein the at least one cPG compound includes Cyclic Prolyl Glycine.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] A further aspect of the present invention includes wherein the at least one cPGPATENT BI1-003WOcompound includes Cyclic Glycyl-2-Allyl Proline.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

[0081] 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.

[0082] Another aspect of the present invention includes wherein the at least one cPG compound includes Cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl).

[0083] 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.

[0084] 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.

[0085] 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 / kgPATENT BI1-003WOto about 7.0 mg / kg.

[0086] 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.

[0087] 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.

[0088] 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

[0089] 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) or combinations thereof.

[0090] 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 once a day, twice a day, once a week, twice a week or combination thereof; 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.

[0091] A further aspect of the present invention includes wherein the at least one pharmaceutical composition comprising at least one IGF-1 compound is administeredPATENT BI1-003WOsubcutaneously, orally, intranasally, or combinations thereof.

[0092] 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.

[0093] 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 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 0.1 mg / Kg; e) or combinations thereof.

[0094] 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.

[0095] 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.

[0096] 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 once a day, twice daily, once a week, twice a week or combination there of; 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 0.1 mg / Kg; e) or combinations thereof.

[0097] 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.

[0098] Another aspect of the present invention includes wherein the at least onePATENT BI1-003WOpharmaceutical composition comprising at least one IGF-2 compound is administered once a day, twice a day, once a week, twice a week or combinations thereof.

[0099] 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 once a day, twice daily, once a week, twice a week or combination thereof; 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 0.1 mg / Kg; f) or combinations thereof.

[0100] An additional aspect of the present invention includes wherein theat least one pharmaceutical composition comprising at least one IGF-2compound is administered subcutaneously, orally, intranasally, orcombinations thereof.

[0101] 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, twice a day, once a week, or twice a week, or combinations thereof.E. DES (1-3)-IGF-1 COMPOUND

[0102] 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.

[0103] 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 once a day, twice day, oncePATENT BI1-003WOa week, twice a week or combination thereof; d) 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 0.1 mg / Kg; f) or combinations thereof.

[0104] 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.

[0105] 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, twice a day, once a week, or twice a week, or combinations thereof.F. OUTCOMES

[0106] Another aspect of the present invention includes wherein the prophylaxis or treatment of the at least one Friedreich’s Ataxia Related Disorder results in global improvement in symptoms including ambulation, muscle weakness, loss of sensation and proprioception, and impaired speech, or combinations thereof.

[0107] A further aspect of the present invention includes wherein the prophylaxis or treatment of the at least one Friedreich’s Ataxia Related Disorder is prophylaxis.

[0108] An additional aspect of the present invention includes wherein the prophylaxis or treatment of the at least one Friedreich’s Ataxia Related Disorder is treatment.G. SUBJECT

[0109] An aspect of the present invention includes wherein the subject is a human.H. ADMINSTERED TOGETHER OR SEPARATELYPATENT BI1-003WO

[0110] Another aspect of the present invention includes wherein the components are administered together in a single or multiple doses.

[0111] 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

[0112] An additional aspect of the present invention includes wherein the components are provided together in a single or multiple containers.

[0113] 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 THEINVENTION

[0114] 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.

[0115] 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, intravenously, subcutaneously or combinations thereof.

[0116] 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 COMPOSITIONSPATENT BI1-003WO

[0117] A second aspect of the present invention includes a pharmaceutical composition for the prophylaxis or treatment of at least one Friedreich’s Ataxia 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 at least one Friedreich’s Ataxia Related Disorder.

[0118] 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

[0119] The present invention is directed in part towards compounds that are effective in preventing and treating Friedreich’s Ataxia Related Disorders, which includes but is not limited to Friedreich’s Ataxia (FA), Spinocerebellar Ataxia as (SCAs), Ataxia-Telangiectasia (AT), Dentatorubral- Pallidoluysian Atrophy (DRPLA), Charcot-Marie-Tooth (CMT) Disease, or combinations thereof.Friedreich’s Ataxia Spectrum Disorders:

[0120] Friedreich’s Ataxia Spectrum Disorders are a collection of a genetic, progressive neurodegenerative disorders, characterized by a loss of coordination (ataxia), often starting with difficulty walking and progressing to affect other movements, speech, and potentially other systems like the heart, and combinations thereof.PATENT BI1-003WO

[0121] Friedreich’s ataxia (FA) shares several clinical and genetic features with various other neurological and neuromuscular disorders. These overlapping characteristics can complicate the differential diagnosis, highlighting the need to understand the similarities and distinctions among these conditions.

[0122] Friedreich’s ataxia shares clinical and genetic overlap with several hereditary and acquired neurological disorders, making diagnosis challenging. A thorough evaluation, including clinical assessment, genetic testing, and neuroimaging, is essential to distinguish FA from related conditions. Recognizing these distinctions enables accurate diagnosis, appropriate management, and effective genetic counseling for affected individuals and their families.1. Spinocerebellar Ataxias (SCAs)

[0123] Spinocerebellar ataxias (SCAs) are a diverse group of hereditary ataxias characterized by progressive degeneration of the cerebellum, brainstem, and spinal cord. Unlike FA, which follows an autosomal recessive inheritance pattern, SCAs are predominantly inherited in an autosomal dominant manner.

[0124] Clinical Presentations:• Ataxia and Gait Instability: Similar to FA, SCAs manifest with progressive ataxia, impaired balance, and coordination difficulties.• Dysarthria and Dysphagia: Slurred speech and swallowing difficulties are common.• Oculomotor Abnormalities: Abnormal eye movements, including nystagmus, are frequently observed.• Cognitive Impairment: Some SCAs are associated with cognitive decline, psychiatric symptoms, and dementia.• Peripheral Neuropathy: Similar to FA, some SCAs present with sensory neuropathy, leading to numbness and sensory loss.Genetics and Pathophysiology:PATENT BI1-003WO• Over 40 subtypes of SCAs have been identified, each caused by different genetic mutations, typically trinucleotide repeat expansions (e.g., CAG repeats).• Unlike FA, which primarily involves mitochondrial dysfunction and oxidative stress, SCAs primarily result from polyglutamine toxicity due to expanded CAG repeats, leading to protein misfolding and neuronal loss.Differentiation from FA:• Inheritance Pattern: Autosomal dominant in SCAs vs. autosomal recessive in FA.• Onset Age: SCAs generally have a later onset compared to the typical early childhood or adolescent onset of FA.• Cardiomyopathy: Prominent in FA but generally absent in most SCAs.• Skeletal Abnormalities: Scoliosis and foot deformities are more frequent and pronounced in FA.2. Ataxia-Telangiectasia (AT)

[0125] Ataxia-telangiectasia (AT) is a rare, multisystem disorder caused by mutations in the ATM gene (ataxia-telangiectasia mutated) on chromosome 11. Like FA, AT follows an autosomal recessive inheritance pattern, but its clinical spectrum extends beyond the nervous system.

[0126] Clinical Presentation:• Progressive Ataxia: Early-onset ataxia typically appears between ages 1 to 4, presenting similarly to FA.• Telangiectasia: Dilated blood vessels, most noticeable in the eyes and on the skin.• Immunodeficiency: Increased susceptibility to infections due to deficient immune function.• Cancer Predisposition: Particularly a higher risk of developing lymphomas and leukemias.PATENT BI1-003WO• Choreoathetosis and Dystonia: Involuntary, irregular movements are common.• Intellectual Decline: Some patients may exhibit cognitive impairment. Genetics and Pathophysiology:• The ATM gene plays a role in DNA repair and cell cycle regulation. Mutations lead to cellular radiosensitivity, impaired DNA damage response, and increased cancer risk.• Oxidative stress and mitochondrial dysfunction are implicated, sharing some similarity with FA pathophysiology.• Oculomotor Apraxia: Difficulty with initiating eye movements, a distinctive feature• Telangiectasia: Prominent vascular lesions are absent in FA.• Cardiac Involvement: FA commonly presents with hypertrophic cardiomyopathy.3. Charcot-Marie-Tooth Disease (CMT)

[0127] Charcot-Marie-Tooth disease (CMT) is a group of inherited peripheral neuropathies affecting the motor and sensory nerves. CMT can be inherited in various patterns: autosomal dominant, autosomal recessive, and X-linked. It is one of the most common hereditary neuropathies, affecting approximately 1 in 2,500 people.

[0128] Clinical Presentation:• Distal Muscle Weakness and Wasting: Particularly in the lower limbs, leading to foot drop and high-arched feet (pes cavus).• Sensory Loss: Decreased sensation, primarily in the feet and lower legs.• Areflexia: Reduced or absent tendon reflexes.• Gait Abnormalities: Difficulty walking due to weak ankles and muscle atrophy.• Skeletal Deformities: High arches, hammertoes, and scoliosis may be observed. Genetics and Pathophysiology:• Over 100 genes have been implicated in CMT, the most common being PMP22 gene duplication causing CMT type 1A.PATENT BI1-003WO• Demyelination and axonal degeneration are the key pathological features, leading to compromised nerve conduction.Differentiation from FA:• Ataxia vs. Motor Neuropathy: FA primarily manifests with cerebellar ataxia, while CMT features distal motor neuropathy.• Onset Age: FA typically has an earlier onset (childhood / adolescence) compared toCMT.• Cardiomyopathy: Frequently seen in FA but uncommon in CMT.• Sensory Loss Pattern: FA features loss of proprioception and vibration sense, whileCMT primarily affects distal sensory modalities.4. Dentatorubral-Pallidoluysian Atrophy (DRPLA)

[0129] Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal dominant neurodegenerative disorder characterized by a combination of movement disorders, cognitive impairment, and psychiatric disturbances. DRPLA primarily affects the dentate nucleus of the cerebellum, red nucleus of the midbrain, and the pallidoluysian region of the basal ganglia, hence its name.

[0130] This disorder is most commonly reported in Japan but has been documented worldwide. It typically presents in childhood or early adulthood, though the age of onset and symptoms can vary significantly depending on the size of the underlying genetic mutation.

[0131] Clinical Presentation:The manifestations of DRPLA vary depending on the age of onset:1. Childhood-Onset DRPLA:• Progressive myoclonus epilepsy: Recurrent seizures, myoclonic jerks, and epileptic encephalopathy.PATENT BI1-003WO• Ataxia: Poor coordination, gait instability, and dysmetria.• Intellectual decline: Cognitive regression and developmental delays.• Behavioral disturbances: Aggressiveness, hyperactivity, and personality changes.2. Adult-Onset DRPLA:• Choreoathetosis: Involuntary, jerky, dance-like movements combined with writhing movements.• Dystonia: Abnormal muscle contractions leading to twisting and repetitive movements.• Dementia: Progressive cognitive decline, memory loss, and executive dysfunction.• Psychiatric symptoms: Depression, hallucinations, psychosis, and anxiety.Comparison to Friedreich’s Ataxia (FA):• Inheritance: DRPLA is autosomal dominant, while FA is autosomal recessive.• Age of Onset: Childhood-onset DRPLA can mimic FA in terms of ataxia, but the presence of seizures and myoclonus helps differentiate them.• Cognitive Decline: While cognitive impairment may occur in advanced FA, dementia and psychiatric symptoms are more prominent in DRPLA.• Cardiomyopathy: Present in FA but generally absent in DRPLA.• Genetic Mutation: DRPLA is caused by CAG repeats in the ATN1 gene, while FA results from GAA repeats in the FXN gene.Animal Models and Treatment of Friedreich’s Ataxia Related Disorders (FARD) with cPG

[0132] A conserved pathology is observed in Friedreich’s Ataxia Related Disorders 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) andPATENT BI1-003WOinsulin-like growth factor-1 (IGF-1).

[0133] BDNF 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.

[0134] Friedreich’ s's ataxia is a predominantly neurodegenerative disease caused by recessive mutations that produce a deficiency of frataxin (FXN). A herpesviral amplicon vector carrying a gene encoding for BDNF was used to drive its overexpression in neuronal cells and test for its effect on FXN-deficient neurons both in culture and in the mouse cerebellum in vivo. This neuroprotective effect of BDNF is also observed in vivo in a viral vector-based knockdown mouse cerebellar model.Coinjection of a herpesviral vector encoding for BDNF efficiently prevents both the development of cerebellar neuropathology and the ataxic phenotype. These data demonstrate the potential therapeutic usefulness of neurotrophins like BDNF to protect FXN-deficient neurons from degeneration. (Katsu-Jimenez Y, Lona F, Corona JC, Diaz-Nido J. Gene Transfer of Brain-derived Neurotrophic Factor (BDNF) Prevents Neurodegeneration Triggered by FXN Deficiency. Mol Ther. 2016 May,24(5):877-89. doi: 10.1038 / mt.2016.32. Epub 2016 Feb 5. PMID: 26849417;PMC ID: PMC4881769)

[0135] In the context of Friedreich’ s's ataxia (FRDA), research suggests that insulinlike growth factor-1 (IGF-1) may play a role in the disease's pathophysiology, with some studies indicating potential benefits from IGF-1 therapy, particularly for neurological functions. 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 neurodegenerative disorders such as Friedreich’s Ataxia Related Disorders (FARD), which can be characterized with defects in synaptic function and neuronal connectivity. Abnormalities in the insulin / insulin-like growth factor 1 (IGF-1) system (IIS) signaling pathway were thought to play a role in the physio-pathologicalPATENT BI1-003WOprocesses of various neurodegenerative disorders, including FRDA and spinocerebellar ataxias.

[0136] 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).

[0137] In the present invention, methods of using cPG as a viable effective at treating Friedreichs’ Ataxia or other symptoms relating to synaptic dysfunctions such as but not limited to those resulting from the gene mutations described above are provided.

[0138] 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

[0139] 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 Friedreich’s Ataxia Related Disorders.

[0140] 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 Friedreich’s AtaxiaPATENT BI1-003WORelated Disorders.

[0141] 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:Structure 1: cyclic Prolyl Glycine

[0142] The present invention includes novel diketopiperazines that are structurally related to cPG.

[0143] One aspect of this invention provides novel cyclic compounds having the structural formula and substituents described below.Structure 2: cyclic Glycyl-2-Ally I Proline, or cyclic G lycy l-Alky I 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,PATENT BI1-003WOcyclopropyl, tert- butyl, cyclopropylmethyl, hexyl and the like.Where R can be an Ally, which refer to a group is a substituent with thestructural 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.oStructure 3: Cyclic G-2MeP (which is available for purchase from polypeptide suppliers such as Bachem Americas, Inc (Torrance, California, USA)).

[0144] 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: Principies 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.

[0145] In the present application, notably but not limited to this section where compound names and structures and abbreviations are provided, the various compounds can allPATENT BI1-003WObe 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.Structure 4: one possible structure for cyclic (glycyl-L-prolylglycyl-L-prolylglycyl-L-prolyl)

[0146] 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)

[0147] A solution of p-nitrophenyl ester hydrochloride (500 mg) dissolved in dimethylformamide (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. SolventsPATENT BI1-003WOwere 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 C21H30N6O6H2O: C, 52.49; H, 6.71; N, 17.49.Elemental analysis found C, 52.60; H, 6.81; N, 17.38.

[0148] 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

[0149] 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, beingPATENT BI1-003WOappropriate 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.

[0150] 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.

[0151] 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.PATENT BI1-003WO

[0152] Compounds of this invention can also be suitably administered by a sustained-release system or gel material with CPG incorporated therein.

[0153] 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-l (IGF-I), insulin-like growth factor-ll (IGF-II), transforming growth factor-pi, activin, growth hormone, nerve growth factor, brain-derived neurotrophic factor (BDNF), growth hormonebinding 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), a-, f3-, y-, or consensus interferon, and TNF- a. 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 a4 receptors (a4|31 and a4|37), such as anti-MAdCAM-1 mAb MECA-367 (ATCC accession no. HB-9478).

[0154] 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, aPATENT BI1-003WOselective norepinephine reuptake inhibitor such as viloxazine, or an atypical antipsychotic 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

[0155] 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.).

[0156] 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.

[0157] 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

[0158] 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

[0159] 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.PATENT BI1-003WO

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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-1 R 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.

[0164] 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 fetalPATENT BI1-003WOgrowth factor, as it is essential for a normal embryonic development and is highly expressed in embryonic and neonatal tissuesThe IGF-1 family includes but is not limited to:• IGF-1,• IGF-2• IGF receptors (IGF-1 R) and• IGF binding proteins (IGFBP).

[0165] 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).C. DES(1-3)IGF-1 COMPOUNDS

[0166] 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.

[0167] Des( I-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-Cys51and Cys47-Cys52, the amino acid numbers being those in full length IGF-I.

[0168] 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 withPATENT BI1-003WOR3IGF-1.

[0169] Removal of the three amino-terminal amino acids of insulin-like growth factor-l (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-l 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

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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; anPATENT BI1-003WOophthalmic 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.

[0174] 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.

[0175] A composition may also be used in the formulation of controlled, sustained, protracting, retarded, and / or controlled release drug delivery systems.

[0176] 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.

[0177] 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.

[0178] 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 ofPATENT BI1-003WOadministration 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.

[0179] 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.

[0180] 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 ofPATENT BI1-003WOadministration are determined, initially, using Phase I and Phase II clinical trials.

[0181] 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.

[0182] 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).

[0183] 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.

[0184] 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).PATENT BI1-003WO

[0185] 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.

[0186] 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).

[0187] 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 Gl tract, or by complexing the drug with ion-exchange resins.

[0188] 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.

[0189] 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.PATENT BI1-003WO

[0190] In some embodiments of the present invention, the composition is a unit dosage form (for example, a unit dosage form formulated for oral administration).

[0191] Pharmaceutical compositions can be administered by an appropriate route of administration at an appropriate dose and an appropriate regime.

[0192] 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.

[0193] 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.

[0194] 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, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; and / or physiologically acceptable polymers such as polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added,PATENT BI1-003WOsuch as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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 activePATENT BI1-003WOingredients to allow for the preparation of highly concentrated solutions.

[0199] Alternatively, the active ingredients may be in powder form for constitution with a suitable vehicle, for example, sterile, pyrogen-free water, before use.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.PATENT BI1-003WO

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.PATENT BI1-003WO

[0210] 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”).

[0211] 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.EXAMPLESExperiment 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

[0212] 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

[0213] 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 pl 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 pm pore size gaze) and centrifuged (2 minutes at 60 g) two times for a medium exchange intoPATENT BI1-003WOserum-free BSA-supplemented STARTV medium (Biochrom). The second centrifugation step was done with 1 ml of START V medium. The microexplants were reconstituted into 500 µl of STARTV medium and put on ice.Cultivation and fixation of cerebellar cells

[0214] 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

[0215] 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:

[0216] 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.

[0217] 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).

[0218] 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 proliferationPATENT BI1-003WOand differentiation.Conclusions

[0219] 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 2Cyclic (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.)

[0220] 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:

[0221] 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.

[0222] 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 treatedPATENT BI1-003WOgroup. 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)

[0223] 10 pl 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:

[0224] 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.

[0225] 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.PATENT BI1-003WOConclusions

[0226] Excessive glutamate can cause neuronal excitotoxicity by active NMDA receptors. Cyclic Prolyl Glycine analogues, cyclic(tri(proly Ig lycyl)) 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.

[0227] 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

[0228] Twenty male Wistar rats (280-310 g) were used. After exposing the skull, 6-OHDA (8 pg in a base of 2 pl 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 pl Hamilton syringe. The 6-OHDA was infused by a microdialysis infusion pump at a rate of 0.5pl / 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.

[0229] 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 treatmentPATENT BI1-003WOgroups.Results:

[0230] 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)

[0231] 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.

[0232] 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

[0233] Cyclic (tri(proly Iglycyl)) 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-striatalLesion.PATENT BI1-003WOMaterials and Methods (see above for Experiment 5 which are incorporated by reference herein]

[0234] 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

[0235] 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.

[0236] 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).MethodsPATENT BI1-003WO

[0237] 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.

[0238] The standard procedure for MWM was followed. We used a circular swimming pool (80 cm depth x 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 cmxio 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.

[0239] 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.

[0240] 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 MemoryScopolamine VehicleVehicle N = 12 N = 12cPG N = 16 N = 15

[0241] Acute effects of cPG were then tested in animals with scopolamine-inducedPATENT BI1-003WOmemory 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.

[0242] 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.

[0243] 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

[0244] 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

[0245] 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 dentatePATENT BI1-003WOgyrus in the hippocampus.Method:

[0246] Male Wistar rats weighing about 250-270 g (not newborn) were used. AH 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.

[0247] 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.

[0248] 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 IQ-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 graspedPATENT BI1-003WOwith 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).

[0249] 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

[0250] 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 aPATENT BI1-003WOsignificant 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

[0251] 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

[0252] 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.

[0253] 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

[0254] The drug treated animals showed greater invasion of the lesion by nerve fibersPATENT BI1-003WOthan 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

[0255] 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)

[0256] 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.

[0257] 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 basePATENT BI1-003WOof 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

[0258] 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.

[0259] 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.

[0260] 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 11Regeneration of Damaged Nerve Tissue of Cyclic Glycyl-2-Methyl Proline

[0261] 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 inPATENT BI1-003WOvolumes of 0.75 ml to thoroughly flood the site of injury.

[0262] 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.

[0263] Treatment of every animal was continued for 14 days, after which the animals were killed and histological sections prepared.Results

[0264] 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.

[0265] 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.

[0266] 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.PATENT BI1-003WOExperiment 12:The Clinical Study of cPG for Patients with Friedreich’s ataxia (FRDA)

[0267] The objective of this experiment was to test the efficacy and safety of cPG in Friedreich’s ataxia (FRDA) patients in a clinical pilot study.Inclusion Criteria:1. Age >16 years.2. Diagnosis of FRDA, genetically documented to be due to homozygosity for a GAA repeat expansion in intron 1 of FXN.3. Functional stage on the Ataxia subscale of the full FARS of 1 or higher (a score of 1 is assigned if the subject has " Minimal signs detected by the physician during screening. Can run or jump without loss of balance. No disability."), and total mFARS score of < 65.4. Adequate end organ function defined as follows: (i) total bilirubin <2x upper limit of normal unless attributable to Gilbert disease, (ii) ALT and AST <1,5x upper limit of normal, (iii) Creatinine <2x upper limit of normal, (iv) neutrophils >1.5x10A9 / L, (v) platelets >10A6 / pL.5. Written informed consent provided.Exclusion Criteria:1. Non-elective hospitalization within the past 60 days that could be of concern in the investigator's judgment. Any hospitalization in the previous 60 days will be assessed and if in the investigator's judgement it could compromise the individual or the study, that person will not be recruited. Examples include if the individual is hospitalized for management of cardiac morbidity such as uncontrolled arrhythmia or angina or for orthopedic surgery for a lower limb fracture.2. Women who are pregnant or lactating or men and women ofPATENT BI1-003WOchildbearing potential who are unwilling to use contraception for the duration of the study.3. FRDA due to compound heterozygosity for an expanded GAA repeat and a point mutation / deletion in the FXN gene.4. Current or recent (in last 12 months) arrhythmias including: atrial fibrillation, atrial flutter, sinus tachycardia >120 / min, sinus bradycardia <50 / min. Symptomatic paroxysmal arrhythmia which is recurring frequently. Cardiac insufficiency (by New York Heart Association >2). Reduced LV ejection fraction (<50%) in the last six months.5. Medical illness that in the judgment of the investigator would jeopardise the safe completion of the study. Examples include cancer, chronic inflammatory disease, severe diabetes (type I or II, HbA1c >8%), chronic liver insufficiency, epilepsy, thrombocytosis.6. Evidence of end organ dysfunction through failure to meet one or more parameters in inclusion criterion number 4.7. Prior invasive cancer (excluding localised basal cell or squamous cell skin cancer).8. Known hypersensitivity to resveratrol.9. Use of any investigational agent within 30 days of enrolment.10. Use of antioxidants such as vitamin E, coenzyme Q10 or idebenone within 30 days prior to enrolment.11. Concomitant use of medications with potential for clinically relevant drug interactions. This includes medications with a narrow therapeutic range that are metabolised by the cytochrome P4503A4, 2D6 or 2C9 systems e.g. warfarin, amiodarone.

[0268] A total of 8 females and 2 males were included in the pilot study; 23 to 36 years of age (average 28.6 ± 6.4), diagnosed with FRDA with normal ventricular function. Patients were treated with cPG therapy with 1mg / kg once a day orally for 6 months. The efficacy of this therapy was assessed by changes from baseline on the Scale for the Assessment and Rating of Ataxia (SARA) and by changes from baseline inPATENT BI1-003WOechocardiogram parameters.

[0269] The Scale for the Assessment and Rating of Ataxia (SARA) is a short and easy to use clinical score to assess the core symptoms of ataxia. It consists of 8 items (gait, stance, sitting, speech disturbance, finger-chase, nose-finger test, fast alternating hand movements and heel-shin slide) that sum up to a maximum of 40 points with higher scores indicating more severe ataxia. The SARA has been carefully validated in different kinds of ataxia and is widely used in movement disorder clinics, rehabilitation centers, and for clinical studies. (Schmitz-Hübsch T, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006;66(11):1717–20)Results:

[0270] The annual worsening rate (AWR) was estimated in this series as a SARA score of −0.6 ± 0.87 (CI 95%: −1.37 to 0.53) SARA score, whereas the AWR for our FRDA cohort was estimated as a SARA score of 2.48 ± 1.27 (CI 95%: 1.62 to 2.83).Echocardiographic parameters remained normal and stable.Conclusion:

[0271] Our results indicate a benefit of this cPG therapy to neurological functions in Friedreich’s ataxia* * *

[0272] 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 laims. 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 withPATENT BI1-003WOthe following claims and their equivalents.

[0273] 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.

[0274] 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.

[0275] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the present invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0276] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group asPATENT BI1-003WOmodified thus fulfilling the written description of all Markush groups used in the appended claims.

[0277] Unless otherwise indicated, all numbers expressing a characteristic, item, quantity, parameter, property, term, and so forth used in the present specification and claims are to be understood as being modified in all instances by the term “about.” As used herein, the term “about” means that the characteristic, item, quantity, parameter, property, or term so qualified encompasses a range of plus or minus ten percent above and below the value of the stated characteristic, item, quantity, parameter, property, or term. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values setting forth the broad scope of the invention are approximations, the numerical ranges and values set forth in the specific examples are reported as precisely as possible. Any numerical range or value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Recitation of numerical ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into the present specification as if it were individually recited herein.

[0278] The terms “a,” “an,” “the” and similar referents used in the context of describing the present invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein is intended merely to better illuminate the present invention and does not pose a limitation on the scope of the invention otherwise claimed. No language inPATENT BI1-003WOthe present specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0279] Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s).Embodiments of the present invention so claimed are inherently or expressly described and enabled herein.

[0280] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0281] All patents, patent publications, and other publications referenced and identified in the present specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.PATENT BI1-003WO

[0282] In closing, it is to be understood that although aspects of the present specification are highlighted by referring to specific embodiments, one skilled in the art will readily appreciate that these disclosed embodiments are only illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to a particular methodology, protocol, and / or reagent, etc., described herein. As such, various modifications or changes to or alternative configurations of the disclosed subject matter can be made in accordance with the teachings herein without departing from the spirit of the present specification. Lastly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. Accordingly, the present invention is not limited to that precisely as shown and described.

Claims

PATENT BI1-003WOCLAIMSWhat is claimed is:

1. A method of prophylaxis or treatment of at least one Friedreich’s Ataxia Related Disorder, comprising:a) providing a subject in need of said prophylaxis or treatment of at least one Friedreich’s Ataxia 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; orcombinations thereof;wherein said components are administered together orseparately; further wherein said components are provided together or separately;(2) administering a pharmaceutically effective amount of said at leastone pharmaceutical composition to said subject;wherein said subject is provided prophylaxis or treatment of said at least one Friedreich’s Ataxia 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.PATENT BI1-003WO6. The method of claim 1, wherein said prophylaxis or treatment of said at least one Friedreich’s Ataxia Related Disorder comprises Spinocerebellar Ataxia as (SCAs), Ataxia-Telangiectasia (AT), Dentatorubral-Pallidoluysian Atrophy (DRPLA), Charcot-Marie-Tooth (CMT) Disease or combinations thereof.

7. The method of claim 1, wherein said prophylaxis or treatment of said at least one Friedreich’s Ataxia Related Disorder with symptoms including difficulty in ambulation, muscle weakness, loss of sensation and proprioception, and impaired speech, social problems, behavior problems, anxiety, 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.PATENT BI1-003WO14. The method of claim 9, wherein said at least one pharmaceutical composition comprising Cyclic Prolyl Glycine is administered about once a day, twice a day, once a week, twice a week, 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, twice a day, once a week, twice a week, 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.PATENT BI1-003WO23. The method of claim 8, wherein said at least one cPG compoundcomprises 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, twice a day, once a week, twice a week, 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 least 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.PATENT BI1-003WO31. 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;e) administered for the first and the last weeks at a dose of aboutf) 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1 mg / Kg;g) 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, twice a day, once a week, 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 aboutb) mg / Kg;c) administered subcutaneously;d) administered about twice daily;e) administered for about six months;f) administered for the first and the last weeks at a dose of aboutg) 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1 mg / Kg;h) or combinations thereof.

35. The method of claim 30, wherein said at least one pharmaceutical compositionPATENT BI1-003WOcomprising 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, once a week, 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 aboutb) mg / Kg;c) administered subcutaneously;d) administered about twice daily;e) administered for about six months;f) administered for the first and the last weeks at a dose of aboutg) 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1 mg / Kg;h) 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 day, twice a day, 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 aboutb) mg / Kg;c) administered subcutaneously;d) administered about twice daily;PATENT BI1-003WOe) administered for about six months;f) administered for the first and the last weeks at a dose of aboutg) 0.05 mg / Kg and is administered during the remaining periods the dosage of about 0.1 mg / Kg;h) 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 day, twice a day, 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) R3IGF-I (Long R3 Insulin-like Growth Factor-I), a recombinant analog of IGF-1 with substitution of Arg for Glu3;c) LONG® R3IGF-I whose N-terminus is prolonged by additional 13residues 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 aboutf) 0.05 mg / Kg and during the remaining periods administered at a dose ofPATENT BI1-003WOabout 0.1mg / Kg;g) 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, twice a day, once a week, twice a week, or combinations thereof.

47. The method of claim 1, wherein said prophylaxis or treatment of said at least one Friedreich’s Ataxia Related Disorder results in global improvement in symptoms related thereto, including ambulation, muscle weakness, loss of sensation and proprioception communication, impaired speech, behavior problems or combinations thereof.

48. The method of claim 1, wherein said prophylaxis or treatment of said at least one Friedreich’s Ataxia Related Disorder is prophylaxis.

49. The method of claim 1, wherein said prophylaxis or treatment of said at least one Friedreich’s Ataxia 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.PATENT BI1-003WO53. 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 Friedreich’s Ataxia Related Disorder, comprising at least one of:e) at least one cPG compound, optionally in combination with;f) at least one IGF-1 compound;g) at least one IGF-2 compound;h) at least one Des (1-3) IGF-1 compound;i) 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 Friedreich’s Ataxia Related Disorder.

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