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  Pharmaceutical Patents  

 

Title:  Treatment of rett syndrome
United States Patent: 
7,994,127
Issued: 
August 9, 2011

Inventors:
 Sur; Mriganka (Cambridge, MA), Tropea; Daniela (Cambridge, MA), Giacometti; Emanuela (Cambridge, MA), Jaenisch; Rudolf (Brookline, MA), Wilson; Nathan R. (Cambridge, MA)
Assignee:
  Massachusetts Institute of Technology (Cambridge, MA), Whitehead Institute of Biomedical Research (Cambridge, MA)
Appl. No.:
 12/134,707
Filed:
 June 6, 2008


 

Executive MBA in Pharmaceutical Management, U. Colorado


Abstract

The invention relates to methods for treatment of Rett Syndrome and other disorders of synaptic function and maturation using IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules.

Description of the Invention

FIELD OF THE INVENTION

The invention relates to methods for treatment of Rett Syndrome and other disorders of synaptic function and maturation.

BACKGROUND OF THE INVENTION

Rett Syndrome (RTT) is a developmental disorder linked to mutations in the X chromosome gene methyl CpG-binding protein 2 (MeCP2). MeCP2 codes for a protein that regulates transcription. It forms a transcription repressor complex that binds to methylated gene sequences, and induces chromatin condensation.

Patients with Rett Syndrome, who are almost exclusively females, show distinctive hand movements, slowed brain growth, regression of language and motor skills, seizures, cognitive impairment and mental retardation. Cortical structure is relatively preserved, but dendritic structure is altered and dendritic spines appear structurally immature.

Mouse models of Rett Syndrome have been made (Chen et al., Nat Genet. 27 (3):327-31, 2001; Guy et al., Nat Genet. 27 (3):322-6, 2001; Shahbazian et al., Neuron 35 (2):243-54, 2002). MeCP2 knockout (KO) mice show movement and respiratory phenotype, smaller pyramidal neurons, and electrophysiological abnormalities suggestive of synaptic and neuronal immaturity. A truncating mutation of MeCP2 leads to motor and social dysfunction, alterations in synaptic plasticity and memory.

Restoration of MeCP2 levels in a conditional MeCP2 KO mouse model restores movement function (Guy et al., Science 315 (5815):1143-7, 2007). Enhanced BDNF expression in KO mice reverses the movement and electrophysiological phenotype (Chang et al., Neuron 49 (3):341-8, 2006). These and other data suggest that synapses remain in an immature state in the mouse models, and appropriate treatments even late in development can re-establish function.

SUMMARY OF THE INVENTION

There is a strong incentive to identify new and/or better treatment options for Rett syndrome and other disorders that have synaptic and neuronal immaturity or alterations in synaptic plasticity, such as autism spectrum disorders.

Working under a hypothesis that genes and molecules that enhance synapse maturation might restore synaptic and behavioral function in MeCP2 KO mice, the applicants have determined that insulin-like growth factor (IGF1) or (1-3)IGF-1 (also known as glycyl-L-prolyl-L-glutamic acid, glycine-proline-glutamate and GPE), a peptide fragment of IGF1, unexpectedly are viable candidates for restoring function in MeCP2 KO mice and for human RTT therapeutics. Both of these molecules, and other analogous molecules such as (1-3)IGF-1 analogs that also can be used in the invention, cross the blood-brain barrier, and thus can be administered systemically as small molecule therapeutics for RTT and other disorders. In contrast, larger molecule such as brain-derived neurotrophic factor (BDNF) and most other synaptic plasticity molecules do not cross the blood-brain barrier, and therefore would require direct brain infusion, which is not practical in humans.

According to one aspect of the invention, methods for treating Rett Syndrome are provided. The methods include administering to a subject in need of such treatment an effective amount of insulin-like growth factor (IGF1), (1-3)IGF-1, and/or a (1-3)IGF-1 analog to treat the subject.

In some embodiments, IGF1 is administered. Preferably the IGF1 is recombinant IGF1 or human IGF1. In preferred embodiments, the dose of IGF1 administered is about 0.1-10 mg/kg/day, more preferably about 0.1-2 mg/kg/day.

In other embodiments, (1-3)IGF-1 is administered. In preferred embodiments, the dose of (1-3)IGF-1 administered is about 0.1-100 mg/kg/day, more preferably about 6-20 mg/kg/day.

In still other embodiments, a (1-3)IGF-1 analog is administered. Preferably the (1-3)IGF-1 analog is Gly-Pro; Pro-Glu; a (1-3)IGF-1 substitution analog wherein the Gly of Gly-Pro-Glu is replaced by any of Ala, Ser, Thr, or Pro or wherein the Pro of Gly-Pro-Glu is replaced by any of Ala, Ser, Thr, or Gly or wherein the Glu of Gly-Pro-Glu is replaced by any of Asn, Asp, or Gln; a (1-3)IGF-1 amide, a (1-3)IGF-1 stearate, a (1-3)IGF-1 analog having one or two D-amino acids, or a (1-3)IGF-1 analog having one or two non-hydrolyzable peptide bonds.

In additional embodiments, a related therapeutic molecule is administered. Preferably the related therapeutic molecule is an IGF1 secretagogue, a growth hormone or precursor, a growth hormone secretagogue, a growth hormone releasing peptide, or a growth hormone releasing hormone or analog.

In preferred embodiments of the methods, the subject is a human.

In certain embodiments of the methods, the IGF1, (1-3)IGF-1 and/or (1-3)IGF-1 analog is administered orally, intravenously, intramuscularly, intranasally, intraperitoneally, subcutaneously, or intrathecally.

The IGF1, (1-3)IGF-1 and/or (1-3)IGF-1 analog can be administered after diagnosis of Rett syndrome, or can be administered prophylactically before diagnosis of Rett syndrome.

In further embodiments, the subject is free of symptoms otherwise calling for treatment with the IGF1, (1-3)IGF-1 or (1-3)IGF-1 analog.

In further embodiments, the methods also include first testing the subject for a mutation in a gene coding for methyl CpG-binding protein 2 (MeCP2).

In some embodiments, the methods also include administering to the subject a second therapeutic, wherein the second therapeutic is tPA, BDNF, a molecule that regulates inhibition such as a benzodiazepine, or a molecule that is a neurotransmitter agonist, antagonist or analog, and wherein the second therapeutic and the IGF1, (1-3)IGF-1, (1-3)IGF1 analog(s) and/or related therapeutic molecules are administered in a combined amount effective to treat the subject.

In the foregoing methods, the amount of IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules is effective to restore synaptic function and/or maturation, consolidate synapses and/or regulate neuronal plasticity.

According to another aspect of the invention, methods for treating a disorder of synaptic function and/or maturation in a subject are provided. The methods include administering to a subject in need of such treatment an effective amount of insulin-like growth factor (IGF1), glycyl-L-prolyl-L-glutamic acid ((1-3)IGF-1), and/or a (1-3)IGF-1 analog to treat the subject.

In some embodiments, IGF1 is administered. Preferably the IGF1 is recombinant IGF1 or human IGF1. In preferred embodiments, the dose of IGF1 administered is about 0.1-10 mg/kg/day, more preferably about 0.1-2 mg/kg/day.

In other embodiments, (1-3)IGF-1 is administered. In preferred embodiments, the dose of (1-3)IGF-1 administered is about 0.1-100 mg/kg/day, more preferably about 6-20 mg/kg/day.

In still other embodiments, a (1-3)IGF-1 analog is administered. Preferably the (1-3)IGF-1 analog is Gly-Pro; Pro-Glu; a (1-3)IGF-1 substitution analog wherein the Gly of Gly-Pro-Glu is replaced by any of Ala, Ser, Thr, or Pro or wherein the Pro of Gly-Pro-Glu is replaced by any of Ala, Ser, Thr, or Gly or wherein the Glu of Gly-Pro-Glu is replaced by any of Asn, Asp, or Gln; a (1-3)IGF-1 amide, a (1-3)IGF-1 stearate, a (1-3)IGF-1 analog having one or two D-amino acids, or a (1-3)IGF-1 analog having one or two non-hydrolyzable peptide bonds.

In additional embodiments, a related therapeutic molecule is administered. Preferably the related therapeutic molecule is an IGF1 secretagogue, a growth hormone or precursor, a growth hormone secretagogue, a growth hormone releasing peptide, or a growth hormone releasing hormone or analog.

In preferred embodiments of the methods, the subject is a human.

In certain embodiments of the methods, the IGF1, (1-3)IGF-1 and/or (1-3)IGF-1 analog is administered orally, intravenously, intramuscularly, intranasally, intraperitoneally, subcutaneously, or intrathecally.

The IGF1, (1-3)IGF-1 and/or (1-3)IGF-1 analog can be administered after diagnosis of the disorder, or can be administered prophylactically before diagnosis of the disorder.

In preferred embodiments, the disorder is autism, autism spectrum disorder, Angelmann's Syndrome, tuberous sclerosis, Fragile X syndrome, schizophrenia, depression, neurodegenerative disorders including Parkinson's disease, Huntington's disease and Alzheimer's disease, stroke or trauma.

In further embodiments, the subject is free of symptoms otherwise calling for treatment with the IGF1, (1-3)IGF-1 or (1-3)IGF-1 analog.

In some embodiments, the methods also include first testing the subject for a mutation in a gene that is a genetic basis for the disorder or a gene that is a target of or downstream of such a gene.

In other embodiments, the methods also include administering to the subject a second therapeutic, wherein the second therapeutic is tPA, BDNF, a molecule that regulates inhibition such as a benzodiazepine, and/or a molecule that is a neurotransmitter agonist, antagonist or analog. In such embodiments, the second therapeutic and the IGF1, (1-3)IGF-1 and/or (1-3)IGF1 analog are administered in a combined amount effective to treat the subject.

In the foregoing methods, the amount of IGF1, (1-3)IGF-1 and/or (1-3)IGF-1 analog is effective to restore synaptic function and/or maturation, consolidate synapses and/or regulate neuronal plasticity.

According to a third aspect of the invention, methods for increasing synaptic maturation are provided. The methods include contacting one or more neurons comprising one or more synapses with an amount of IGF1, (1-3)IGF-1, and/or a (1-3)IGF-1 analog effective to increase the maturation of the one or more synapses of the one or more neurons.

In some embodiments, the one or more neurons are contacted with IGF1. Preferably the IGF1 is recombinant IGF1 or human IGF1.

In other embodiments, the one or more neurons are contacted with (1-3)IGF-1 or a (1-3)IGF-1 analog. Preferably the (1-3)IGF-1 analog is Gly-Pro; Pro-Glu; a (1-3)IGF-1 substitution analog wherein the Gly of Gly-Pro-Glu is replaced by any of Ala, Ser, Thr, or Pro or wherein the Pro of Gly-Pro-Glu is replaced by any of Ala, Ser, Thr, or Gly or wherein the Glu of Gly-Pro-Glu is replaced by any of Asn, Asp, or Gln; a (1-3)IGF-1 amide, a (1-3)IGF-1 stearate, a (1-3)IGF-1 analog having one or two D-amino acids, or a (1-3)IGF-1 analog having one or two non-hydrolyzable peptide bonds.

In additional embodiments, a related therapeutic molecule is administered. Preferably the related therapeutic molecule is an IGF1 secretagogue, a growth hormone or precursor, a growth hormone secretagogue, a growth hormone releasing peptide, or a growth hormone releasing hormone or analog.

In preferred embodiments, the one or more neurons are human neurons.

In certain embodiments, the one or more neurons are contacted in vitro. In other embodiments, the one or more neurons are contacted in vivo. Preferably the contacting in vivo is performed by administering the IGF1, (1-3)IGF-1 and/or (1-3)IGF-1 analog to a subject. Preferably the IGF1, (1-3)IGF-1 and/or (1-3)IGF-1 analog is administered orally, intravenously, intramuscularly, intranasally, intraperitoneally, subcutaneously, or intrathecally.

Other related therapeutic molecules that can be used in a similar manner to treat the disorders as described herein include IGF1 secretagogues, growth hormones or precursors, growth hormone secretagogues, growth hormone releasing peptides, growth hormone releasing hormone and its analogs.

The treatment methods described herein also can include administering molecules that upregulate or enhance inhibition, such as benzodiazepines or others known to the person of skill in the art. The molecules that upregulate or enhance inhibition can be used alone or in combination with IGF1, (1-3)IGF-1 and/or (1-3)IGF-1 analog, etc, as described herein.

DETAILED DESCRIPTION OF THE INVENTION

Rett Syndrome (RTT) is a severe form of X-linked mental retardation caused by mutations in the gene coding for methyl CpG-binding protein 2 (MeCP2).

Reasonable evidence exists that synapses are in an immature state in MeCP2 knockout (KO) mice made as models of Rett Syndrome (RTT). A potential target of MeCP2 appears to be IGFBP3. IGFBP3 levels are upregulated in MeCP2 KO mice and in human RTT patients, and IGFBP3 transgenic mice have some of the brain pathology of MeCP2 KO mice.

Additionally, slowed brain growth and retardation of physical growth in RTT patients may indicate deficiencies in IGF1/growth hormone.

Low concentrations of IGF1 have been detected in the cerebrospinal fluid (CSF) of autistic patients (and patients with encephalopathies and white matter diseases); while no IGF1 deficit has been detected in the CSF of RTT patients, the sample sizes are small.

Here we show that adult Mecp2 mutant mice exhibit physiological signatures indicative of immature cortical circuitry, including weaker synaptic function in vitro and persistent cortical plasticity in vivo. Systemic treatment with (1-3)IGF-1, also referred to as GPE, a 3 amino acid active fragment of insulin-like growth factor 1 (IGF-1), restored the circuitry of the adult RTT mouse to more mature levels, by stimulating synaptic function and stabilizing the plasticity of the circuit. Additionally, treatment with the tri-peptide ameliorated bradycardia, improved locomotor function, and extended the life span of the knockout mice, which we observed to be significantly impaired in these areas. Our results suggest (1-3)IGF-1 as a strong candidate for pharmacological treatment of Rett Syndrome and potentially of other CNS disorders caused by delayed synapse maturation.

Based on these observations, we have determined that insulin-like growth factor (IGF1) or (1-3)IGF-1 (also referred to as glycyl-L-prolyl-L-glutamic acid, glycine-proline-glutamate, or GPE), a terminal fragment of IGF1, unexpectedly restore function in MeCP2 KO mice and, accordingly, are useful as human RTT therapeutics. Both of these molecules, and other analogous molecules such as (1-3)IGF-1 analogs that also can be used in the invention, cross the blood-brain barrier, and thus can be administered systemically as small molecule therapeutics for RTT and other disorders.

Without intending to be bound by any particular theory or mechanism of IGF1 action, it is believed that IGF1 may offset the effects of MeCP2 loss: by upregulating BDNF directly and through tPA cleavage of BDNF; by acting through PI3K to strengthen synapses or regulate a range of neuronal functions; by offsetting the effect of MeCP2 on IGFBPs; by upregulating inhibition and inhibitory circuits; or by directly influencing acetylation (e.g., of H3 and H4 histones) or MeCP2-mediated transcription.

Thus, the invention involves, in some aspects, administering an effective amount of IGF1, (1-3)IGF-1, a (1-3)IGF-1 analog, and/or a related therapeutic molecule to a subject to treat the subject. The term "treatment" or "treat" is intended to include prophylaxis, amelioration, prevention or cure of a condition. Treatment after a condition has stated aims to reduce, ameliorate or altogether eliminate the condition, and/or one or more of its associated symptoms, or prevent it from becoming worse. Treatment of subjects before a condition has started (i.e., prophylactic treatment) aims to reduce the risk of developing the condition and/or lessen its severity if the condition later develops. As used herein, the term "prevent" refers to the prophylactic treatment of subjects who are at risk of developing a condition which treatment results in a decrease in the probability that the subject will develop the condition, or results in an increase in the probability that the condition is less severe than it would have been absent the treatment. Treatments may reduce mortality, or extend life expectancy, of subjects having the condition as compared to subjects not treated as described herein in accordance with the invention.

A "subject" shall mean a human or animal including, but not limited to, a dog, cat, horse, cow, pig, sheep, goat, chicken, rodent, e.g., rats and mice, and primate, e.g., monkey. Preferred subjects are human subjects. The human subject may be a pediatric, adult or a geriatric subject.

The methods of the invention have broader application to disorders in addition to Rett Syndrome. Brain development, and hence developmental disorders of the brain, involve neurogenesis, neuronal migration, cellular differentiation and growth, and synaptic maturation. Because the data described herein pertain to the effects of IGF1/(1-3)IGF-1 on synaptic function and maturation and to the effect on molecules related to synaptic transmission and signaling, disorders, conditions or diseases that involve the synapse, including synaptic reorganization as a means to recover loss of function, are treatable in accordance with the invention. Thus, examples of disorders, conditions or diseases treatable by the methods and compositions of the invention include: Rett Syndrome, Autism and Autism Spectrum Disorders, Angelmann's Syndrome, tuberous sclerosis, Fragile X syndrome, schizophrenia, depression, neurodegenerative disorders including Parkinson's disease, Huntington's disease and Alzheimer's disease, stroke or brain trauma. In preferred embodiments, the disorders, conditions or diseases are those in which synaptic function and/or maturation is implicated as a causative factor in the disorder, condition or disease. In a particularly preferred embodiment, the disorder, condition or disease is Rett Syndrome.

The subject can be known to have a particular disorder, condition or disease that is amenable to such therapy, or may be suspected of having such a disorder, condition or disease. In some embodiments, the subject is free of symptoms otherwise calling for treatment with the IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules.

Autism and Autism Spectrum Disorders are clinically diagnosed disorders with both single and complex multi-gene etiology. Single gene conditions such as Rett Syndrome and Fragile X contribute to a small fraction of autism cases directly (ca. 5-10%). However, because the single genes can also contribute to multi-gene conditions, therapeutics for single gene conditions have the potential to impact a much larger fraction of autism cases.

The applicability of the therapeutic methods of the invention to certain disorders, conditions or diseases is supported by an understanding of the IGF1 signaling pathway, including phosphoinositol-3 kinase (PI3K) and Akt/PKB.

PI3K is directly implicated in tuberous sclerosis, and in certain forms of autism that involve the PTEN gene. Recent evidence that BDNF acts through PI3K to effect changes in PSD95 and hence increase excitatory synaptic strength increases the potential importance of PI3K. Thus, increasing PI3K levels by IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules may offset memory loss due to cognitive decline or due to neurodegenerative disorders including Parkinson's disease and Alzheimer's disease. Because changes in PSD95 are implicated in developmental disorders of synaptic dysfunction such as Fragile X syndrome, IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules can be used for treating such disorders.

Akt is a central part of an anti-apoptotic pathway. It is implicated in countering loss of neurons due to stroke and Alzheimer's disease, and in neuro-protection after brain insult or injury. Akt affects the GSK3beta pathway, which is implicated in schizophrenia (lithium acts on this pathway). Application of IGF1 increases neurogenesis in the dentate gyrus of the hippocampus, by either the direct action of Akt or indirect actions of PI3K. Such neurogenesis is a major potential mechanism for anti-depressant action; hence IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules can be used for treating schizophrenia or depression.

More broadly, IGF1 promotes neurogenesis and cell survival, neuronal growth and differentiation, and synaptic maturation. Thus, therapy with IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules has the potential to be useful for a wide range of neurodegenerative disorders of diverse etiology, including Parkinson's disease, Huntington's disease and Alzheimer's disease, multiple sclerosis and spinal cord diseases such as ALS.

In certain cases, the disorders can be treated with combination therapy. (1-3)IGF-1/IGF1 consolidates synapses and promotes certain kinds of plasticity (which rely on stabilizing a few weak synapses out of a broad set potentially available). The latter is important for promoting functional reorganization after stroke, particularly in combination therapy, such as (in addition to IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules) rehabilitation therapy and administration of other molecules such as tPA, BDNF, a molecule that regulates inhibition such as a benzodiazepine, or a molecule that is a neurotransmitter agonist, antagonist or analog. Such molecules provide synergistically beneficial effects for treatment.

Many benzodiazepines are well known in the art, including hypnotic benzodiazepines and anxiolytic benzodiazepines. Similarly, a related class of drugs that interact with benzodiazepine receptors, the "nonbenzodiazepines", also can be used in the same manner as benzodiazepines in the methods described herein.

In a particular embodiment, as shown in the Examples below, (1-3)IGF-1 upregulates tPA. tPA promotes functional and structural reorganization at synapses. Thus (1-3)IGF-1 and tPA work in positive feedback. Similarly, (1-3)IGF-1 upregulates BDNF, and IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules and BDNF are highly likely to work better in combination than individually.

The invention involves in certain embodiments methods of treatment comprising administering an effective amount of a (1-3)IGF-1 analog. As used herein, a "(1-3)IGF-1 analog" (or a "GPE analog") includes compounds that have pharmacological properties and therapeutic activities substantially similar to those of (1-3)IGF-1.

(1-3)IGF-1 analogs known in the art can be used in the invention. EP 0 366 638 describes the (1-3)IGF-1 analogs Gly-Pro and Pro-Glu. WO02/16408 describes a variety of (1-3)IGF-1 analogs including those containing substitutions where the Gly of Gly-Pro-Glu is replaced by any of Ala, Ser, Thr, or Pro; where the Pro of Gly-Pro-Glu is replaced by any of Ala, Ser, Thr, or Gly; and where the Glu of Gly-Pro-Glu is replaced by any of Asn, Asp, or Gln. Additional (1-3)IGF-1 analogs described in WO02/16408 include (1-3)IGF-1 amides and stearates. Specific analogs described in WO02/16408 also include the following: (1-3)IGF-1 amide, (1-3)IGF-1 stearate, Gly-Pro-D-glutamate (GP-D-E) Gly-Pro-Thr (GPT) Gly-Glu-Pro (GEP) Glu-Gly-Pro (EGP) Glu-Pro-Gly (EPG), all of which can be readily synthesized using standard techniques. U.S. Pat. No. 7,041,314 describes additional (1-3)IGF-1 analogs and peptidomimetics that are useful in accordance with the invention.

The (1-3)IGF-1 analog also can be a peptide as described herein that is non-hydrolyzable, e.g., having one or more (i.e., one or two) non-hydrolyzable peptide bonds or amino acids. Preferred non-hydrolyzable peptides include peptides comprising D-amino acids, peptides comprising a -psi[CH.sub.2NH]-reduced amide peptide bond, peptides comprising a -psi[COCH.sub.2]-ketomethylene peptide bond, peptides comprising a -psi[CH(CN)NH]-(cyanomethylene)amino peptide bond, peptides comprising a -psi[CH.sub.2CH(OH)]-hydroxyethylene peptide bond, peptides comprising a -psi[CH.sub.2O]-peptide bond, and peptides comprising a -psi[CH.sub.2S]-thiomethylene peptide bond.

Additional (1-3)IGF-1 analogs that can be used in accordance with the present invention can be identified as having one or more properties that are at least substantially equivalent to (1-3)IGF-1, such as the properties described herein, or properties of (1-3)IGF-1 that can be assessed by various assays known to those of skill in the art, such as assays of the ability to cross the blood brain barrier, etc.

Other "related therapeutic molecules" that can be used in a similar manner as IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) to treat the disorders as described herein include IGF-1 secretagogues, growth hormones or precursors, growth hormone secretagogues, growth hormone releasing peptides, growth hormone releasing hormone and its analogs.

IGF-1 secretagogues are known in the art, for example as described in United States published patent application 2006/0100287.

Growth hormones or precursors thereof include human growth hormone (hGH) such as Nutropin (Genentech), Protropin (Genentech), Humatrope (Lilly), Genotropin (Pfizer), Norditropin (Novo), Saizen (Merck Serono) and Omnitrope (Sandoz).

Growth hormone secretagogues, growth hormone releasing peptides, growth hormone releasing hormone and analogs include ipamorelin and derivatives thereof (e.g., growth hormone secretagogues, derived from ipamorelin, are described in Ankersen et al. Eur. J. Med. Chem. 34 (10): 783-790, 1999), MK677 (Merck; N-[1(R){[1,2-dihydro-1-methanesulfonylspiro-(3H-indole-3,4'-piperidine)-1- '-yl]carbonyl}-2-(phenylmethoxy)-ethyl]-2-amino-2-methylpropanamide methanesulfonate), NN703 (tabimorelin, Novo Nordisk) and derivatives thereof (GH secretagogues based on modifications in the C-terminal end of NN703 are described in Ankersen et al. Eur. J. Med. Chem. 35 (5): 487-497, 2000), SM 130686 (Sumitomo) capromorelin (Pfizer), sermorelin (Salk Institute, Bio-Technology General), ghrelin, hexarelin (examorelin), tabimorelin; CP 464709 (Pfizer), LY 426410 (Lilly), LY 444711 (Lilly; shown to increase IGF1 levels (Seyler et al., Drug Devel. Res. 49 (4): 260-265, 2000)), 8-(aminoalkoxyimino)-8H-dibenzo[a,e]triazolo[4,5-cycloheptenes as disclosed in WO2002057241, 2-substituted dibenzo[a,e]1,2,3-triazolo[4,5-c][7]annulen-8-ones as described in WO2002056873, growth hormone releasing peptides GHRP-1, GHRP-2 and GHRP-6 as described in U.S. Pat. No. 4,411,890, and publications WO 89/07110, WO 89/07111, B-HT920, growth hormone releasing hormone (GHRH, also designated GRF) and its analogs, and additional growth hormone secretagogues as described in U.S. Pat. No. 6,559,150.

IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules are administered in an amount effective to treat the disorder, condition or disease in the subject. An effective amount is a dosage of the therapeutic agent(s) sufficient to provide a medically desirable response. For example the desirable response may be inhibiting the progression of the disorder, condition or disease. This may involve only slowing the progression of the disorder, condition or disease temporarily, although more preferably, it involves halting the progression of the disorder, condition or disease permanently. This can be monitored by routine diagnostic methods known to those of ordinary skill in the art.

It should be understood that the therapeutic agents of the invention are used to treat or prevent the disorder, condition or disease, that is, they may be used prophylactically in subjects at risk of developing the disorder, condition or disease. Thus, an effective amount is that amount which can lower the risk of, lessen the severity of, or perhaps prevent altogether the development of the disorder, condition or disease.

The factors involved in determining an effective amount are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the therapeutic agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.

IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules may be administered alone, in a pharmaceutical composition or combined with other therapeutic agent(s) or regimens. Optionally other therapeutic agent(s) may be administered simultaneously or sequentially. When the other therapeutic agent(s) are administered simultaneously they can be administered in the same or separate formulations, but are administered at the same time. The other therapeutic agent(s) may be administered sequentially with one another and with the IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules when the administration of the other therapeutic agent(s) and the IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules are temporally separated. The separation in time between the administration of these compounds may be a matter of minutes or it may be longer, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours, or more, including 1, 2, 3, 4, 5, 6, 7 days or more.

The pharmaceutical compositions used in the methods of the invention are preferably sterile and contain effective amounts of the IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules for producing the desired response in a unit of weight or volume suitable for administration to a subject. The doses of pharmacological agent(s) administered to a subject can be chosen in accordance with different parameters, in particular in accordance with the mode of administration used and the state of the subject. Other factors include the desired period of treatment. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. The dosage of a pharmacological agent may be adjusted by the individual physician or veterinarian, particularly in the event of any complication. A therapeutically effective amount typically varies from 0.01 mg/kg to about 1000 mg/kg, preferably from about 0.1 mg/kg to about 200 mg/kg, and most preferably from about 0.2 mg/kg to about 20 mg/kg, in one or more dose administrations daily, for one or more days.

Several studies have been conducted in which (1-3)IGF-1 or IGF1 was administered systemically and produced an effect on brain function.

In Tropea et al. (Nat Neurosci 9, 660-8, 2006), (1-3)IGF-1 was infused IP, simultaneously to monocular deprivation (MD). (1-3)IGF-1 was injected at about 20 .mu.g/gr/day for 7 days.

In another study (Sizonenko et al., Brain Res 922, 42-50, 2001) performed on developing (P21) rats there was one single injection of (1-3)IGF-1 (6.7 .mu.g/gr) after 2 hours of induced ischemia.

In another study (Lupien et al., J Neurosci Res 74, 512-23, 2003), diabetic rats were treated with IGF1 in order to improve the learning deficits normally observed in diabetes. Adult rats (about 400 gr) were implanted with minipumps that released 20 .mu.g/day per animal, which is equivalent to about 0.05 .mu.g/gr per day. In this case the release was subcutaneous for 7.5 weeks.

In another study (Saatman et al., Exp Neurol 147, 418-27, 1997) observing the improvement in motor learning, IGF1 was delivered for 14 days, either by subcutaneous injections each 12 hours 1 .mu.g/gr (equivalent to 2 .mu.g/gr per day), or by a subcutaneous pump (4 .mu.g/gr/day) in monkeys.

Aberg et al. (J Neurosci 20, 2896-903, 2000) delivered recombinant IGF1 (Genentech, South San Francisco, Calif.) to P50 rats subcutaneously with a minipump for six days or 20 days, using a dosage of 1.25 mg/kg/day and 0.9 mg/kg/day, respectively.

The FDA approved dose for Increlex (Tercica, rhIGF1) is 0.08-0.12 mg/kg/BID, which equals 0.16-0.24 mg/kg/day.

For the methods of the invention described herein, preferred doses of IGF1 are about 0.01-50 mg/kg/day, more preferably about 0.1-10 mg/kg/day, administered in one dose or in multiple daily doses. IGF1 preferably is human IGF1 (hIGF1), and preferably is recombinantly produced (rIGF1), most preferably recombinant human IGF1 (rhIGF1). More preferably, the doses of recombinant IGF1 are about 0.1-2 mg/kg/day. The FDA approved dose for rhIGF1 is particularly contemplated for use in the methods of the invention, although as described elsewhere herein, higher or lower doses also are contemplated.

For the methods of the invention described herein, preferred doses of (1-3)IGF-1 are about 0.1-100 mg/kg/day, administered in one dose or in multiple daily doses. More preferably, the doses of (1-3)IGF-1 are about 6-20 mg/kg/day.

Various modes of administration are known to those of ordinary skill in the art which effectively deliver the pharmacological agents of the invention to a desired tissue, cell, or bodily fluid. Administration of the molecules of the invention includes, but is not limited to, oral, intravenous infusion, subcutaneous injection, intramuscular, topical, depo injection, implantation, time-release mode, intracavitary, intranasal, inhalation, intratumor, intraocular, and controlled release. The pharmaceutical compositions of the invention also may be introduced parenterally, transmucosally (e.g., orally), nasally, rectally, intravaginally, sublingually, submucosally, or transdermally. Preferably, administration is parenteral, i.e., not through the alimentary canal but rather through some other route via, for example, intravenous, subcutaneous, intramuscular, intraperitoneal, intraorbital, intracapsular, intraspinal, intrasternal, intra-arterial, or intradermal administration. The skilled artisan can appreciate the specific advantages and disadvantages to be considered in choosing a mode of administration.

The invention is not limited by the particular modes of administration disclosed herein. Standard references in the art (e.g., Remington's Pharmaceutical Sciences, 20th Edition, Lippincott, Williams and Wilkins, Baltimore Md., 2001) provide modes of administration and formulations for delivery of various pharmaceutical preparations and formulations in pharmaceutical carriers. Other protocols which are useful for the administration of pharmacological agents of the invention will be known to one of ordinary skill in the art, in which the dose amount, schedule of administration, sites of administration, mode of administration and the like vary from those presented herein.

Administration of pharmacological agents of the invention to mammals other than humans, e.g., for testing purposes or veterinary therapeutic purposes, is carried out under substantially the same conditions as described above. It will be understood by one of ordinary skill in the art that this invention is applicable to both human and animal diseases.

When administered, the pharmaceutical preparations of the invention are applied in pharmaceutically-acceptable amounts and in pharmaceutically-acceptable compositions. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically-acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like. Also, pharmaceutically-acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.

A pharmacological agent or composition may be combined, if desired, with a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier" as used herein means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration into a human. The term "carrier" denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being co-mingled with the pharmacological agents of the invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.

The pharmaceutical compositions may contain suitable buffering agents, as described above, including: acetate, phosphate, citrate, glycine, borate, carbonate, bicarbonate, hydroxide (and other bases) and pharmaceutically acceptable salts of the foregoing compounds. The pharmaceutical compositions also may contain, optionally, suitable preservatives, such as: benzalkonium chloride; chlorobutanol; parabens and thimerosal.

The pharmaceutical compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active agent into association with a carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

The compounds, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or 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 compounds to allow for the preparation of highly concentrated solutions.

Alternatively, the compounds may be in powder form for constitution with a suitable vehicle (e.g., saline, buffer, or sterile pyrogen-free water) before use.

Compositions suitable for oral administration may be presented as discrete units, such as capsules, tablets, pills, lozenges, each containing a predetermined amount of the active compound(s). Other compositions include suspensions in aqueous liquids or non-aqueous liquids such as a syrup, elixir, an emulsion, or a gel.

Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, sorbitol or cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations may also be formulated in saline or buffers, i.e., EDTA for neutralizing internal acid conditions or may be administered without any carriers.

Also specifically contemplated are oral dosage forms of the above component or components. The component or components may be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of proteolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the component or components and increase in circulation time in the body.

For the component (or derivative) the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of the molecule(s) or by release of the biologically active molecule(s) beyond the stomach environment, such as in the intestine.

To ensure full gastric resistance a coating impermeable to at least pH 5.0 is essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and Shellac. These coatings may be used as mixed films.

A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic i.e., powder; for liquid forms, a soft gelatin shell may be used. The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used.

One may dilute or increase the volume of the therapeutic agent with an inert material. These diluents could include carbohydrates, especially mannitol, a-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may be also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell.

Disintegrants may be included in the formulation of the therapeutic into a solid dosage form. Materials used as disintegrants include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic.

An anti-frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000.

Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate.

To aid dissolution of the therapeutic into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents might be used and could include benzalkonium chloride or benzethomium chloride. The list of potential non-ionic detergents that could be included in the formulation as surfactants are lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation either alone or as a mixture in different ratios.

Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

For administration intranasally or by inhalation, the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

Also contemplated herein is pulmonary delivery of the molecule(s). The molecule(s) are delivered to the lungs of a mammal while inhaling and traverse across the lung epithelial lining to the blood stream.

Contemplated for use in the practice of this invention are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art.

Nasal (or intranasal) delivery of a pharmaceutical composition of the present invention is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung.

For nasal administration, a useful device is a small, hard bottle to which a metered dose sprayer is attached. In one embodiment, the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available.

Alternatively, a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug.

In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

The molecule(s) are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer, Science 249:1527-1533, 1990, which is incorporated herein by reference.

The therapeutic agent(s) may be contained in controlled release systems. The term "controlled release" is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations. The term "sustained release" (also referred to as "extended release") is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. The term "delayed release" is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug therefrom. "Delayed release" may or may not involve gradual release of drug over an extended period of time, and thus may or may not be "sustained release."

Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. "Long-term" release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above.

The invention also contemplates the use of kits. In some aspects of the invention, the kit can include a pharmaceutical preparation vial, a pharmaceutical preparation diluent vial, and the molecule(s) of the invention as described herein. The vial containing the diluent for the pharmaceutical preparation is optional. The diluent vial contains a diluent such as physiological saline for diluting what could be a concentrated solution or lyophilized powder of the molecule(s). The instructions can include instructions for mixing a particular amount of the diluent with a particular amount of the concentrated pharmaceutical preparation, whereby a final formulation for injection or infusion is prepared. The instructions may include instructions for treating a subject with an effective amount of the molecule(s). It also will be understood that the containers containing the preparations, whether the container is a bottle, a vial with a septum, an ampoule with a septum, an infusion bag, and the like, can contain indicia such as conventional markings which change color when the preparation has been autoclaved or otherwise sterilized.

Also contemplated is the use of diagnostic methods in combination with therapy. For example, given that Rett Syndrome is known to be associated with and caused by mutations or variations in the gene encoding MeCP2 in a large majority of cases, a subject can be first screened for such mutations. This can be done to determine the suitability of the subject for treatment with IGF1, (1-3)IGF-1, (1-3)IGF-1 analog(s) and/or related therapeutic molecules as described herein. Subjects having other diseases, conditions and disorders that have a genetic basis and are amenable to the therapies described herein also can diagnosed and treated in the same way. In particular, subjects with mutations or variations in genes that are targets of MeCP2 or are downstream of MeCP2 are amenable to the therapies described herein and can be diagnosed and treated in the same way.

Standard clinical diagnostic methods are well known in the art. Typically these methods include obtaining a sample from the subject, which may be without limitation a tissue sample, biopsy, fluid sample (e.g., blood, urine, saliva, cerebrospinal fluid), etc., and then subjecting the sample to the diagnostic procedure. Many well-known methodologies are available to the practitioner to analyze the sample, such as various nucleic acid detection and amplification methods, including polymerase chain reaction-based methods, and various protein detection methods, including antibody-based detection methods. In other instances it may be possible to use imaging techniques for non-invasive diagnosis.

Diagnostic methods also may be combined with therapeutic methods to follow the course of disease during therapy, and to aid in the selection of appropriate therapy. Such applications of diagnostic methods in combination with therapeutic methods is routinely practiced in the medical arts.
 

Claim 1 of 20 Claims

1. A method for treating Rett Syndrome characterized by methyl CpG-binding protein 2 (MeCP2) deficiency comprising administering to a subject in need of such treatment an effective amount of insulin-like growth factor 1 (IGF1) and/or (1-3)IGF-1, to treat the subject.
 

 

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