title: Insulinlike growth factor (IGF)-1 administration ameliorates disease manifestations in a mouse model of spinal and bulbar muscular atrophy.
abstract: Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by polyglutamine expansion in the androgen receptor. Patients develop slowly progressive proximal muscle weakness, muscle atrophy and fasciculations. Affected individuals often show gynecomastia, testicular atrophy and reduced fertility as a result of mild androgen insensitivity. No effective disease-modifying therapy is currently available for this disease. Our recent studies have demonstrated that insulinlike growth factor (IGF)-1 reduces the mutant androgen receptor toxicity through activation of Akt in vitro, and spinal and bulbar muscular atrophy transgenic mice that also overexpress a noncirculating muscle isoform of IGF-1 have a less severe phenotype. Here we sought to establish the efficacy of daily intraperitoneal injections of mecasermin rinfabate, recombinant human IGF-1 and IGF-1 binding protein 3, in a transgenic mouse model expressing the mutant androgen receptor with an expanded 97 glutamine tract. The study was done in a controlled, randomized, blinded fashion, and, to reflect the clinical settings, the injections were started after the onset of disease manifestations. The treatment resulted in increased Akt phosphorylation and reduced mutant androgen receptor aggregation in muscle. In comparison to vehicle-treated controls, IGF-1-treated transgenic mice showed improved motor performance, attenuated weight loss and increased survival. Our results suggest that peripheral tissue can be targeted to improve the spinal and bulbar muscular atrophy phenotype and indicate that IGF-1 warrants further investigation in clinical trials as a potential treatment for this disease.
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-3705, USA. rinaldic@ninds.nih.gov
authors.forename: Carlo
authors.initials: C
authors.lastname: Rinaldi
authors.forename: Laura C
authors.initials: LC
authors.lastname: Bott
authors.forename: Ke-lian
authors.initials: KL
authors.lastname: Chen
authors.forename: George G
authors.initials: GG
authors.lastname: Harmison
authors.forename: Masahisa
authors.initials: M
authors.lastname: Katsuno
authors.forename: Gen
authors.initials: G
authors.lastname: Sobue
authors.forename: Maria
authors.initials: M
authors.lastname: Pennuto
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D009132:Muscles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020966:Muscular Disorders, Atrophic / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020836:Protein Structure, Quaternary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
chemical_list: D050505:Mutant Proteins; D011944:Receptors, Androgen; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt