G munoz e tandon a kwon d y sumner c j fischbeck

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Unformatted text preview: muscles. Spinal muscular atrophy (SMA) •  Autosomal recessive neuromuscular disease –  –  –  –  Due to mutations in the SMN gene Affects the anterior horn cells of the spinal cord atrophy of the proximal muscles of the limbs and trunk Different people have different numbers of the SMN2 gene 1. SMA Type I Proximal muscle weakness, patients never sit unaided death in 6 months – 2 years of age SMN1 inactivated, 1 ­2 copies of SMN2 2. SMA Type II Proximal muscle weakness, patients sit unaided become wheelchair bound, develop scoliosis of spine at 6–18 months SMN1 inactivated, at least 3 copies of the SMN2 gene 3. SMA Type III Proximal muscle weakness, patients walk unaided, normal lifespan SMN1 inactivated, at least 4 copies of the SMN2 gene Therapeutic Options 1  ­ Drugs •  SMN2 activation –  aims at increasing expression of the SMN2 gene and thus increasing the amount of full ­length SMN available –  Passini, M. A.; Cheng, S. H. (2011). "Prospects for the gene therapy of spinal muscular atrophy". Trends in Molecular Medicine 17 (5): 259–265 •  SMN2 alternative splicing modulation –  targets the alternative splicing of the SMN2 gene –  Increase % full ­length SMN2 transcripts (gene conversion SMN2→SMN1) •  SMN stabilization –  Increases stability of SMNΔ7 protein so that it is able to sustain neuronal cells –  Burnett, B. G.; Munoz, E.; Tandon, A.; Kwon, D. Y.; Sumner, C. J.; Fischbeck, K. H. (2008). Regulation of SMN Protein Stability". Molecular and Cellular Biology 29 (5): 1107–1115. Therapeutic Options 2 – gene and stem cell therapy •  Gene therapy –  Correct SMN1 gene function by providing normal SMN1 gene in viral vectors –  Ohio State University and Nationwide Children's Hospital, USA, and the University of ShefGield, United Kingdom, as well as by Genzyme Corporation, USA, and Généthon, France •  Best survival increase achieved to ­date in a SMNΔ7 mouse model –  median survival of 400 days in treated mice as opposed to 15 days in untreated mice). –  Bevan, A. K.; Duque, S.; Foust, K. D.; Morales, P. R.; Braun, L.; Schmelzer, L.; Chan, C. M.; McCrate, M. et al. (2011) "Systemic Gene Delivery in Large Species for Targeting Spinal C...
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This document was uploaded on 01/18/2014.

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