Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and is the most common genetic cause of infantile death. The SMA-determining gene is located on chromosome 5q, and is called survival motor neuron-1 (SMN1). Remarkably, a nearly identical copy gene is present called SMN2. This gene has the capacity to encode an identical protein compared to SMN1, however, due to a single silent non-polymorphic nucleotide difference, the majority of SMN2-derived transcripts are alternatively spliced and encode a truncated and biochemically defective protein called SMN?7. To date, SMN2 is the only SMA modifying gene. Milder phenotypes correlate with an increase in the number of SMN2 copies, typically ranging from two to four copies. The genetic context of SMA makes this disease especially amenable to therapeutic intervention including: SMN2 is retained in essentially all SMA patients;SMN2 is ubiquitously expressed in all tissues;and SMN2 retains the capacity to encode a normal, full-length SMN protein. Therefore, SMN2 has been identified as a major target for a potential SMA therapies. The most attractive possibilities include stimulating total SMN2 transcription and/or modulation of the SMN2 alternative splicing event. To take advantage of the unique SMA genetic context, the goal of this application is to develop novel RNAs that modulate SMN2 splicing. Through the use of a viral delivery system (Aim 1), these RNAs will be examined in a variety of experimental contexts designed to identify RNAs that induces the highest level of full-length SMN2 expression (Aim 1 and 2). The top candidate RNAs will then be examined in a murine model of SMA to determine whether the RNAs can modulate SMN2 in an organism and whether this expected increase in full-length SMN2 expression lessens the well described mild SMA phenotype in transgenic mice (Aim 3). While the experiments described in this application have immediate implications for the development of a SMA therapy, the results could be used as a model for a broad range of genetic disorders in which correcting a splicing defect would restore functionality to a disease-causing gene.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD054413-03
Application #
7622157
Study Section
Special Emphasis Panel (ZHD1-MRG-C (03))
Program Officer
Urv, Tiina K
Project Start
2007-08-10
Project End
2012-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
3
Fiscal Year
2009
Total Cost
$259,194
Indirect Cost
Name
University of Missouri-Columbia
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
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Glascock, Jacqueline J; Osman, Erkan Y; Wetz, Mary J et al. (2012) Decreasing disease severity in symptomatic, Smn(-/-);SMN2(+/+), spinal muscular atrophy mice following scAAV9-SMN delivery. Hum Gene Ther 23:330-5
Osman, Erkan Y; Yen, Pei-Fen; Lorson, Christian L (2012) Bifunctional RNAs targeting the intronic splicing silencer N1 increase SMN levels and reduce disease severity in an animal model of spinal muscular atrophy. Mol Ther 20:119-26
Mattis, Virginia B; Tom Chang, Cheng-Wei; Lorson, Christian L (2012) Analysis of a read-through promoting compound in a severe mouse model of spinal muscular atrophy. Neurosci Lett 525:72-5
Glascock, Jacqueline J; Shababi, Monir; Wetz, Mary J et al. (2012) Direct central nervous system delivery provides enhanced protection following vector mediated gene replacement in a severe model of spinal muscular atrophy. Biochem Biophys Res Commun 417:376-81
Glascock, Jacqueline J; Osman, Erkan Y; Coady, Tristan H et al. (2011) Delivery of therapeutic agents through intracerebroventricular (ICV) and intravenous (IV) injection in mice. J Vis Exp :
Dale, Jeffrey M; Shen, Hailian; Barry, Devin M et al. (2011) The spinal muscular atrophy mouse model, SMAýý7, displays altered axonal transport without global neurofilament alterations. Acta Neuropathol 122:331-41
Coady, Tristan H; Lorson, Christian L (2010) Trans-splicing-mediated improvement in a severe mouse model of spinal muscular atrophy. J Neurosci 30:126-30
Shaw, Debra J; Morse, Robert; Todd, Adrian G et al. (2010) Identification of a self-association domain in the Ewing's sarcoma protein: a novel function for arginine-glycine-glycine rich motifs? J Biochem 147:885-93
Lorson, Christian L; Rindt, Hansjorg; Shababi, Monir (2010) Spinal muscular atrophy: mechanisms and therapeutic strategies. Hum Mol Genet 19:R111-8

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