Therapeutic Opportunities in Spinal Muscular Atrophy

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DESCRIPTION (provided by applicant): Spinal muscular atrophy is the most common inherited motor neuron disease in humans, with an incidence of one in 8,000 live births. It is a leading cause of hereditary infant and childhood mortality. Homozygous deletion of the survival motor neuron 1 (SMN1) gene plays a primary role in disease pathogenesis. The SMN1 gene lies in an inverted duplicated region on chromosome 5. A near identical copy of SMN1, designated SMN2, contains a single nucleotide change which alters splicing, resulting in decreased functional protein expression. However, approximately 10% of the transcripts from SMN2 yield a full length SMN mRNA identical to that produced from SMN1. SMN2 copy number is inversely correlated with phenotypic severity in humans and phenotypic rescue in an SMN1 knock-out mouse model. Other genetic modifiers likely exist, since rare individuals within families with SMN genotypes identical to affected siblings are phenotypically normal. Compounds have been identified which up-regulate SMN2 gene expression, moderate disease phenotype in patient cell lines, and prolong survival in an SMA mouse model. The investigator's natural history database includes 117 infants and children with SMA, with more than 500 patient visits. This database, along with ongoing studies involving over 80 children, put her in a unique position to ask specific questions regarding disease pathogenesis, and to investigate treatments which may attenuate disease severity or progression. It is hypothesized that motor neuron dysfunction and loss are due to an increased vulnerability of motor neurons to low levels of SMN protein. The investigator proposes that motor neuron denervation is progressive over time; that severity of denervation correlates with SMN2 copy number; and that increased expression of SMN protein in neurons via up-regulation of SMN2 gene expression will preserve at risk motor neurons and facilitate neuronal sprouting and reinnervation of muscle. She also proposes that intervention within a critical therapeutic window early in the disease process will prove necessary to most effectively moderate disease severity. To address these hypotheses, the investigator proposes to: 1) determine the severity and time course of denervation and functional motor status in a broad cohort of children with SMA; 2) validate diverse clinical outcome measures which assess severity of denervation, functional motor status, and disease biomarkers to permit the evaluation of experimental treatments; 3) perform pilot studies to evaluate potential effects of specific interventions on neuronal sprouting, collateral re-innervation, and functional motor status, and 4) establish a genetic database supported by detailed phenotypic information to identify disease-modifying loci as additional leads to novel therapeutic interventions.