DESCRIPTION (provided by applicant): Spinal Muscular Atrophy (SMA) is an autosomal recessive disorder characterized by progressive muscle weakness and death due to deterioration of motor neurons. SMA results from homozygous mutation of the SMN (survival motor neuron) 1 gene. A nearly identical copy, SMN2, fails to protect from development of SMA as its major mRNA undergoes alternative splicing that encodes for an unstable SMN protein. This alternative spliced product excludes exon 7. A small fraction of SMN2 transcripts include exon 7 and encode the identical SMN protein as does SMN1. We have re-designed and validated a cell-based reporter assay that combines three mechanisms to increase SMN protein: induction the SMN promoter, increased inclusion of exon 7, and stabilizing the SMN RNA or protein. The assay has already been established at the NIH NCGC and is fully operational. The first aim is to perform a HTS with the full MLSCN library. The second aim is to validate the most active compounds in secondary assays. The objective is to define structure activity relationships (SAR) for lead optimization and subsequently test available structural analogues to identify pharmacologically active drug-like compounds.
|Effective start/end date||6/11/08 → 5/31/09|
- National Institutes of Health: $25,000.00
Spinal Muscular Atrophy