Poster abstracts

Poster number 18 submitted by Michelle Hastings

Development of compounds that increase SMN2 splicing as a treatment for spinal muscular atrophy

Michelle L. Hastings (Dept. of Cell Biology and Anatomy, Chicago Medical School), Joel Berniac (Paratek Pharmaceuticals, Inc.), Ying Hsiu Liu (Cold Spring Harbor Laboratory), Paul Higgins (Paratek Pharmaceuticals, Inc), Adrian R. Krainer (Cold Spring Harbor Laboratory)

Abstract:
Spinal muscular atrophy (SMA) is a pediatric neurodegenerative disease caused by loss of the survival of motor neuron 1 (SMN1) gene. A second gene, SMN2 is nearly identical to SMN1 but cannot compensate for the loss of SMN1 because most SMN2 mRNA transcripts lack exon 7 as a result of a C to T conversion at position +6 of exon 7. Transcripts lacking exon 7 produce a truncated protein that cannot function in place of the full-length SMN protein. Correcting aberrant SMN2 exon 7 splicing is one way to increase full-length SMN protein expression from SMN2 as an approach for SMA therapy. We developed an in vitro cell-free assay to test for compounds that improve SMN2 exon 7 splicing directly. One class of compounds tested was modified tetracycline (TC) derivatives and one compound, P1033, emerged as a promising hit. P1033 treatment leads to a 6-fold increase in SMN2 exon 7 inclusion in our in vitro assay and leads to a 40% increase in SMN protein levels in SMA patient-derived fibroblasts. P1033 increases exon 7 inclusion by 74% in mice carrying the human SMN2 transgene, demonstrating the promise of this molecule as a therapeutic. Medicinal chemistry using structure-activity relationship (SAR) analysis has yielded additional TC derivatives with activity in the splicing assay. Future efforts will focus on optimizing the potency and pharmacokinetic profile of these novel derivatives to identify a pre-clinical candidate for the treatment of SMA.

Keywords: splicing, disease