Abstract: Series 113, Lecture 3
The Harvey Lectures Series 113 (2017—2018)
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Lecture #3: Thursday, January 18, 2018 — Watch Video of Lecture
Antisense Therapy for Spinal Muscular Atrophy: Harnessing the Power of a Backup Gene
Adrian Krainer, PhD
Professor & Chair, Cancer & Molecular Biology
Cold Spring Harbor Laboratory
Cold Spring Harbor, New York
SMA is a motor-neuron disease, caused by mutations in the SMN1 gene. Patients retain one or more copies of the nearly identical SMN2 gene, which mainly expresses mRNA lacking exon 7, coding for an unstable protein isoform. The small amount of full-length mRNA and protein expressed from SMN2 only partially compensates for the loss of SMN1. Together with Ionis Pharmaceuticals, we developed nusinersen, a splice-switching antisense oligonucleotide (ASO) that efficiently promotes SMN2 exon 7 inclusion and restores SMN protein levels. Nusinersen hybridizes to intron 7 of the SMN2 pre-mRNA, preventing binding of the splicing repressors hnRNPA1/A2 to a bipartite intronic splicing silencer; this in turn facilitates binding of U1 snRNP to the intron 7 5′ splice site, resulting in enhanced exon 7 inclusion. Nusinersen, the first approved treatment for SMA, is an example of a targeted therapeutic designed on the basis of fundamental knowledge of gene-expression mechanisms. This successful clinical application comes >120 years after the first description of the disease, and 40 years after the discovery of RNA splicing and the first reported use of antisense technology. We are continuing to explore aspects of SMA pathogenesis and treatment, using ASO therapy in SMA mouse models. We found that SMA is not motor-neuron cell-autonomous in the mouse models, such that correcting SMN2 splicing in peripheral tissues exclusively is sufficient for full phenotypic rescue in mice. We are also exploring prenatal ASO treatment, as it is likely that early intervention will maximize the clinical benefit.