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SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy

Science  08 Aug 2014:
Vol. 345, Issue 6197, pp. 688-693
DOI: 10.1126/science.1250127

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Drugs that provide the splice of life

Motor neurons relay signals from the nervous system to muscle fibers. In patients with spinal muscular atrophy, a protein required for the survival of these neurons is deficient or missing altogether, so the neurons gradually die and the patients' muscles waste away. The disease is currently untreatable. Naryshkin et al. discovered small-molecule drugs that cause cells to produce the missing protein by altering how a specific mRNA is put together, or “spliced” (see the Perspective by Vigevani and Valcárcel). When the researchers used the drugs to treat diseased mice, the mice showed marked improvement in muscle mass, motor function, and survival.

Science, this issue p. 688; see also p. 624

Abstract

Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.

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