RESEARCH HIGHLIGHTS

NEUROMUSCULAR DISORDERS Beefing up the right splice variant to treat

Spinal muscular atrophy (SMA), compounds that alter SMN2 splicing, SMN-C3, levels were partially the leading genetic cause of infant thereby increasing the production restored in the brain and spinal mortality, is characterized by of full-length SMN2 transcripts. cord, and fully restored in muscle to progressive degeneration of motor By screening a library of ~200,000 those levels observed in unaffected neurons in the anterior horn of the compounds and performing further heterozygous Smn1+/– mice. spinal cord and atrophy of skeletal chemical optimization for molecules In a mouse model of severe muscles. SMA results from muta- that increase the ratio of full-length SMA (Δ7 mice), administration tions in survival of motor neuron 1 to Δ7 SMN2 mRNA, they found of SMN-C2 or SMN-C3 (by intra- (SMN1). Naryshkin et al. have now three compound series — exempli- peritoneal injection until postnatal identified orally available small- fied by compounds named SMN-C1, day 23 and oral administration molecule compounds that alter the SMN-C2 and SMN-C3 — that thereafter) increased SMN protein splicing of the nearly identical SMN2, increased the fraction of SMN2 levels and prolonged survival; which can improve motor function mRNAs that contain exon 7. approximately 90% of animals and extend lifespan in mouse models These compounds were then survived beyond postnatal day 65, of SMA. tested in two cell types from patients when the study was terminated. SMN2 is thought to have arisen with SMA: motor neurons generated By contrast, untreated Δ7 mice died from an SMN1 duplication from induced pluripotent stem cells within 3 weeks of birth (median event. The coding regions of SMN1 and fibroblasts. Treatment with any survival 18 days). Treating mice with and SMN2 differ by only one trans- one of the three compounds altered SMN-C3 also restored weight gain lationally silent polymorphism SMN2 splicing, thereby increasing and motor function to normal or that alters splicing and the levels of both full-length SMN near-normal levels. excludes exon 7 from transcripts and SMN protein in both The observed systemic effects in most SMN2 transcripts cell types. Of note, these compounds the Δ7 mice treated with SMN-C3 (Δ7). A small amount of did not seem to affect overall splicing, were associated with reduced SMN- full-length SMN mRNA transcription or translation, as the related neuromuscular pathology. is produced from expression of only twelve was Loss of spinal cord neurons, dener­ SMN2, altered by a factor of >two in SMA vation of the neuromuscular junction but most fibroblasts that were treated with in the splenius capitis and atrophy of the SMN-C3. Furthermore, an analysis of of the extensor digitorum longus tran- annotated splice junctions within the were all prevented by treatment with scripts transcripts identified only a handful SMN-C3 in a dose-dependent manner. lack of splicing alterations in response to These newly identified small exon 7, SMN-C3 treatment. molecules have nanomolar potency, SMA and The investigators then used a penetrate into muscle and the central the Δ7 mouse model of mild SMA (SmnC/C), nervous system and seem to be

V . protein is in which the animals have a normal highly selective for SMN splicing. S u m unstable. lifespan but have muscle weakness, Analogues of these compounds are m e rs As disease peripheral necrosis and reduced currently in clinical testing, and by /N PG severity inversely weight. Daily oral treatment of these could become a promising therapy correlates with mice with SMN-C2 or SMN-C3­ for patients with SMA. levels of functional shifted Smn gene expression to favour Megan Cully

SMN protein and the production of full-length Smn2 ORIGINAL RESEARCH PAPER Naryshkin, N. A. with SMN2 copy mRNA (from 40% full-length, 60% et al. SMN2 splicing modifiers improve motor number, Naryshkin Δ7 to 90% full-length, 10% Δ7). function and longevity in mice with spinal muscular atrophy. Science 345, 688–693 (2014) et al. sought to identify After 10 days of treatment with

NATURE REVIEWS | DRUG DISCOVERY VOLUME 13 | OCTOBER 2014

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