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Science DOI:10.1126/science.1250127

Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.

Publication TypeJournal Article
Year of Publication2014
AuthorsNaryshkin, NA, Weetall, M, Dakka, A, Narasimhan, J, Zhao, X, Feng, Z, K Y Ling, K, Karp, GM, Qi, H, Woll, MG, Chen, G, Zhang, N, Gabbeta, V, Vazirani, P, Bhattacharyya, A, Furia, B, Risher, N, Sheedy, J, Kong, R, Ma, J, Turpoff, A, Lee, C-S, Zhang, X, Moon, Y-C, Trifillis, P, Welch, EM, Colacino, JM, Babiak, J, Almstead, NG, Peltz, SW, Eng, LA, Chen, KS, Mull, JL, Lynes, MS, Rubin, LL, Fontoura, P, Santarelli, L, Haehnke, D, McCarthy, KD, Schmucki, R, Ebeling, M, Sivaramakrishnan, M, Ko, C-P, Paushkin, SV, Ratni, H, Gerlach, I, Ghosh, A, Metzger, F
Date Published2014 Aug 08
KeywordsAdministration, Oral, Alternative Splicing, Animals, Cells, Cultured, Coumarins, Disease Models, Animal, Drug Evaluation, Preclinical, Humans, Isocoumarins, Longevity, Mice, Muscular Atrophy, Spinal, Pyrimidinones, RNA, Messenger, Sequence Deletion, Small Molecule Libraries, Survival of Motor Neuron 2 Protein

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.


Alternate JournalScience
PubMed ID25104390