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

作者：Naryshkin Nikolai A; Weetall Marla; Dakka Amal; Narasimhan Jana; Zhao Xin; Feng Zhihua; Ling Karen K Y; Karp Gary M; Qi Hongyan; Woll Matthew G; Chen Guangming; Zhang Nanjing; Gabbeta Vijayalakshmi; Vazirani Priya; Bhattacharyya Anuradha; Furia Bansri; Risher Nicole; Sheedy Josephine; Kong Ronald; Ma Jiyuan; Turpoff Anthony; Lee Chang Sun; Zhang Xiaoyan; Moon Young Choon; Trifillis Panayiota; Welch Ellen M; Colacino Joseph M; Babiak John; Almstead Neil G

来源：Science, 2014, 345(6197): 688-693.

DOI：10.1126/science.1250127

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 D7 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.

• 出版日期2014-8-8