| Literature DB >> 25104390 |
Nikolai A Naryshkin1, Marla Weetall1, Amal Dakka1, Jana Narasimhan1, Xin Zhao1, Zhihua Feng2, Karen K Y Ling2, Gary M Karp1, Hongyan Qi1, Matthew G Woll1, Guangming Chen1, Nanjing Zhang1, Vijayalakshmi Gabbeta1, Priya Vazirani1, Anuradha Bhattacharyya1, Bansri Furia1, Nicole Risher1, Josephine Sheedy1, Ronald Kong1, Jiyuan Ma1, Anthony Turpoff1, Chang-Sun Lee1, Xiaoyan Zhang1, Young-Choon Moon1, Panayiota Trifillis1, Ellen M Welch1, Joseph M Colacino1, John Babiak1, Neil G Almstead1, Stuart W Peltz3, Loren A Eng4, Karen S Chen4, Jesse L Mull5, Maureen S Lynes5, Lee L Rubin5, Paulo Fontoura6, Luca Santarelli6, Daniel Haehnke6, Kathleen D McCarthy4, Roland Schmucki6, Martin Ebeling6, Manaswini Sivaramakrishnan6, Chien-Ping Ko2, Sergey V Paushkin4, Hasane Ratni6, Irene Gerlach6, Anirvan Ghosh6, Friedrich Metzger7.
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.Entities:
Mesh：
Substances：
Year: 2014 PMID： 25104390 DOI： 10.1126/science.1250127
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728