• Nikolai A Naryshkin, Marla Weetall, Amal Dakka, Jana Narasimhan, Xin Zhao, Zhihua Feng, Karen K Y Ling, Gary M Karp, Hongyan Qi, Matthew G Woll, Guangming Chen, Nanjing Zhang, Vijayalakshmi Gabbeta, Priya Vazirani, Anuradha Bhattacharyya, Bansri Furia, Nicole Risher, Josephine Sheedy, Ronald Kong, Jiyuan Ma, Anthony Turpoff, Chang-Sun Lee, Xiaoyan Zhang, Young-Choon Moon, Panayiota Trifillis, Ellen M Welch, Joseph M Colacino, John Babiak, Neil G Almstead, Stuart W Peltz, Loren A Eng, Karen S Chen, Jesse L Mull, Maureen S Lynes, Lee L Rubin, Paulo Fontoura, Luca Santarelli, Daniel Haehnke, Kathleen D McCarthy, Roland Schmucki, Martin Ebeling, Manaswini Sivaramakrishnan, Chien-Ping Ko, Sergey V Paushkin, Hasane Ratni, Irene Gerlach, Anirvan Ghosh, and Friedrich Metzger.
• PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
• Science. 2014 Aug 8; 345 (6197): 688-93.

AbstractSpinal 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.Copyright © 2014, American Association for the Advancement of Science.

38 keywords...

hide…