很多遗传疾病是由一个信使RNA（mRNA）向蛋白质内转录过程中的过早终止造成的，肌营养不良症就是这样一种疾病。现在，Welch等人报告，一个名为PTC124的小分子能使这一转录“机器”绕开会引起过早终止的点，但仍会在mRNA的端点正常终止。在人体和小鼠细胞中，该药物能恢复在肌营养不良症中发生突变的基因的正常转录，它在该人类疾病的mdx小鼠模型中还能恢复肌肉功能。这项工作为也许可用于以无用突变为作用目标，并在各种不同的疾病中恢复蛋白功能的类似药物提供了希望。PTC124目前正在进行治疗肌营养不良症和囊性纤维瘤的临床试验
英文原文:
Nature 447, 87-91 (3 May 2007) | doi:10.1038/nature05756; Received 6 September 2006; Accepted 16 March 2007; Published online 22 April 2007
PTC124 targets genetic disorders caused by nonsense mutations
Ellen M. Welch1,4, Elisabeth R. Barton2,4, Jin Zhuo1, Yuki Tomizawa1, Westley J. Friesen1, Panayiota Trifillis1, Sergey Paushkin1, Meenal Patel1, Christopher R. Trotta1, Seongwoo Hwang1, Richard G. Wilde1, Gary Karp1, James Takasugi1, Guangming Chen1, Stephen Jones1, Hongyu Ren1, Young-Choon Moon1, Donald Corson1, Anthony A. Turpoff1, Jeffrey A. Campbell1, M. Morgan Conn1, Atiyya Khan1, Neil G. Almstead1, Jean Hedrick1, Anna Mollin1, Nicole Risher1, Marla Weetall1, Shirley Yeh1, Arthur A. Branstrom1, Joseph M. Colacino1, John Babiak1, William D. Ju1, Samit Hirawat1, Valerie J. Northcutt1, Langdon L. Miller1, Phyllis Spatrick3, Feng He3, Masataka Kawana2, Huisheng Feng2, Allan Jacobson3, Stuart W. Peltz1 & H. Lee Sweeney2
PTC Therapeutics, 100 Corporate Court, South Plainfield, New Jersey 07080, USA
Department of Physiology, University of Pennsylvania School of Medicine, 3700 Hamilton Walk, Philadelphia, Pennsylvania 19104, USA
Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA
These authors contributed equally to this work.
Correspondence to: Correspondence and requests for materials should be addressed to S.W.P. (Email: speltz@ptcbio.com).
Top of page
Nonsense mutations promote premature translational termination and cause anywhere from 5–70% of the individual cases of most inherited diseases1. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease2, 3. To address the need for a drug capable of suppressing premature termination, we identified PTC124—a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2–8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.
