很多遺傳疾病是由一個信使RNA（mRNA）向蛋白質內轉錄過程中的過早終止造成的，肌營養(yǎng)不良癥就是這樣一種疾病?，F在,，Welch等人報告，一個名為PTC124的小分子能使這一轉錄“機器”繞開會引起過早終止的點,，但仍會在mRNA的端點正常終止。在人體和小鼠細胞中,，該藥物能恢復在肌營養(yǎng)不良癥中發(fā)生突變的基因的正常轉錄,，它在該人類疾病的mdx小鼠模型中還能恢復肌肉功能。這項工作為也許可用于以無用突變?yōu)樽饔媚繕?，并在各種不同的疾病中恢復蛋白功能的類似藥物提供了希望,。PTC124目前正在進行治療肌營養(yǎng)不良癥和囊性纖維瘤的臨床試驗
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: [email protected]).
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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.
