ATALUREN TREATMENT OF PATIENTS WITH NONSENSE MUTATION DYSTROPHINOPATHY

被引：333

作者：

Bushby, Katharine ^{[1
]}

Finkel, Richard ^{[2
]}

Wong, Brenda ^{[3
]}

Barohn, Richard ^{[4
]}

Campbell, Craig ^{[5
]}

Comi, Giacomo P. ^{[6
]}

Connolly, Anne M. ^{[7
]}

Day, John W. ^{[8
]}

Flanigan, Kevin M. ^{[9
,10
]}

Goemans, Nathalie ^{[11
]}

Jones, Kristi J. ^{[12
,13
,14
]}

Mercuri, Eugenio ^{[15
]}

Quinlivan, Ros ^{[16
]}

Renfroe, James B. ^{[17
]}

Russman, Barry ^{[18
,19
]}

Ryan, Monique M. ^{[20
,21
]}

Tulinius, Mar ^{[22
]}

Voit, Thomas ^{[23
]}

Moore, Steven A. ^{[24
]}

Sweeney, H. Lee ^{[25
]}

Abresch, Richard T. ^{[26
]}

Coleman, Kim L. ^{[27
]}

Eagle, Michelle ^{[1
]}

Florence, Julaine ^{[7
]}

Gappmaier, Eduard ^{[28
]}

Glanzman, Allan M. ^{[2
]}

Henricson, Erik ^{[26
]}

Barth, Jay ^{[29
]}

Elfring, Gary L. ^{[29
]}

Reha, Allen ^{[29
]}

Spiegel, Robert J. ^{[29
]}

O'Donnell, Michael W. ^{[29
]}

Peltz, Stuart W. ^{[29
]}

McDonald, Craig M. ^{[26
]}

机构：

[1] Newcastle Univ, Inst Genet Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[2] Childrens Hosp Philadelphia, Philadelphia, PA USA

[3] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA

[4] Univ Kansas, Med Ctr, Lawrence, KS 66045 USA

[5] Univ Western Ontario, London, ON, Canada

[6] Univ Milan, Dino Ferrari Ctr, Dept Neurol Sci, IRCCS Fdn Ca Granda,Osped Maggiore Policlin, Milan, Italy

[7] Washington Univ, Sch Med, St Louis, MO USA

[8] Univ Minnesota, Minneapolis, MN USA

[9] Nationwide Childrens Hosp, Columbus, OH USA

[10] Ohio State Univ, Columbus, OH 43210 USA

[11] Univ Hosp Leuven, Leuven, Belgium

[12] Sydney Childrens Hosp Network, Dept Clin Genet, Sydney, NSW, Australia

[13] Univ Sydney, Discipline Genet, Fac Med, Sydney, NSW 2006, Australia

[14] Univ Sydney, Discipline Paediat & Child Hlth, Fac Med, Sydney, NSW 2006, Australia

[15] Univ Cattolica Sacro Cuore, Polilcin Gemelli, Pediat Neurol Unit, Rome, Italy

[16] Inst Neurol, London WC1N 3BG, England

[17] Northwest Florida Clin Res Grp, Gulf Breeze, FL USA

[18] Oregon Hlth & Sci Univ, Portland, OR 97201 USA

[19] Shriners Hosp Children, Portland, OR USA

[20] Royal Childrens Hosp, Murdoch Childrens Res Inst, Parkville, Vic 3052, Australia

[21] Univ Melbourne, Parkville, Vic 3052, Australia

[22] Univ Gothenburg, Dept Pediat, Gothenburg, Sweden

[23] Univ Paris 06, CNRS, INSERM, UM76,U974,UMR 7215,Inst Myol, Paris, France

[24] Univ Iowa, Iowa City, IA 52242 USA

[25] Univ Penn, Philadelphia, PA 19104 USA

[26] UC Davis Childrens Hosp, Lawrence J Ellison Ambulatory Care Ctr, Sacramento, CA 95817 USA

[27] OrthoCare Innovat, Mountlake Terrace, WA USA

[28] Univ Utah, Sch Med, Salt Lake City, UT USA

[29] PTC Therapeut, South Plainfield, NJ USA

来源：

MUSCLE & NERVE | 2014年 / 50卷 / 04期

基金：

英国医学研究理事会;

关键词：

Duchenne muscular dystrophy; genetic; pediatric; nonsense mutation; orphan; GIANT AXONAL NEUROPATHY; INTERMEDIATE-FILAMENTS; GENOTYPE-PHENOTYPE; MOLECULAR FINDINGS; MOUSE MODEL; SIBLINGS; PROTEIN; GIGAXONIN; GENE; DISEASE;

D O I：

10.1002/mus.24332

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

100204 [神经病学];

摘要：

Introduction: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. Methods: Randomized, double-blind, placebo-controlled study; males >= 5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48. Results: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Delta=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. Conclusions: As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need.

引用

页码：477 / 487

页数：11

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