Eteplirsen for the Treatment of Duchenne Muscular Dystrophy

被引:549
作者
Mendell, Jerry R. [1 ,2 ,3 ,4 ]
Rodino-Klapac, Louise R. [1 ,4 ]
Sahenk, Zarife [1 ,2 ,3 ,4 ]
Roush, Kandice [5 ]
Bird, Loren [5 ]
Lowes, Linda P. [4 ]
Alfano, Lindsay [4 ]
Gomez, Ann Maria [1 ,4 ]
Lewis, Sarah [1 ,4 ]
Kota, Janaiah [1 ,4 ]
Malik, Vinod [1 ,4 ]
Shontz, Kim [1 ,4 ]
Walker, Christopher M. [1 ,4 ,6 ]
Flanigan, Kevin M. [1 ,2 ,3 ,4 ]
Corridore, Marco [7 ,8 ]
Kean, John R. [4 ,7 ,8 ]
Allen, Hugh D. [1 ,4 ]
Shilling, Chris [1 ,3 ,4 ]
Melia, Kathleen R. [9 ]
Sazani, Peter [9 ]
Saoud, Jay B. [9 ]
Kaye, Edward M. [9 ]
机构
[1] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA
[2] Ohio State Univ, Dept Neurol, Columbus, OH 43210 USA
[3] Nationwide Childrens Hosp, Gene Therapy Ctr, Columbus, OH 43205 USA
[4] Nationwide Childrens Hosp, Paul D Wellstone Ctr, Columbus, OH 43205 USA
[5] Nationwide Childrens Hosp, Clin Res Serv, Dept Pediat, Columbus, OH 43205 USA
[6] Nationwide Childrens Hosp, Ctr Vaccines & Immun, Columbus, OH 43205 USA
[7] Nationwide Childrens Hosp, Dept Surg, Columbus, OH 43205 USA
[8] Nationwide Childrens Hosp, Dept Anesthesiol, Columbus, OH 43205 USA
[9] Sarepta Therapeut, Cambridge, MA USA
关键词
6-MINUTE WALK TEST; MORPHOLINO OLIGOMER; RESTORATION; THERAPY; ONSET; GENE;
D O I
10.1002/ana.23982
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
ObjectiveIn prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer, enabled dystrophin production in Duchenne muscular dystrophy (DMD) with genetic mutations amenable to skipping exon 51. The present study used a double-blind placebo-controlled protocol to test eteplirsen's ability to induce dystrophin production and improve distance walked on the 6-minute walk test (6MWT). MethodsDMD boys aged 7 to 13 years, with confirmed deletions correctable by skipping exon 51 and ability to walk 200 to 400 m on 6 MWT, were randomized to weekly intravenous infusions of 30 or 50 mg/kg/wk eteplirsen or placebo for 24 weeks (n=4/group). Placebo patients switched to 30 or 50 mg/kg eteplirsen (n=2/group) at week 25; treatment was open label thereafter. All patients had muscle biopsies at baseline and week 48. Efficacy included dystrophin-positive fibers and distance walked on the 6MWT. ResultsAt week 24, the 30 mg/kg eteplirsen patients were biopsied, and percentage of dystrophin-positive fibers was increased to 23% of normal; no increases were detected in placebo-treated patients (p0.002). Even greater increases occurred at week 48 (52% and 43% in the 30 and 50 mg/kg cohorts, respectively), suggesting that dystrophin increases with longer treatment. Restoration of functional dystrophin was confirmed by detection of sarcoglycans and neuronal nitric oxide synthase at the sarcolemma. Ambulation-evaluable eteplirsen-treated patients experienced a 67.3 m benefit compared to placebo/delayed patients (p0.001). InterpretationEteplirsen restored dystrophin in the 30 and 50 mg/kg/wk cohorts, and in subsequently treated, placebo-controlled subjects. Duration, more than dose, accounted for dystrophin production, also resulting in ambulation stability. No severe adverse events were encountered. Ann Neurol 2013;74:637-647
引用
收藏
页码:637 / 647
页数:11
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