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脊髓性肌萎缩的单剂基因替代治疗
Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy


Jerry R. Mendell ... 妇产科和儿科 • 2017.11.02
相关阅读
• nusinersen或假对照治疗婴儿期发病的脊髓性肌萎缩 • nusinersen或假对照治疗婴儿期发病的脊髓性肌萎缩

基因疗法成功治疗绝症婴儿脊髓性肌萎缩

 

程黎明,许东升*

同济大学附属同济医院脊柱外科;同济大学附属同济医院脊柱神经康复中心

*通讯作者

 

2017年11月2日《新英格兰医学杂志》发表背靠背研究,报道了通过反义寡核苷酸或基因疗法治疗脊髓性肌萎缩(SMA)的临床试验,两项结果均非常振奋人心。本文将着重介绍基因疗法这篇文章。

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摘要


背景

Ⅰ型脊髓性肌萎缩(SMA1)是一种在婴儿期发病的进行性运动神经元单基因疾病,该病导致患者无法达到运动功能里程碑,以及在2岁之前死亡或需要机械通气。该病中运动神经元存活蛋白1的编码基因(survival motor neuron 1,SMN1)出现突变。我们研究了该突变基因的功能性替代。

 

方法

15例SMA1患者接受了腺相关病毒血清型9的单次静脉给药,这些病毒携带与SMN互补的DNA,可以编码患者体内缺失的SMN蛋白。对3例患者施用了小剂量(6.7×1013 vg/kg[每千克体重的载体基因组拷贝数])治疗,12例患者施用了大剂量(2.0×1014 vg/kg)治疗。主要结局是安全性。次要结局是至死亡的时间或至需要长期辅助通气的时间。在探索性分析中,我们根据费城儿童医院婴儿神经肌肉疾病测试(Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders,CHOP INTEND)量表得出了运动功能评分(评分范围为0~64分,评分较高说明功能较好),在两个队列中进行比较,并将大剂量队列的运动功能里程碑与SMA1自然史研究中的历史队列评分进行了比较。

 

结果

截至数据截止日期2017年8月7日,15例患者都存活而且在20月龄时无任何相关事件发生,而历史队列中20月龄时的生存率仅为8%。大量队列中,在基因治疗后CHOP INTEND量表得出的评分从基线时出现快速提高,治疗后1个月时提高了9.8分,治疗后3个月时提高了15.4分,而历史队列的这一评分是降低的。接受大剂量治疗的12例患者中,有11例可以独立地坐,9例可以翻身,11例可以经口喂养并能说话,2例可以独立行走。有4例患者的血清转氨酶水平升高,使用泼尼松龙治疗后其水平降低

 

结论

SMA1患者接受含有SMN蛋白编码DNA的腺相关病毒载体单次静脉输入延长了生存期,达到运动功能里程碑的情况优良,而且运动功能比历史队列好。然而,我们需要进一步研究,以确定这种基因治疗的安全性和有效性(研究由AveXis公司等资助;在ClinicalTrials.gov注册号为NCT02122952)。





作者信息

Jerry R. Mendell, M.D., Samiah Al-Zaidy, M.D., Richard Shell, M.D., W. Dave Arnold, M.D., Louise R. Rodino-Klapac, Ph.D., Thomas W. Prior, Ph.D., Linda Lowes, P.T., Ph.D., Lindsay Alfano, D.P.T., Katherine Berry, P.T., Kathleen Church, M.S.W., John T. Kissel, M.D., Sukumar Nagendran, M.D., James L’Italien, Ph.D., Douglas M. Sproule, M.D., Courtney Wells, B.S., Jessica A. Cardenas, Ph.D., Marjet D. Heitzer, Ph.D., Allan Kaspar, Ph.D., Sarah Corcoran, B.S., Lyndsey Braun, B.S., Shibi Likhite, Ph.D., Carlos Miranda, Ph.D., Kathrin Meyer, Ph.D., K.D. Foust, Ph.D., Arthur H.M. Burghes, Ph.D., and Brian K. Kaspar, Ph.D.
From the Center for Gene Therapy at the Research Institute at Nationwide Children’s Hospital (J.R.M., S.A.-Z., L.R.R.-K., L.L., L.A., K.B., K.C., S.L., C.M., K.M., B.K.K.) and the Departments of Pediatrics (J.R.M., S.A.-Z., R.S., L.L., L.A., K.B., K.C., J.T.K., B.K.K.), Neurology (J.R.M., W.D.A., L.R.R.-K., A.H.M.B., B.K.K.), Pathology (T.W.P.), and Molecular and Cellular Biochemistry (A.H.M.B.), Ohio State University — both in Columbus; and AveXis, Bannockburn, IL (S.N., J.L., D.M.S., C.W., J.A.C., M.D.H., A.K., S.C., L.B., K.D.F., B.K.K.). Address reprint requests to Dr. Mendell at the Research Institute at Nationwide Children’s Hospital, 700 Children’s Dr., Columbus, OH 43205, or at jerry.mendell@nationwidechildrens.org.

 

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