AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models.
AAV.Dysferlin Overlap Vectors Restore Function in Dysferlinopathy Animal Models.
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DOI：
10.1002/acn3.172
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发表时间：
2015-03
影响因子：
5.3
通讯作者：
Rodino-Klapac, Louise R.
中科院分区：
文献类型：
--
作者：
Sondergaard, Patricia C.;Griffin, Danielle A.;Pozsgai, Eric R.;Johnson, Ryan W.;Grose, William E.;Heller, Kristin N.;Shontz, Kim M.;Montgomery, Chrystal L.;Liu, Joseph;Clark, Kelly Reed;Sahenk, Zarife;Mendell, Jerry R.;Rodino-Klapac, Louise R.
Dysferlin 病是由 Dysferlin 基因突变引起的一类无法治疗的肌肉疾病。缺乏 Dysferlin 蛋白会导致进行性营养不良，并伴有慢性肌纤维损失、炎症、脂肪替代和纤维化；导致肌肉无力恶化。这项工作的目的是证明基因治疗后 Dysferlin 表达的有效和安全恢复。传统的基因治疗受到腺相关病毒（AAV）包装容量的限制，然而，使用双载体策略可以递送超大基因，包括dysferlin。两个载体系统 (AAV.DYSF.DV) 通过使用由 1 kb 同源区域定义的两个离散载体，利用 AAV 血清型 rh.74 包装 Dysferlin cDNA。比较了在 Dysferlin 缺陷小鼠和非人灵长类动物中通过肌内和血管递送途径递送 AAV.DYSF.DV 的效率和安全性。对治疗后的肌肉进行了 Dysferlin 表达、整体肌肉组织学以及损伤后修复能力的测试。所有接受治疗的肌肉群都显示出高水平的 Dysferlin 过度表达，并且功能结果指标（膜修复能力和膈肌比力）恢复至野生型水平。在灵长类动物中，dysferlin 表达强烈，且不存在安全问题。治疗后的肌肉显示出高水平的 Dysferlin 表达，功能恢复，没有毒性或免疫反应的证据，为转化为 Dysferlin 病患者提供了原理证明。
Dysferlinopathies are a family of untreatable muscle disorders caused by mutations in the dysferlin gene. Lack of dysferlin protein results in progressive dystrophy with chronic muscle fiber loss, inflammation, fat replacement, and fibrosis; leading to deteriorating muscle weakness. The objective of this work is to demonstrate efficient and safe restoration of dysferlin expression following gene therapy treatment. Traditional gene therapy is restricted by the packaging capacity limit of adeno-associated virus (AAV), however, use of a dual vector strategy allows for delivery of over-sized genes, including dysferlin. The two vector system (AAV.DYSF.DV) packages the dysferlin cDNA utilizing AAV serotype rh.74 through the use of two discrete vectors defined by a 1 kb region of homology. Delivery of AAV.DYSF.DV via intramuscular and vascular delivery routes in dysferlin deficient mice and nonhuman primates was compared for efficiency and safety. Treated muscles were tested for dysferlin expression, overall muscle histology, and ability to repair following injury. High levels of dysferlin overexpression was shown for all muscle groups treated as well as restoration of functional outcome measures (membrane repair ability and diaphragm specific force) to wild-type levels. In primates, strong dysferlin expression was demonstrated with no safety concerns. Treated muscles showed high levels of dysferlin expression with functional restoration with no evidence of toxicity or immune response providing proof of principle for translation to dysferlinopathy patients.
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影响因子：
12.4
作者：
Chicoine, Louis G.;Rodino-Klapac, Louise R.;Martin, Paul T.
通讯作者：
Martin, Paul T.
影响因子：
4.2
作者：
Koo, Taeyoung;Popplewell, Linda;Dickson, George
通讯作者：
Dickson, George
影响因子：
82.9
作者：
Duan, DS;Yue, YP;Engelhardt, JF
通讯作者：
Engelhardt, JF
影响因子：
17.1
作者：
Kota J;Handy CR;Haidet AM;Montgomery CL;Eagle A;Rodino-Klapac LR;Tucker D;Shilling CJ;Therlfall WR;Walker CM;Weisbrode SE;Janssen PM;Clark KR;Sahenk Z;Mendell JR;Kaspar BK
通讯作者：
Kaspar BK
影响因子：
11.2
作者：
Glover, Louise E.;Newton, Kimberly;Krishnan, Gomathi;Bronson, Roderick;Boyle, Alexandra;Krivickas, Lisa S.;Brown, Robert H., Jr.
通讯作者：
Brown, Robert H., Jr.