AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann-Pick type C1 disease.
AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann-Pick type C1 disease.
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DOI：
10.1093/hmg/ddy212
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发表时间：
2018-09-01
影响因子：
3.5
通讯作者：
Rahim AA
中科院分区：
文献类型：
--
作者：
Hughes MP;Smith DA;Morris L;Fletcher C;Colaco A;Huebecker M;Tordo J;Palomar N;Massaro G;Henckaerts E;Waddington SN;Platt FM;Rahim AA
C型尼曼-匹克病（NP-C）是一种致死性神经退行性溶酶体贮积症。在95%的病例中，它是由编码NPC 1的NPC 1基因突变引起的，NPC 1是一种定位于溶酶体界膜的完整跨膜蛋白。NP-C无法治愈，但有一种疾病修饰药物（麦格司他）可以减缓疾病进展，但具有相关的副作用。在这里，我们在一个充分表征的NP-C小鼠模型中证明，对大脑单次施用AAV介导的基因治疗可以显著延长寿命，改善生活质量，预防或改善神经变性，减少生化病理学，并使运动功能的各种指标正常化或改善。人NPC 1的过表达不会在脑中引起不良影响，并正确定位于晚期内体/溶酶体区室。此外，我们直接比较了基因治疗与许可的麦格司他。即使在低剂量下，基因治疗也具有麦格司他的所有获益，但无不良反应。基于这些发现和该领域的持续优势，我们提出脑室内基因治疗作为NP-C临床应用的潜在治疗选择。
Niemann–Pick type C disease (NP-C) is a fatal neurodegenerative lysosomal storage disorder. It is caused in 95% of cases by a mutation in the NPC1 gene that encodes NPC1, an integral transmembrane protein localized to the limiting membrane of the lysosome. There is no cure for NP-C but there is a disease-modifying drug (miglustat) that slows disease progression but with associated side effects. Here, we demonstrate in a well-characterized mouse model of NP-C that a single administration of AAV-mediated gene therapy to the brain can significantly extend lifespan, improve quality of life, prevent or ameliorate neurodegeneration, reduce biochemical pathology and normalize or improve various indices of motor function. Over-expression of human NPC1 does not cause adverse effects in the brain and correctly localizes to late endosomal/lysosomal compartments. Furthermore, we directly compare gene therapy to licensed miglustat. Even at a low dose, gene therapy has all the benefits of miglustat but without adverse effects. On the basis of these findings and on-going ascendency of the field, we propose intracerebroventricular gene therapy as a potential therapeutic option for clinical use in NP-C.
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影响因子：
4.2
作者：
Pontikis, Charles C.;Davidson, Cristin D.;Walkley, Steven U.;Platt, Frances M.;Begley, David J.
通讯作者：
Begley, David J.
DOI：
10.1016/s0140-6736(17)31465-4
发表时间：
2017-10-14
期刊：
Lancet (London, England)
影响因子：
--
作者：
Ory DS;Ottinger EA;Farhat NY;King KA;Jiang X;Weissfeld L;Berry-Kravis E;Davidson CD;Bianconi S;Keener LA;Rao R;Soldatos A;Sidhu R;Walters KA;Xu X;Thurm A;Solomon B;Pavan WJ;Machielse BN;Kao M;Silber SA;McKew JC;Brewer CC;Vite CH;Walkley SU;Austin CP;Porter FD
通讯作者：
Porter FD
影响因子：
3.9
作者：
Bauer, P;Knoblich, R;Rolfs, A
通讯作者：
Rolfs, A
影响因子：
2
作者：
Gundersen, HJG;Jensen, EBV;Nielsen, J
通讯作者：
Nielsen, J
影响因子：
--
作者：
Kohlbrenner, Erik;Henckaerts, Els;Weber, Thomas
通讯作者：
Weber, Thomas