A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency.
A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency.
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DOI：
10.1093/brain/awy126
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发表时间：
2018-07-01
期刊：
影响因子：
--
通讯作者：
Henckaerts E
中科院分区：
文献类型：
--
作者：
Tordo J;O'Leary C;Antunes ASLM;Palomar N;Aldrin-Kirk P;Basche M;Bennett A;D'Souza Z;Gleitz H;Godwin A;Holley RJ;Parker H;Liao AY;Rouse P;Youshani AS;Dridi L;Martins C;Levade T;Stacey KB;Davis DM;Dyer A;Clément N;Björklund T;Ali RR;Agbandje-McKenna M;Rahim AA;Pshezhetsky A;Waddington SN;Linden RM;Bigger BW;Henckaerts E
Tordo等人提出了一种新的AAV基因治疗载体AAV-TT，其超过了目前的基准嗜神经血清型AAV 9和AAVrh 10，并能够前所未有地纠正溶酶体跨膜酶缺乏症。因此，基于AAV-TT的基因疗法可能适用于治疗以全局神经病理学为特征的人类神经系统疾病。重组腺相关病毒（AAV）是常用的体内基因转移载体。然而，实现治疗效果所需的载体剂量很高，并且中枢神经系统中的一些靶组织仍然难以被抑制。使用AAV治疗神经系统疾病的基因治疗试验很少导致证明的临床疗效。重要的促成因素是低转导率和载体的低效分布。为了克服这些障碍，已经利用多种衣壳工程化方法来产生具有改善的转导特性的衣壳。在这里，我们描述了一种替代方法，衣壳工程，它借鉴了病毒的自然进化，目的是产生更适合感染人体组织的衣壳。我们产生了AAV衣壳以包括在天然AAV 2分离株中保守的氨基酸，并测试了其在小鼠和大鼠中的生物分布特性。有趣的是，这种新的变体AAV-TT在啮齿动物中表现出强烈的神经向性，并且与AAV 2相比，在整个中枢神经系统中显示出显著改善的分布。此外，与AAV 2相比，小鼠视网膜下注射显示出感光细胞的转导显著增强。重要的是，AAV-TT超过了基准嗜神经血清型AAV 9和AAVrh 10在小鼠中枢神经系统中的分布能力，并且是当以低剂量施用时能够校正粘多糖样变性IIIC（一种跨膜酶溶酶体贮积病）小鼠模型中的神经学表型的唯一病毒，所述粘多糖样变性IIIC需要递送至每个细胞以进行生化校正。这些数据代表了小鼠中溶酶体跨膜酶缺乏的前所未有的校正，并表明基于AAV-TT的基因疗法可能适用于治疗人类神经系统疾病，如粘多糖样变性IIIC，其特征在于全局神经病理学。
Tordo et al. present a novel AAV gene therapy vector, AAV-TT, which exceeds the current benchmark neurotropic serotypes AAV9 and AAVrh10 and enables unprecedented correction of a lysosomal transmembrane enzyme deficiency. AAV-TT based gene therapies may thus be suitable for the treatment of human neurological diseases characterised by global neuropathology. Recombinant adeno-associated viruses (AAVs) are popular in vivo gene transfer vehicles. However, vector doses needed to achieve therapeutic effect are high and some target tissues in the central nervous system remain difficult to transduce. Gene therapy trials using AAV for the treatment of neurological disorders have seldom led to demonstrated clinical efficacy. Important contributing factors are low transduction rates and inefficient distribution of the vector. To overcome these hurdles, a variety of capsid engineering methods have been utilized to generate capsids with improved transduction properties. Here we describe an alternative approach to capsid engineering, which draws on the natural evolution of the virus and aims to yield capsids that are better suited to infect human tissues. We generated an AAV capsid to include amino acids that are conserved among natural AAV2 isolates and tested its biodistribution properties in mice and rats. Intriguingly, this novel variant, AAV-TT, demonstrates strong neurotropism in rodents and displays significantly improved distribution throughout the central nervous system as compared to AAV2. Additionally, sub-retinal injections in mice revealed markedly enhanced transduction of photoreceptor cells when compared to AAV2. Importantly, AAV-TT exceeds the distribution abilities of benchmark neurotropic serotypes AAV9 and AAVrh10 in the central nervous system of mice, and is the only virus, when administered at low dose, that is able to correct the neurological phenotype in a mouse model of mucopolysaccharidosis IIIC, a transmembrane enzyme lysosomal storage disease, which requires delivery to every cell for biochemical correction. These data represent unprecedented correction of a lysosomal transmembrane enzyme deficiency in mice and suggest that AAV-TT-based gene therapies may be suitable for treatment of human neurological diseases such as mucopolysaccharidosis IIIC, which is characterized by global neuropathology.
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影响因子：
16.6
作者：
Adachi, Kei;Enoki, Tatsuji;Nakai, Hiroyuki
通讯作者：
Nakai, Hiroyuki
影响因子：
12.4
作者：
Cearley, CN;Wolfe, JH
通讯作者：
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用于针对小儿疾病的脊髓，大脑和周围组织的大物种中的全身基因递送。
DOI：
10.1038/mt.2011.157
发表时间：
2011-11
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.182412299
发表时间：
2002-09-03
影响因子：
11.1
作者：
Gao, GP;Alvira, MR;Wilson, JM
通讯作者：
Wilson, JM
影响因子：
4.8
作者：
Durand, Stephanie;Feldhammer, Matthew;Pshezhetsky, Alexey V.
通讯作者：
Pshezhetsky, Alexey V.