Vector platforms for gene therapy of inherited retinopathies.
Vector platforms for gene therapy of inherited retinopathies.
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DOI：
10.1016/j.preteyeres.2014.08.001
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发表时间：
2014-11
影响因子：
17.8
通讯作者：
Auricchio, Alberto
中科院分区：
文献类型：
--
作者：
Trapani, Ivana;Puppo, Agostina;Auricchio, Alberto
遗传性视网膜病（IR）是常见的无法治愈的致盲疾病。它们中的大多数是作为单基因疾病遗传的，这是由于在视网膜光感受器（PR）和视网膜色素上皮（RPE）中表达的基因突变。视网膜与基因转移的兼容性使得通过病毒和非病毒载体在小型和大型动物模型中转导不同的视网膜细胞层成为可能。新病毒的持续鉴定以及基于合理设计或定向进化对现有病毒的修饰已经产生了具有改善的转导特性的载体变体。已经在使用病毒和非病毒载体的IR动物模型中获得了数十个有希望的概念证明，其中一些已经被用于临床试验。迄今为止，基于腺相关病毒（AAV）的重组载体代表了视网膜基因治疗的最有前途的工具，因为它们能够有效地将治疗基因递送到PR和RPE两者，并且它们在人类中具有优异的安全性和有效性。然而，AAV有限的载物能力阻碍了病毒载体应用于需要转移编码序列大于5kb的基因的治疗。具有更大容量的载体，即纳米颗粒、腺病毒和慢病毒载体正在被开发用于在动物模型中以及最近在人类中向视网膜的基因转移。本文综述了视网膜基因治疗对抗遗传性失明的可用平台，突出了它们的主要优势，并探讨了克服它们的一些局限性的努力。
Inherited retinopathies (IR) are common untreatable blinding conditions. Most of them are inherited as monogenic disorders, due to mutations in genes expressed in retinal photoreceptors (PR) and in retinal pigment epithelium (RPE). The retina’s compatibility with gene transfer has made transduction of different retinal cell layers in small and large animal models via viral and non-viral vectors possible. The ongoing identification of novel viruses as well as modifications of existing ones based either on rational design or directed evolution have generated vector variants with improved transduction properties. Dozens of promising proofs of concept have been obtained in IR animal models with both viral and non-viral vectors, and some of them have been relayed to clinical trials. To date, recombinant vectors based on the adeno-associated virus (AAV) represent the most promising tool for retinal gene therapy, given their ability to efficiently deliver therapeutic genes to both PR and RPE and their excellent safety and efficacy profiles in humans. However, AAVs’ limited cargo capacity has prevented application of the viral vector to treatments requiring transfer of genes with a coding sequence larger than 5 kb. Vectors with larger capacity, i.e. nanoparticles, adenoviral and lentiviral vectors are being exploited for gene transfer to the retina in animal models and, more recently, in humans. This review focuses on the available platforms for retinal gene therapy to fight inherited blindness, highlights their main strengths and examines the efforts to overcome some of their limitations.
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影响因子：
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作者：
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