Adeno-associated Virus (AAV) Dual Vector Strategies for Gene Therapy Encoding Large Transgenes
Adeno-associated Virus (AAV) Dual Vector Strategies for Gene Therapy Encoding Large Transgenes
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发表时间：
2017-12
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通讯作者：
M. McClements;R. MacLaren
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作者：
M. McClements;R. MacLaren
在过去的十年里，腺相关病毒(AAV)载体用于遗传性疾病的基因治疗的速度加快了，各种组织类型的多项临床试验正在进行中，每年都会有新的临床试验开始。除了显示有效性的证据外，这些载体在临床试验中表现出低免疫原性，这清楚地表明它们是任何潜在基因治疗治疗的当前标准载体。然而，AAV载体在包装能力上确实存在限制，能够携带不超过5kb的DNA，并且在治疗性转基因场景中，除了目的基因编码序列(CDS)之外，这一长度的DNA将需要包括遗传控制元件。鉴于许多疾病是由CDS超过3.5kb的基因突变引起的，这使得将更大的基因打包到单个AAV衣壳中是不可能的。由于这个问题，然而，随着使用AAV载体的愿望，研究小组已经调整了标准的AAV基因治疗方法，以便能够使用双AAV载体系统将如此大的基因输送到靶细胞。在这里，我们回顾了目前使用的AAV双载体策略，并强调了每种方法的优点和缺点以及这些方法成功的可能性。
The use of adeno-associated viral (AAV) vectors for gene therapy treatments of inherited disorders has accelerated over the past decade with multiple clinical trials ongoing in varying tissue types and new ones initiating every year. These vectors are exhibiting low-immunogenicity across the clinical trials in addition to showing evidence of efficacy, making it clear they are the current standard vector for any potential gene therapy treatment. However, AAV vectors do have a limitation in their packaging capacity, being capable of holding no more than ~5kb of DNA and in a therapeutic transgene scenario, this length of DNA would need to include genetic control elements in addition to the gene coding sequence (CDS) of interest. Given that numerous diseases are caused by mutations in genes with a CDS exceeding 3.5kb, this makes packaging into a single AAV capsid not possible for larger genes. Due to this problem, yet with the desire to use AAV vectors, research groups have adapted the standard AAV gene therapy approach to enable delivery of such large genes to target cells using dual AAV vector systems. Here we review the AAV dual vector strategies currently employed and highlight the virtues and drawbacks of each method plus the likelihood of success with such approaches.