Abstract
Gene therapy using adeno-associated viral (AAV) vectors currently represents the most promising approach for the treatment of many inherited retinal diseases (IRDs), given AAV’s ability to efficiently deliver therapeutic genes to both photoreceptors and retinal pigment epithelium, and their excellent safety and efficacy profiles in humans. However, one of the main obstacles to widespread AAV application is their limited packaging capacity, which precludes their use from the treatment of IRDs which are caused by mutations in genes whose coding sequence exceeds 5 kb. Therefore, in recent years, considerable effort has been made to identify strategies to increase the transfer capacity of AAV vectors. This review will discuss these new developed strategies, highlighting the advancements as well as the limitations that the field has still to overcome to finally expand the applicability of AAV vectors to IRDs due to mutations in large genes.
Highlights
The eye is an ideal target for gene therapy thanks to its small and enclosed structure, relative immune privilege and easy accessibility [1,2]
The Choice of the Best Platform for Large Gene Delivery to the Retina. The efficacy of both oversized and dual associated viral (AAV) vectors in the retina has been evaluated in a number of studies using different reporter and therapeutic genes, such as ABCA4 and MYO7A mutated in Stargardt disease (STGD1) [31] and Usher syndrome type 1B (USH1B) [32], respectively
The growing number of clinical trials that show good safety and efficacy of the subretinal delivery of AAV vectors are contributing to the establishment of AAV as vectors of choice for retinal gene transfer
Summary
The eye is an ideal target for gene therapy thanks to its small and enclosed structure, relative immune privilege and easy accessibility [1,2]. AAV are small (25 nm), nonenveloped, icosahedral viruses belonging to the Parvoviridae family [7] They package a linear single-stranded DNA genome of ~4.7 kb, flanked by two 145 bp long palindromic inverted terminal repeats (ITRs) [7]. Genes 2019, 10, 287 abilities have been identified through either rational design or directed evolution [4,8] This is one of the most attractive features of AAV vectors for retinal gene therapy, since alternative, both non-viral and viral, vectors tested far have shown more limited transduction abilities of adult photoreceptors [2,9]. The development of strategies to overcome AAV packaging limitation has become a key area of research within the gene therapy field
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