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Review
. 2023 May 30:16:111-130.
doi: 10.2147/TACG.S383453. eCollection 2023.

Adeno-Associated Virus (AAV) - Based Gene Therapies for Retinal Diseases: Where are We?

Divya Ail  1 , Hugo Malki  1 , Emilia A Zin  1 , Deniz Dalkara  1
Affiliations
Review

Adeno-Associated Virus (AAV) - Based Gene Therapies for Retinal Diseases: Where are We?

Divya Ail et al. Appl Clin Genet. .

Abstract

Owing to their small size and safety profiles, adeno-associated viruses (AAVs) have become the vector of choice for gene therapy applications in the retina. In addition to the naturally occurring AAVs, several engineered variants with enhanced properties are being developed for experimental and therapeutic applications. Nonetheless, there are still some challenges impeding successful application of AAVs for a broader range of retinal gene therapies. The small size of AAV particles ensures efficient tissue transduction but also limits the packaging capacity to a few kilobases. Further, AAV's ability to cross retinal barriers is still an obstacle to pan-retinal transduction of the outer retina with tolerable doses. Lastly, despite overall safety, there have been recent reports of immune responses to AAVs in the eye. Hence, evaluation and prediction of immune responses to AAVs has come to be considered an integral part of future clinical success. This review focuses on the use of AAV in clinical trials for retinal diseases, and discusses developments of variants and novel strategies to overcome immune responses to AAVs.

Keywords: AAV; adeno-associated virus; capsid variants; clinical trials; immune responses; retinal gene therapy.

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Conflict of interest statement

Dr Deniz Dalkara reports grants from Foundation Fighting Blindness, USA and European Research Council, during the conduct of the study; Dr Deniz Dalkara is a co-inventor on patent #9193956 (Adeno-associated virus virions with variant capsid and methods of use thereof), with royalties paid to Adverum Biotechnologies and on pending patent applications on noninvasive methods to target cone photoreceptors (EP17306429.6 and EP17306430.4) licensed to Gamut Tx now Sparting- Vision. Dr Deniz Dalkara also has personal financial interests in Tenpoint Tx. and SparingVision, outside the submitted work. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Distribution of (A) Naturally occurring AAVs (blue) and engineered AAVs (Orange) used in 53 clinical trials for retinal diseases; (B) distribution of AAV serotypes being used in clinical trials with the naturally occurring ones (AAV2, AAV4, AAV5 and AAV8) in shades of blue and the engineered variants (AAV2tYF, 4D-R100 and AAV2-7m8) in shades of Orange; (C) distribution of the therapeutic strategy used in clinical trials; (D) distribution of clinical trials using the subretinal delivery route for outer retina or other regions of the retina; (E) distribution of clinical trials by injection route including subretinal (Orange) and intravitreal (blue) injections; (F) distribution of trials using intravitreal delivery routes and targeting the inner, outer or other regions of the retina.
See this image and copyright information in PMC

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