Focused Update on AAV-Based Gene Therapy Clinical Trials for Inherited Retinal Degeneration
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Focused Update on AAV‑Based Gene Therapy Clinical Trials for Inherited Retinal Degeneration Paula I. Fuller‑Carter1 · Hamed Basiri1 · Alan R. Harvey2,3 · Livia S. Carvalho1
© Springer Nature Switzerland AG 2020
Abstract Inherited retinal diseases (IRDs) comprise a clinically and genetically heterogeneous group of disorders that can ultimately result in photoreceptor dysfunction/death and vision loss. With over 270 genes known to be involved in IRDs, translation of treatment strategies into clinical applications has been historically difficult. However, in recent years there have been significant advances in basic research findings as well as translational studies, culminating in an increasing number of clinical trials with the ultimate goal of reducing vision loss and associated morbidities. The recent approval of L uxturna® (voretigene neparvovec-rzyl) for Leber congenital amaurosis type 2 (LCA2) prompts a review of the current clinical trials for IRDs, with a particular focus on the importance of adeno-associated virus (AAV)-based gene therapies. The present article reviews the current state of AAV use in gene therapy clinical trials for IRDs, with a brief background on AAV and the reasons behind its dominance in ocular gene therapy. It will also discuss pre-clinical progress in AAV-based therapies aimed at treating other ocular conditions that can have hereditable links, and what alternative technologies are progressing in the same therapeutic space.
1 Adeno‑Associated Virus (AAV)‑Based Retinal Gene Therapy: Long Time Coming The eye has several advantages as a target for the use of molecular therapies such as viral vector-based gene therapy: (1) the retina is relatively immune-privileged (due to tight junctions of the blood–retina barrier [1]), thus minimising any systemic inflammatory response from the introduction of a foreign antigen [2]; (2) small amounts of treatment vector
Paula I. Fuller-Carter and Hamed Basiri are equally contributing first authors. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40259-020-00453-8) contains supplementary material, which is available to authorized users. * Livia S. Carvalho [email protected] 1
Centre for Ophthalmology and Visual Sciences (Incorporating Lions Eye Institute), The University of Western Australia, Nedlands, WA, Australia
2
School of Human Sciences, The University of Western Australia, Crawley, WA, Australia
3
Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia
are needed to achieve ‘therapeutic response’ and vectors are essentially quarantined from systemic circulation [3]; (3) the retina is readily accessible by surgery and vectors can be delivered close to target cells [4] and (4) there is the ability to non-invasively monitor disease progression in terms of both retinal structure and physiology [5]. Furthermore, all retinal neurons are post-mitotic [6], reducing the likelihood of dilution or progressive loss of the expression of
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