Sight of Action: the Rationale and Evolution of Gene Therapy Approaches to the Treatment of Retinal Diseases
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REGENERATIVE MEDICINE IN OPHTHALMOLOGY (D MYUNG, SECTION EDITOR)
Sight of Action: the Rationale and Evolution of Gene Therapy Approaches to the Treatment of Retinal Diseases Kathryn W. Woodburn 1 & Sharmila Vijay 2 & Mark S. Blumenkranz 1
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Purpose of Review This review will summarize ocular gene therapy clinical trials and associated technology that have been initiated within the last 5 years. Recent Findings Initial programs utilized subretinal administration of an AAV2 serotype coupled with a ubiquitous promoter and a transgene targeting both monogenic inherited retinal diseases and acquired chronic ocular diseases polygenic in origin such as age-related macular degeneration and diabetic retinopathy. Cellular specific viral vectors with optimization of the expression cassette to include cellular-specific promoters and cassette regulatory elements to improve yields and durability with less invasive administration routes are now being clinically evaluated. Summary These developments open the door for potential treatment of rare monogenic diseases and more common polygenic heterogeneous ocular disorders, where in situ expression of therapeutic proteins may reduce the need for repeated intravitreal injections. While initial reports are promising, only time will confirm whether sustained durable “curative” expression is a reality. Keywords Adeno-associated virus . Clinical trials . Gene therapy . Retinal disorders . Vector design . Serotype
Introduction The approval of Luxturna® (voretigene neparvovec-rzyl), December 18, 2017, as a gene therapy for Leber congenital amaurosis (LCA), due to a mutation in the RPE65 gene, by the United States Food and Drug Administration (FDA), was a seminal milestone in the treatment of previously irreversible blindness and validates the potential of ocular gene therapy. Recent innovations in gene therapy, such as alternative administration routes, vector element and promoter optimization,
This article is part of the Topical Collection on Regenerative Medicine in Ophthalmology * Mark S. Blumenkranz [email protected]
and capsid selection, may transform patient care and obviate the need for chronic care through single dose treatments. Gene therapy introduces genetic material into cells via viral or non-viral vectors to repair, replace, augment, or delete a genetic sequence, with subsequent expression resulting in therapeutic benefit. Gene augmentation introduces a copy of a missing or dysfunctional gene, termed transgene, into cells by integrating it into the host’s genome or having it remain separate (episomal) and is typically delivered by way of a viral carrier (Fig. 1). Gene editing uses CRISPR/Cas9–based RNA-guided targeting to remove defective mutations. Additionally, gene therapy via optogenetics is also being pursued with the introduction of light-sensitive proteins to convert secondary or tertiary neurons into “photoreceptors.” This review will focus on ocular clinical trials that are li
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