A 2020 vision of ocular gene therapy.

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Date: May 2021
From: Gene Therapy(Vol. 28, Issue 5)
Publisher: Nature Publishing Group
Document Type: Report
Length: 1,769 words
Lexile Measure: 1570L

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Author(s): Robert E. MacLaren 1

Author Affiliations:

(1) Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, University of Oxford and Oxford University Hospitals NHS Foundation Trust NIHR Biomedical Research Centre, West Wing John Radcliffe Hospital, Oxford, UK

This special issue highlights several ocular gene therapy papers that summarise progress made in the field in recent years. It is not surprising that the first gene replacement therapy to be approved and widely adopted (Luxturna® ) is a treatment for an inherited retinal degeneration. The eye is a favourable target organ for gene therapy, due to the relatively small size and compartmentalised structure. Single gene disorders--broadly classified as inherited retinal degenerations--are the most common cause of untreatable sight loss in young people and age-related macular degeneration (AMD), which involves many genes acting on or around the alternate complement pathway is the most common cause of untreatable blindness overall. The identification of genetic factors in the majority of eye diseases provides an array of potential targets for gene replacement, knockdown or editing therapies.

The papers published in Gene Therapy investigate factors relevant to improving the efficacy of gene therapy using adeno associated viral (AAV) vectors. Rodriguez-Estevez et al. assess different AAV serotypes in their ability to target the trabecular meshwork--a key target for controlling intraocular pressure which could potentially lead to a gene therapy treatment for glaucoma [1]. They found that AAV2 was most efficient but use of a self-complimentary (sc) transgene was essential which would limit the size of transgene. Borras et al. target the trabecular meshwork with an scAAV2 vector encoding matrix metalloproteinase 1, an enzyme which is known to reduce resistance to fluid outflow from the eye [2]. In a sheep model of steroid induced glaucoma, they show reductions in intraocular pressure which would be clinically significant if applied to humans. Instead of injecting AAV into the anterior chamber, an alternate route for glaucoma treatments might be via the subconjunctival space and Song et al. found the scAAV6 and 8 serotypes to be most efficacious in this regard in the mouse model [3].

In addition to pressure control, an alternate gene therapy treatment for glaucoma might be to target retinal ganglion cells to make them more resistant to injury. Nascimento-Dos-Santos et al. assess pigment epithelium-derived factor delivered by intravitreal AAV and found this to enhance ganglion cell survival after crush injury--even more so when combined with a human mesenchymal stem cell sheet [4]. Cao et al. again assess different AAV serotypes in transducing ganglion cells in the mouse eye and found AAV2 to be optimal when delivered by intravitreal injection [5]. It is, however, difficult to extrapolate to humans because the small vitreous...

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