Ocular Disease and Gene Therapy

While gene therapy was advancing, it became evident that some tissues are more amenable than others to be targeted by gene delivery. Among them is the eye, which offers several advantages. Retinal gene therapy has advanced considerably in the past three decades. Initial efforts have been devoted to comprehensively explore and optimize the transduction abilities of gene delivery vectors, define the appropriate intraocular administration routes and obtain evidence of efficacy in animal models of inherited retinal diseases (IRDs).¹

Inherited Diseases of the Eye

Inherited retinal dystrophies (IRDs) include a number of rare disorders caused by genetic defects. These disorders lead to progressive retinal degeneration. IRDs are well suited for gene therapy as the underlying mutations are well understood. In addition delivery of the therapeutic via AAVs or LVs has proven to work. The development of ocular gene therapy over the prior two decades has mainly targeted hereditary retinal diseases because the genetics of many of these diseases have been well characterized and treatment options for these rare diseases are limited.

The most common IRDs are:³

Leber congenital amaurosis (LCA)

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Choroideremia

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Leber's hereditary optic neuropathy (LHON)

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Retinitis pigmentosa

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Achromatopsia

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X-linked retinoschisis (XLRS)

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Usher type 1B syndrome

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Stargardt's disease

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Non-hereditary Diseases of the Eye

The achievements in clinical trials investigating gene therapy for inherited ocular diseases have prompted the research community to use gene therapy to manage some of the most common nonhereditary ocular diseases, particularly diseases for which the current treatments are effective but are not sustainable in the long term, such as glaucoma, neovascular age-related macular degeneration (AMD), and diabetic retinopathy. Although these diseases involve multiple genes and are more complex and heterogeneous, progress has been made towards treatments in humans.

The most common non-hereditary diseases are:³

Open-angle glaucoma

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Age-related macular degeneration (AMD)

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Diabetic Macular Edema (DME)

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Glaucoma

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Diabetic Retinopathy

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References

• (1) Ivana Trapani, Alberto Auricchio, Has retinal gene therapy come of age? From bench to bedside and back to bench, Human Molecular Genetics, Volume 28, Issue R1, October 2019, Pages R108–R118, https://doi.org/10.1093/hmg/ddz130
• (2) Kathleen Gordon, Amy Del Medico, Ian Sander, Arvind Kumar, Bashar Hamad. Gene therapies in ophthalmic disease. Nature Reviews Drug Discovery 18, 415-416 (2019).
• (3) https://academic.oup.com/view-large/164513896
• (4) Jia Hui Lee, Jiang-Hui Wang, Jinying Chen, Fan Li, Thomas L. Edwards, Alex W. Hewitt, Guei-Sheung Liu, Gene therapy for visual loss: Opportunities and concerns, Progress in Retinal and Eye Research, Volume 68, 2019, Pages 31-53
• (5) Jiang-Hui Wang, Damien Ling, Leilei Tu, Peter van Wijngaarden, Gregory J. Dusting, Guei-Sheung Liu, Gene therapy for diabetic retinopathy: Are we ready to make the leap from bench to bedside?, Pharmacology & Therapeutics, Volume 173, 2017, Pages 1-18
• (6) Jiang-Hui Wang1 & Georgina Eloise Roberts 1 & Guei-Sheung Liu. Updates on Gene Therapy for Diabetic Retinopathy. Current Diabetes Reports (2020) 20: 22.