Gene therapy and genome surgery in the retina
James E. DiCarlo, Vinit B. Mahajan, Stephen H. Tsang
James E. DiCarlo, Vinit B. Mahajan, Stephen H. Tsang
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Review Genetics Ophthalmology

Gene therapy and genome surgery in the retina

Abstract

Precision medicine seeks to treat disease with molecular specificity. Advances in genome sequence analysis, gene delivery, and genome surgery have allowed clinician-scientists to treat genetic conditions at the level of their pathology. As a result, progress in treating retinal disease using genetic tools has advanced tremendously over the past several decades. Breakthroughs in gene delivery vectors, both viral and nonviral, have allowed the delivery of genetic payloads in preclinical models of retinal disorders and have paved the way for numerous successful clinical trials. Moreover, the adaptation of CRISPR-Cas systems for genome engineering have enabled the correction of both recessive and dominant pathogenic alleles, expanding the disease-modifying power of gene therapies. Here, we highlight the translational progress of gene therapy and genome editing of several retinal disorders, including RPE65-, CEP290-, and GUY2D-associated Leber congenital amaurosis, as well as choroideremia, achromatopsia, Mer tyrosine kinase– (MERTK–) and RPGR X-linked retinitis pigmentosa, Usher syndrome, neovascular age-related macular degeneration, X-linked retinoschisis, Stargardt disease, and Leber hereditary optic neuropathy.

Authors

James E. DiCarlo, Vinit B. Mahajan, Stephen H. Tsang

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Figure 2

RPE65-associated LCA2.

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RPE65-associated LCA2. Mutations in the gene encoding RPE65 isomerase re...
Mutations in the gene encoding RPE65 isomerase results in autosomal recessive LCA. This gene is largely active in the RPE and is responsible for the isomerization of all-trans-retinyl esters to 11-cis-retinyl esters, the rate-limiting step in the retinal visual cycle, and mutations in RPE65 result in RPE degeneration and photoreceptor death. Salt and pepper retinopathy and arteriole attenuation seen in a 28-year-old man with compound heterozygote mutations (c.11 + 5G > A) and (c.715T > G) in RPE65. Fundoscopy revealed optic disc pallor and a relatively spared macula. Note the absence of bone spicule–like pigmentation in the periphery.