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
Published June 1, 2018
Citation Information: J Clin Invest. 2018;128(6):2177-2188. https://doi.org/10.1172/JCI120429.
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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 1

Examples of gene supplementation versus genome surgery in the retina.

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Examples of gene supplementation versus genome surgery in the retina. Co...
Conventional gene supplementation works well for mutations that are inherited in an autosomal recessive manner; however, dominant-negative conditions require elimination or repression of the mutant allele to correct the disease phenotype and are unlikely to be ameliorated by supplementation. (A) Schematic of gene supplementation as well as vectors that have been used to treat retinal diseases in current or planned clinical trials. (B) Schematic of genome surgery. For dominant-negative conditions, scientists have focused on genetic tools to modulate gene expression, such as RNAi, or tools that modify the patient’s genome to mutate the pathogenic allele, such as site-specific nucleases like CRISPR-Cas. (C) Description of different approaches used to affect gene expression.