CRISPR-Mediated Ophthalmic Genome Surgery

Abstract

Purpose of review Clustered regularly interspaced short palindromic repeats (CRISPR) is a genome engineering system with great potential for clinical applications due to its versatility and programmability. This review highlights the development and use of CRISPR-mediated ophthalmic genome surgery in recent years. Recent findings Diverse CRISPR techniques are in development to target a wide array of ophthalmic conditions, including inherited and acquired conditions. Preclinical disease modeling and recent successes in gene editing suggest potential efficacy of CRISPR as a therapeutic for inherited conditions. In particular, the treatment of Leber congenital amaurosis with CRISPR-mediated genome surgery is expected to reach clinical trials in the near future. Summary Treatment options for inherited retinal dystrophies are currently limited. CRISPR-mediated genome surgery methods may be able to address this unmet need in the future.

Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects

“…162 Another animal model of RP, the transgenic S334ter-3 rat, possesses the mutation RhoS334, which shows similar phenotypes to human class I RHO mistracking mutations, leading to a continual degeneration of photoreceptors and vision decline. 163,164 The protospacer adjacent motif (PAM) sequence in RhoS334 (5′-TGG-3′) diverges from the PAM in RhoWT (5′-TGC-3′) by only one nucleotide. Benjamin et al reported that an allele-specific disruption of RhoS334 via a single subretinal injection of CRISPR/Cas9 and gRNA by electroporation prevented retinal degeneration and increased visual acuity.…”

“…172 Additionally, using a smaller S. aureus CRISPR/Cas9 system enables a single AAV vector to deliver the Cas9 gene and two gRNAs, which performs a dual-cut excision of the CEP290 mutation-containing region in primary fibroblasts from LCA10 patients. 164 Recently, Maeder et al developed a candidate genome editing therapy named EDIT-101 to restore vision loss in LCA10. 173 They delivered the Staphylococcus aureus Cas9 and CEP290 gRNA to the photoreceptor via an AAV5 vector.…”

“…Although clinical trials on gene editing for ophthalmic diseases have just begun, the unique qualities of eyes, such as easy accessibility and relative immune-privileged status, make CRISPR-Cas a promising and available strategy for ophthalmic disease treatment in the near future. 164,276 CHALLENGES IN THERAPEUTIC TARGETING In addition to the many benefits of genome editing, there are some technical challenges in translating these treatments to clinical disease therapy, primarily in terms of accuracy, efficacy and delivery hurdles. To cope with these challenges, scientists will need profound knowledge about the molecular nature of cancers, especially heterogeneous solid tumors, as well as carefully designed genome editing platforms in preclinical studies.…”

Translation of CRISPR Genome Surgery to the Bedside for Retinal Diseases

“…While the CRISPR system has great potential for expanding the range of possible treatments for inherited diseases, it cannot be considered a perfect system. Possibly of greatest concern is off-targeting, or unexpected mutations that arise in the process of CRISPR activity (Jamal et al, 2016 ; Cho et al, 2017 ; Schaefer et al, 2017 ). Control of or better understanding of off-targeting should be addressed before CRISPR can be implemented in a broader range of clinical applications.…”

Attenuation of Inherited and Acquired Retinal Degeneration Progression with Gene-based Techniques

“…Gene therapy provides a means of restoring a healthy genome in these diseased cells and, consequently, a hope of returning to their normal function [2]. The appropriate type of gene therapy depends on the inheritance pattern of the disease: whereas recessive conditions and those caused by haploinsufficiency can respond to the addition of wild-type alleles supplied by viral vectors [1,2], dominant or dominant-negative conditions require gene suppression or repair [1,5].…”