• CRISPR-Based Genome Surgery for Retinitis Pigmentosa

    By Lynda Seminara
    Selected By: Stephen D. McLeod, MD

    Journal Highlights

    Ophthalmology, September 2018

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    Tsai et al. set out to develop a universal gene therapy tool, based on CRISPR (clustered regularly interspaced short palindromic repeats) technology, to treat retinitis pigmentosa arising from mutations in rhodopsin. Their novel ablate-and-replace strategy appeared to ameliorate disease progression in a preclinical model, suggesting that it may have clinical potential as well.

    This experimental study included 2 types of mutation knock-in mouse models: RhoP23H and RhoD190N. The ex­periment’s premise was that autosomal-dominant Rho mutations cannot be remedied solely by conventional gene replacement or augmentation; a cure is possible only if the mutant allele is corrected or destroyed while the wild-type allele is kept intact.

    Thus, for this study, the authors applied 2 sets of adeno-associated viruses (AAVs) simultaneously: One ablated the endogenous Rho gene by an improved CRISPR-based strategy while the other delivered exogenous complementary DNA expressing the wild-type Rho protein. For comparison purposes, a proportion of eyes received gene replacement only. Electroretino­graphic and histologic analyses were performed, and an unpaired 2-sided t test was used to compare mRNA levels and electroretinographic responses.

    Three months after administration of gene therapy, the outer nuclear layer (ONL) of eyes that received ablation plus replacement was 17% to 36% thicker than the ONL of eyes that had replacement only.

    Electroretinographic findings demonstrated that the combination of gene ablation and replacement resulted in superior preser­vation of a- and b-waves in both murine models.

    To the authors’ knowl­edge, their findings represent the first electrophysiologic evidence of the efficacy of CRISPR-based therapy for postmitotic neurons. The ablate-and-replace strategy can be applied in a muta­tion-independent manner and there­fore may be a fiscally practical means to overcome allelic heterogeneity in many autosomal-dominant disorders.

    Minor changes could be made to the dual AAV toolset to create a human version suitable for clinical trials. Ulti­mately, this strategy may permit univer­sal treatment of patients, regardless of allelic status.

    The original article can be found here.