Novel Therapeutic Approaches for the Treatment of Retinal Degenerative Diseases: Focus on CRISPR/Cas-Based Gene Editing.

Carmen Gallego,Manuel A F V Gonçalves,Jan Wijnholds

doi:10.3389/fnins.2020.00838

Abstract

Inherited retinal diseases encompass a highly heterogenous group of disorders caused by a wide range of genetic variants and with diverse clinical symptoms that converge in the common trait of retinal degeneration. Indeed, mutations in over 270 genes have been associated with some form of retinal degenerative phenotype. Given the immune privileged status of the eye, cell replacement and gene augmentation therapies have been envisioned. While some of these approaches, such as delivery of genes through recombinant adeno-associated viral vectors, have been successfully tested in clinical trials, not all patients will benefit from current advancements due to their underlying genotype or phenotypic traits. Gene editing arises as an alternative therapeutic strategy seeking to correct mutations at the endogenous locus and rescue normal gene expression. Hence, gene editing technologies can in principle be tailored for treating retinal degeneration. Here we provide an overview of the different gene editing strategies that are being developed to overcome the challenges imposed by the post-mitotic nature of retinal cell types. We further discuss their advantages and drawbacks as well as the hurdles for their implementation in treating retinal diseases, which include the broad range of mutations and, in some instances, the size of the affected genes. Although therapeutic gene editing is at an early stage of development, it has the potential of enriching the portfolio of personalized molecular medicines directed at treating genetic diseases.

Highlights

Inherited retinal diseases (IRDs) constitute a heterogenous group of neurodegenerative conditions affecting the retina, a layered structure of neural origin at the back of the eye
A first proof-of-concept work, in which expression of the yellow fluorescent protein reporter was reduced in the retina of transgenic mice (Hung et al, 2016), paved the way for other researchers starting to investigate the potential of engineered clustered regularly interspaced short palindromic repeats (CRISPR)/Cas systems for disrupting or correcting gene variants associated with IRDs
The use of associated viral (AAV) vectors is limited whenever gene editing interventions depend on the knocking-in of large genetic payloads and/or large RNA-guided nucleases (RGNs) components, such as, S. pyogenes Cas9 and multiplexing guide RNA (gRNA) pairs designed for targeted chromosomal deletions (Cong et al, 2013)

Summary

Introduction

Inherited retinal diseases (IRDs) constitute a heterogenous group of neurodegenerative conditions affecting the retina, a layered structure of neural origin at the back of the eye. A first proof-of-concept work, in which expression of the yellow fluorescent protein reporter was reduced in the retina of transgenic mice (Hung et al, 2016), paved the way for other researchers starting to investigate the potential of engineered CRISPR/Cas systems for disrupting or correcting gene variants associated with IRDs. For instance, Bakondi et al (2016) achieved the disruption of a Rho allele harboring a dominant mutation in a rat model of retinitis pigmentosa.

Results

Conclusion