Toward the Treatment of Inherited Diseases of the Retina Using CRISPR-Based Gene Editing.

Jennifer Hernández-Juárez,Shyamanga Borooah,Genaro Rodríguez-Uribe

doi:10.3389/fmed.2021.698521

Abstract

Inherited retinal dystrophies [IRDs] are a common cause of severe vision loss resulting from pathogenic genetic variants. The eye is an attractive target organ for testing clinical translational approaches in inherited diseases. This has been demonstrated by the approval of the first gene supplementation therapy to treat an autosomal recessive IRD, RPE65-linked Leber congenital amaurosis (type 2), 4 years ago. However, not all diseases are amenable for treatment using gene supplementation therapy, highlighting the need for alternative strategies to overcome the limitations of this supplementation therapeutic modality. Gene editing has become of increasing interest with the discovery of the CRISPR-Cas9 platform. CRISPR-Cas9 offers several advantages over previous gene editing technologies as it facilitates targeted gene editing in an efficient, specific, and modifiable manner. Progress with CRISPR-Cas9 research now means that gene editing is a feasible strategy for the treatment of IRDs. This review will focus on the background of CRISPR-Cas9 and will stress the differences between gene editing using CRISPR-Cas9 and traditional gene supplementation therapy. Additionally, we will review research that has led to the first CRISPR-Cas9 trial for the treatment of CEP290-linked Leber congenital amaurosis (type 10), as well as outline future directions for CRISPR-Cas9 technology in the treatment of IRDs.

Highlights

Inherited retinal dystrophies [IRDs] represent a diverse group of rare diseases in which genetic mutations are the principle cause of visual dysfunction [1]
IRDs result from pathogenic variants in more than 250 genes expressed mainly in photoreceptors, and to a lesser extent in retinal pigment epithelial cells [RPE] [1, 5,6,7]
Genomic editing approaches have been greatly facilitated by the discovery and development of the Clustered Regularly Interspaced Short Palindromic Repeats [CRISPR] and the CRISPR-associated genes [Cas]. These achievements have been underscored by CRISPR Gene Editing in IRDs the award of the 2020 Nobel Prize in Chemistry to Emmanuelle Charpentier and Jennifer Doudna for the discovery of the CRISPR-Cas9 gene editing system

Summary

Introduction

Inherited retinal dystrophies [IRDs] represent a diverse group of rare diseases in which genetic mutations are the principle cause of visual dysfunction [1]. AAV is the most common delivery vector chosen for ocular diseases due to its ability to efficiently transduce various retinal cell types in vivo, with relatively limited immune reaction and without the need to integrate into host DNA to express genes

Results

Conclusion