Gene-editing with CRISPR successfully reverses retinitis pigmentosa in two murine models

In two mouse models of retinitis pigmentosa (RP)—rare, inherited diseases that cause retinal degeneration and eventual blindness—researchers at the University of San Diego School of Medicine, Shiley Eye Institute at UC San Diego Health, and colleagues in China successfully reprogrammed mutated rod photoreceptors to become functioning cone photoreceptors using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9, a gene-editing tool. They published their results in the advance online April issue of the journal Cell Research.

About 100,000 Americans and 1 in 4,000 people worldwide are affected by RP, for which there is currently no treatment. RP causes loss of peripheral and night vision, reduced visual acuity, and color perception.

These researchers used CRISPR/Cas9 to deactivate Nrl, a master switch gene, and Nr2e3, a downstream transcription factor, which in turn reprogrammed rod cells to become cone cells, and thus conferred a specific advantage.

“Cone cells are less vulnerable to the genetic mutations that cause RP. Our strategy was to use gene therapy to make the underlying mutations irrelevant, resulting in the preservation of tissue and vision,” said senior author and lead researcher Kang Zhang, MD, PhD, chief of ophthalmic genetics, founding director of the Institute for Genomic Medicine, and co-director of biomaterials and tissue engineering at the Institute of Engineering in Medicine, both at UC San Diego School of Medicine.

They tested this in two different mouse models of RP, and found a profusion of reprogrammed cone cells, and preserved retinal cellular architecture. Upon testing the rod and cone receptors in live mice via electroretinography, Dr. Zhang and colleagues also observed that visual function had improved.

“Human clinical trials could be planned soon after completion of the preclinical study. There is no treatment for RP so the need is great and pressing. In addition, our approach of reprogramming mutation-sensitive cells to mutation-resistant cells may have broader application to other human diseases, including cancer,” concluded Dr. Zhang.

This study was funded, in part, by the Richard Annesser Fund, the Dick and Carol Hertzberg Fund, the National Basic Research Program of China, Hi-Tech Research and Development Program of China, Hong Kong General Research Fund, and Early Career Scheme and Shenzhen Science and Technology Fund.