A group of scientists of the University of California – San Diego (UCSD), in collaboration with colleagues from China, reversed cellular degeneration and restored visual function in two different mouse models of retinitis pigmantosa. To do that, they used gene-editing tool CRISPR/Cas9 to reprogram mutated rod photoreceptors to become functioning cone photoreceptors.

A group of inherited conditions of the retina that lead to a gradual progressive reduction in vision, known as retinitis pigmantosa (RP), are caused by mutations in more than 60 genes. These mutations affect the cells in the retina that sense and convert light images into electrical signals to send the information to the brain, called photoreceptors. So far, there is no treatment for RP, which affects 1 in 4,000 persons worldwide.

For the study, published in Cell research, the researchers used CRISPR/Cas9 to deactivate a master switch gene called Nrl and a downstream transcription factor called Nr2e3. By deactivating either Nrl or Nr2e3 they were able to reprogram rod cells to become cone cells.

Cone cells are less vulnerable to the genetic mutations that cause RP,” said senior author Kang Zhang, researcher at UCSD School of Medicine.

Our strategy was to use gene therapy to make the underlying mutations irrelevant, resulting in the preservation of tissue and vision,” added Zhang.

The results showed abundant reprogramed cone cells and preserved cellular architecture in the retinas of both mouse models of RP. Additionally, electroretinography testing of rod and cone receptors in live mice show improved function.

To perform the gene-editing, they used adeno-associated virus (AAV), which they said should help advance their work to human clinical trials quicker. “AAV is a common cold virus and has been used in many successful gene therapy treatments with a relatively good safely profile,” said Zhang. “Human clinical trials could be planned soon after completion of 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.”


Source: UC San Diego Health – Newsroom