Gene Therapy to Reverse Retinitis Pigmentosa, Restore Vision

Highlights

• Retinitis pigmentosa causes genetic mutations in the retinal rod photoreceptor cells that leads to its dysfunction and degeneration over time, causing blindness eventually.
• The CRISPR/Cas9 gene-editing tool was used to deactivate a master switch gene called Nrl and a transcription factor called Nr2e3.
• Deactivating either Nrl or Nr2e3 helped to reprogram the mutated rod cells to functioning cone cells, which helped reverse degeneration and restore vision.

CRISPR/Cas9, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, is the gene-editing tool used to reprogram the mutated rod photoreceptors to functioning cone photoreceptors in tow mouse models with retinitis pigmentosa. This has helped to reverse cellular degeneration and restore vision. The study was conducted by a team of researchers from the University of California San Diego School of Medicine and Shiley Eye Institute at UC San Diego Health, with colleagues in China.

Retinitis pigmentosa (RP) is a group of inherited genetic vision disorders caused by numerous mutations in more than 60 genes. It affects around 100,000 Americans and 1 in 4,000 persons worldwide.

The mutations affect the photoreceptors in the eyes. Photoreceptors are specialized cells in the retina that sense and convert light images into electrical signals sent to the brain.

There are two types:

• rod cells for night vision and peripheral vision
• cone cells for central vision (visual acuity) and distinguishing colors

The human retina typically contains 120 million rod cells and 6 million cone cells.

Using CRISPR/Cas9

RP is characterized by rod-specific genetic mutations that causes rod photoreceptor cells to dysfunction and degenerate over time. Over time, cone cells are also affected and they begin to fail and die.

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Symptoms progress from loss of peripheral and night vision,to diminished visual acuity and color perception. As there is no treatment for RP, it may lead to legal blindness eventually.

The research team was led by senior author 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.

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The gene-editing tool, CRISPR/Cas9 was used to deactivate a master switch gene called Nrl and a downstream transcription factor called Nr2e3. This deactivation helped to reprogram rod cells to functioning code cells.

CRISPR, allows researchers to target specific stretches of genetic code and edit DNA at precise locations, modifying select gene functions.

"Cone cells are less vulnerable to the genetic mutations that cause RP," said Zhang. "Our strategy was to use gene therapy to make the underlying mutations irrelevant, resulting in the preservation of tissue and vision."

This approach was tested in two different mouse models of RP. This resulted in an abundance of reprogrammed cone cells and preserved cellular architecture in the retinas. Electroretinography testing of rod and cone receptors in live mice show improved function.

"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." Zhang said.

The findings are published in the online issue of Cell Research.

Reference

1. Kang Zhang et al. Gene and mutation independent therapy via CRISPR-Cas9 mediated cellular reprogramming in rod photoreceptors. Cell Research; (2017) doi: 10.1038/cr.2017.57

Source-Medindia