Using CRISPR to reverse retinitis pigmentosa and restore visual function

April 21, 2017, University of California - San Diego
A confocal micrograph of mouse retina depicting optic fiber layer. Credit: Image courtesy of National Center for Microscopy and Imaging Research, UC San Diego.

Using the gene-editing tool CRISPR/Cas9, researchers at University of California San Diego School of Medicine and Shiley Eye Institute at UC San Diego Health, with colleagues in China, have reprogrammed mutated rod photoreceptors to become functioning cone photoreceptors, reversing cellular degeneration and restoring visual function in two mouse models of retinitis pigmentosa.

The findings are published in the April 21 advance online issue of Cell Research.

Retinitis pigmentosa (RP) is a group of inherited vision disorders caused by numerous mutations in more than 60 genes. The mutations affect the eyes' photoreceptors, specialized in the retina that sense and convert light images into electrical signals sent to the brain. There are two types: rod cells that function for night vision and peripheral vision, and cone cells that provide central vision (visual acuity) and discern color. The human retina typically contains 120 million rod cells and 6 million cone cells.

In RP, which affects approximately 100,000 Americans and 1 in 4,000 persons worldwide, rod-specific genetic mutations cause rod photoreceptor cells to dysfunction and degenerate over time. Initial symptoms are loss of peripheral and night vision, followed by diminished visual acuity and color perception as cone cells also begin to fail and die. There is no treatment for RP. The eventual result may be legal blindness.

In their published research, a team 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, used CRISPR/Cas9 to deactivate a master switch gene called Nrl and a downstream transcription factor called Nr2e3.

CRISPR, which stands for Clustered Regularly Interspaced Short Palindromic Repeats, allows researchers to target specific stretches of genetic code and edit DNA at precise locations, modifying select gene functions. Deactivating either Nrl or Nr2e3 reprogrammed to become cone cells.

"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."

The scientists tested their approach in two different mouse models of RP. In both cases, they found an abundance of reprogrammed and preserved cellular architecture in the retinas. Electroretinography testing of rod and cone receptors in live mice show improved function.

Zhang said a recent independent study led by Zhijian Wu, PhD, at National Eye Institute, part of the National Institutes of Health, also reached similar conclusions.

The researchers used adeno-associated virus (AAV) to perform the gene therapy, 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 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."

Explore further: Scientists deploy CRISPR to preserve photoreceptors in mice

More information: Jie Zhu 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

Related Stories

Scientists deploy CRISPR to preserve photoreceptors in mice

March 14, 2017
Silencing a gene called Nrl in mice prevents the loss of cells from degenerative diseases of the retina, according to a new study. The findings could lead to novel therapies for preventing vision loss from human diseases ...

Altering eye cells may one day restore vision

January 25, 2013
(Medical Xpress)—Doctors may one day treat some forms of blindness by altering the genetic program of the light-sensing cells of the eye, according to scientists at Washington University School of Medicine in St. Louis.

Fish eyes to help understand human inherited blindness

April 5, 2017
Newborns babies can be at risk of congenital blindness, presenting sight defects due to lesions or to genetic mutations in their genome. Among the latter, Leber Congenital Amaurosis—or LCA—is one of the most widespread ...

Improving the view on the genetic causes of retinitis pigmentosa

January 17, 2017
Progressive development of night blindness and tunnel vision, sometimes from the early age of 2, are trademarks of retinitis pigmentosa. Being the most common inherited disorder of the retina, retinitis pigmentosa affects ...

Gene therapy cures canines of inherited form of day blindness

April 21, 2010
Veterinary ophthalmology researchers from the University of Pennsylvania have used gene therapy to restore retinal cone function and day vision in two canine models of congenital achromatopsia, also called rod monochromacy ...

A world without color—researchers find gene mutation that strips color, reduces vision

June 1, 2015
People with achromatopsia, an inherited eye disorder, see the world literally in black and white. Worse yet, their extreme sensitivity to light makes them nearly blind in bright sunlight. Now, researchers at University of ...

Recommended for you

Researchers are one step closer to developing eye drops to treat age-related macular degeneration

July 19, 2018
Scientists at the University of Birmingham are one step closer to developing an eye drop that could revolutionise treatment for age-related macular degeneration (AMD).

An orange a day keeps macular degeneration away: 15-year study

July 12, 2018
A new study has shown that people who regularly eat oranges are less likely to develop macular degeneration than people who do not eat oranges.

Injectable electronics offer powerful new tool in understanding how retinal cells work

June 28, 2018
Charles Lieber and his group are rewriting the rules of how scientists study retinal cells, and they're doing it with a single injection.

Why the eye could be the window to brain degeneration such as Alzheimer's disease

June 26, 2018
Researchers from Queen's University Belfast have shown for the first time that the eye could be a surrogate for brain degeneration like Alzheimer's disease (AD).

Microglia protect sensory cells needed for vision after retinal detachment

June 18, 2018
A research team at Massachusetts Eye and Ear has shown that microglia, the primary immune cells of the brain and retina, play a protective role in response to retinal detachment. Retinal detachment and subsequent degeneration ...

161 genetic factors for myopia identified

June 15, 2018
The international Consortium for Refractive Error and Myopia (CREAM) recently published the largest-ever genetic study of myopia in Nature Genetics. Researchers from the Gutenberg Health Study at the Medical Center of Johannes ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.