According to a new study published in the journal, Nature Communications, silencing a gene, known as Nrl, using CRISPR could preserve photoreceptors in the eye. The research – which was conducted at the National Eye Institute (NEI) – could aid in the development of novel therapies for genetic eye diseases, including retinitis pigmentosa.
The retina is composed of two types of photoreceptors: rods and cones. While the rods allow us to see at night and at other poorly-lit times, the cones function primarily during the day, supporting colour vision.
Most genetic forms of eye disease affect the rod cells, contributing to the development of night blindness in patients with retinitis pigmentosa. Cone degeneration and central vision blindness can also occur, due to fact that rods provide structural support to cone cells.
Researchers at NEI sought out to determine whether preventing rod degeneration could have a protective effect on cones, and in turn, color vision. Since the product of the Nrl gene dictates whether a photoreceptor matures into a rod or a cone, the researchers knocked out this gene to study its effects.
Previous research at NEI has found that if the Nrl gene is removed in genetically engineered mice, the animals develop retinas composed entirely of cone cells. Further, if Nrl gene expression is silenced in mature mice, the rod cells compensate by performing some of the functions normally reserved to cone photoreceptors, even in the presence of gene mutations.
“The evidence suggested to us that coaxing rods into becoming more cone-like by knocking out Nrl was a potential strategy for overriding mutations that would otherwise lead to rod degeneration,” said Dr. Anand Swaroop, chief of NEI’s Neurodegeneration and Repair Laboratory. “Consequently, the neighboring cones would remain functional and viable.”
Using CRISPR, Swaroop and his team removed the Nrl gene from healthy mice, along with three different breeds of mice representing different models of retinal disease. Using gene expression profiling, the researchers found that the rod photoreceptors showed similarities to cone cells, consistent with previous findings.
The cone-like rod photoreceptors promoted survival of surrounding cells, despite being unable to detect light. In the mouse models of retinal disease, degeneration of rod cells was significantly slowed, or even prevented.
The researchers found that this CRISPR gene editing therapy was most effective when used on younger mice. Best of all, the benefits of the technique could be observed in all three models of disease, despite each being engineered to have a different gene defect.
“Unlike conventional gene therapy, in which a normal gene is introduced to replace the defective gene, this approach could treat retinal degeneration caused by a variety of mutant genes,” said Dr. Zhijian Wu, head of the NEI Ocular Gene Therapy Core. Before the approach is tested on human patients in a clinical trial, the safety of CRISPR and any potential off-target effects will need to be determined in further preclinical studies.