Resume: Using a highly versatile form of CRISPR gene editing, researchers have successfully restored vision in mice with retinitis pigmentosa.
Source: Rockefeller University Press
Researchers in China have successfully restored vision to mice with retinitis pigmentosa, one of the leading causes of blindness in humans.
The study, to be published March 17 in the Journal of Experimental Medicineuses a novel, highly versatile form of CRISPR-based genome editing with the potential to correct a wide variety of disease-causing genetic mutations.
Researchers have previously used genome editing to restore vision to mice with genetic diseases, such as Leber congenital amaurosis, that affect the retinal pigment epithelium, a layer of non-neuronal cells in the eye that supports the light-sensitive rod and cone photoreceptor cells. However, most hereditary forms of blindness, including retinitis pigmentosa, are caused by genetic defects in the neural photoreceptors themselves.
“The ability to edit the genome of neural retinal cells, particularly unhealthy or dying photoreceptors, would provide much more compelling evidence for the potential applications of these genome editing tools in the treatment of diseases such as retinitis pigmentosa,” said Kai Yao. , a professor at Wuhan University of Science and Technology.
Retinitis pigmentosa can be caused by mutations in more than 100 different genes and is estimated to cause vision impairment in 1 in 4,000 people. It begins with the dysfunction and death of rod cells that sense dim light before spreading to the cone cells needed for color vision, eventually leading to severe, irreversible vision loss.
Yao and colleagues tried to save the eyesight of mice with retinitis pigmentosa, caused by a mutation in the gene that codes for a crucial enzyme called PDE6β. To do this, Yao’s team developed a new, more versatile CRISPR system called PESmartwhich can be programmed to correct many different types of genetic mutations no matter where they occur in the genome.
When programmed to target the mutant PDE6β gene, the PESmart system was able to efficiently correct the mutation and restore the enzyme’s activity in the mouse retina. This prevented the death of rod and cone photoreceptors and restored their normal electrical responses to light.
Yao and colleagues performed several behavioral tests to confirm that the gene-edited mice retained their eyesight even into old age. For example, the animals could find their way out of a visually guided water maze almost as well as normal, healthy mice and showed typical head movements in response to visual stimuli.
Yao cautions that much work remains to be done to establish both the safety and efficacy of the PESmart system in humans.
“However, our study provides substantial evidence for the in vivo applicability of this novel genome-editing strategy and its potential in diverse research and therapeutic contexts, particularly for inherited retinal disorders such as retinitis pigmentosa,” says Yao.
About this news about gene editing and visual neuroscience research
Author: Press Office
Source: Rockefeller University Press
Contact: Press Service – Rockefeller University Press
Image: The image is credited to Qin et al / JEM
Original research: Open access.
“Vision rescue via unrestricted in vivo prime editing in degenerating neural retinas” by Huan Qin et al. Journal of Experimental Medicine
Vision rescue via unrestricted in vivo prime editing in degenerating neural retinas
Retinitis pigmentosa (RP) is a hereditary retinal dystrophy that causes progressive and irreversible loss of retinal photoreceptors.
Here we developed a genome editing tool characterized by the versatility of prime editors (PEs) and the unrestricted PAM requirement of a SpCas9 variant (SpRY), referred to as PESmart.
The diseased retinas of Pde6b-associated RP mouse model was transduced through a double AAV system packaging PESmart for the in vivo genome editing via a non-NGG PAM (GTG).
Progressive cell loss was reversed once the mutation was corrected, leading to substantial rescue of photoreceptors and production of functional PDE6β. The treated mice showed significant responses to the electroretinogram and showed good performance in both passive and active avoidance tests.
In addition, they showed marked improvement in visual stimulus-driven optomotor responses and efficiently completed visually guided water maze tasks.
Together, our study provides compelling evidence for the prevention of vision loss caused by RP-associated gene mutations via unrestricted in vivo prime editing in the degenerating retinas.