New gene-editing technique could reverse vision loss and blindness in humans
Researchers in China have successfully restored the vision of mice with retinitis pigmentosa, one of the major causes of blindness in humans
[Mar. 20, 2023: JJ Shavit, The Brighter Side of News]
Researchers in China have successfully restored the vision of mice with retinitis pigmentosa, one of the major causes of blindness in humans. (CREDIT: Creative Commons)
Researchers in China have successfully restored the vision of mice with retinitis pigmentosa, one of the major causes of blindness in humans. The study, in the Journal of Experimental Medicine, uses a new, 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 the vision of 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-sensing rod and cone photoreceptor cells. However, most inherited forms of blindness, including retinitis pigmentosa, are caused by genetic defects in the neural photoreceptors themselves.
Retinitis pigmentosa (RP) is one of the leading causes of inherited blindness, affecting about 1 in 4,000 people globally. It is a progressive disease characterized by the death of rod and cone photoreceptor cells, leading to the impairment and loss of vision. RP is caused by mutations in over 100 different genes, and to date, there is no cure or effective treatment for the disease.
However, recent advances in genome editing using CRISPR technology have opened up new possibilities for the development of gene therapies to treat RP and other genetic disorders.
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“The ability to edit the genome of neural retinal cells, particularly unhealthy or dying photoreceptors, would provide much more convincing evidence for the potential applications of these genome-editing tools in treating diseases such as retinitis pigmentosa,” says Kai Yao, a professor at the Wuhan University of Science and Technology.
Yao and colleagues attempted to rescue the vision of mice with retinitis pigmentosa caused by a mutation in the gene encoding a critical enzyme called PDE6β. To do this, Yao’s team developed a new, more versatile CRISPR system called PESpRY, which can be programmed to correct many different types of genetic mutation, regardless of where they occur within the genome.
When programmed to target the mutant PDE6β gene, the PESpRY system was able to efficiently correct the mutation and restore the enzyme’s activity in the retinas of mice. This prevented the death of rod and cone photoreceptors and restored their normal electrical responses to light.
By the age of four months, the retinas of mice carrying a mutation in the gene encoding PDE6β (left) are thin and lack rod photoreceptors (red). But mice who have had this mutation corrected through the PESpRY system (right) have much thicker retinas containing numerous rod cells. (CREDIT: Journal of Experimental Medicine)
Yao and colleagues performed a variety of behavioral tests to confirm that the gene-edited mice retained their vision even into old age. For example, the animals were able to 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.
Previous studies using genome editing to treat retinal diseases have focused on the retinal pigment epithelium (RPE), a layer of non-neuronal cells in the eye that supports the photoreceptor cells. However, most inherited forms of blindness, including RP, are caused by genetic defects in the neural photoreceptors themselves. Therefore, the ability to edit the genome of these cells, particularly unhealthy or dying photoreceptors, would provide much more convincing evidence for the potential applications of genome-editing tools in treating diseases such as RP.
PE SpRY system elicits in vivo targeted genome editing at Pde6b locus. Schematic representations of the split Npu intein–based dual AAV system for the delivery of PESpRY, gRNAs (prime editing and ngRNAs) as well as GFP, and the pegRNA sequences used in in vivo study. The base pairs corresponding to the installed edits are indicated in green. (CREDIT: Journal of Experimental Medicine)
The PESpRY system was designed to be highly versatile and could be programmed to correct many different types of genetic mutations, regardless of where they occur within the genome. When programmed to target the mutant PDE6β gene, the PESpRY system was able to efficiently correct the mutation and restore the enzyme's activity in the retinas of mice. This prevented the death of rod and cone photoreceptors and restored their normal electrical responses to light.
To confirm that the gene-edited mice retained their vision, Yao and his colleagues performed a variety of behavioral tests. For example, the animals were able to 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. These results suggest that the PESpRY system has the potential to be an effective treatment for RP and other inherited retinal diseases.
Yao cautions that much work still needs to be done to establish both the safety and efficacy of the PESpRY system in humans. “However, our study provides substantial evidence for the in vivo applicability of this new genome-editing strategy and its potential in diverse research and therapeutic contexts, in particular for inherited retinal diseases such as retinitis pigmentosa,” Yao says.
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