CRISPR cures blindness
A new study conducted by scientists from the University of California, Irvine, USA, has shown the effectiveness of a new generation of CRISPR technology for the treatment of a wide range of hereditary eye diseases caused by various gene mutations.
Professor Krzysztof Palczewski and his group provided evidence of the clinical potential of editing nitrogenous bases to correct mutations that cause hereditary retinal diseases and to restore visual function.
Hereditary retinal diseases are associated with mutations in more than 250 different genes and lead to irreversible loss of visual functions. Until quite recently, there was no way to cure these diseases until the FDA approved the first technique based on gene replacement therapy for Leber congenital amaurosis.
As an alternative to gene replacement therapy, the group applied a new generation of CRISPR technology – editing of nitrogenous bases – for the treatment of hereditary retinal diseases. To overcome some disadvantages of CRISPR-Cas9, for example, unpredictable mutations outside the target gene or low editing efficiency, the researchers edited cytosine and adenine. The use of these nitrogenous bases as a target made it possible to correct mutations in an accurate and predictable manner, minimizing unwanted mutations that could potentially cause side effects.
Using mouse models of Leber congenital amaurosis carrying a clinically significant pathogenic mutation in the Rpe65 gene, the group successfully demonstrated the therapeutic potential of editing nitrogenous bases for the treatment of this and other hereditary retinal diseases.
Editing of nitrogenous bases led to the restoration of the retina and visual functions in mice with congenital Leber amaurosis to almost normal levels. After treatment, the mice could distinguish visual cues, including their direction, size, contrast, spatial location, and flicker frequency.
A mutation in a mouse model of hereditary blindness stops the expression of RPE65 protein, a key enzyme in the visual cycle. Editing of nitrogenous bases corrected the mutation and restored the level of normal RPE65 (green), thereby restoring vision to mice.
The use of gene therapy for the treatment of hereditary retinal diseases is of particular interest to scientists, since the eye is anatomically accessible for interventions and calm in terms of immune status. In addition, the FDA has already approved the first gene therapy for Leber congenital amaurosis based on the replacement of the defective RPE65 gene. Now, as shown in this study, nitrogenous base editing technology can provide an alternative therapeutic model to permanently restore the function of a vision-related protein disabled by mutations.
Article S.Suh et al. Restoration of visual function in adult mice with an inherited retinal disease via adenine base editing is published in the journal Nature Biomedical Engineering.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the UCI School of Medicine: UCI-led study reveals significant restoration of retinal and visual function following gene therapy.