Single AAV-mediated mutation replacement genome editing in limited number of photoreceptors restores vision in mice

Koji M. Nishiguchi (), Kosuke Fujita, Fuyuki Miya, Shota Katayama and Toru Nakazawa ()
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Koji M. Nishiguchi: Tohoku University Graduate School of Medicine
Kosuke Fujita: Tohoku University Graduate School of Medicine
Fuyuki Miya: Tokyo Medical and Dental University
Shota Katayama: Tohoku University Graduate School of Medicine
Toru Nakazawa: Tohoku University Graduate School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: Abstract Supplementing wildtype copies of functionally defective genes with adeno-associated virus (AAV) is a strategy being explored clinically for various retinal dystrophies. However, the low cargo limit of this vector allows its use in only a fraction of patients with mutations in relatively small pathogenic genes. To overcome this issue, we developed a single AAV platform that allows local replacement of a mutated sequence with its wildtype counterpart, based on combined CRISPR-Cas9 and micro-homology-mediated end-joining (MMEJ). In blind mice, the mutation replacement rescued approximately 10% of photoreceptors, resulting in an improvement in light sensitivity and an increase in visual acuity. These effects were comparable to restoration mediated by gene supplementation, which targets a greater number of photoreceptors. This strategy may be applied for the treatment of inherited disorders caused by mutations in larger genes, for which conventional gene supplementation therapy is not currently feasible.

Date: 2020
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DOI: 10.1038/s41467-019-14181-3

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