Authors
Federica Esposito, Arjun Padmanabhan, Manuel Rhiel, Mariangela Lupo, Elena Marrocco, Stefano Auricchio, Xabier Bujanda Cundin, Simona Pellecchia, Tatjana I Cornu, Geoffroy Andrieux, Manel Llado-Santaeularia, Enrico Maria Surace, Ivana Trapani, Pasqualina Colella, Gennaro Gambardella, Toni Cathomen, Alberto Auricchio
Published in
Cell reports. Medicine. Pages 103047. Sep 11, 2026. Epub Sep 11, 2026.
Abstract
Retinitis pigmentosa (RP) affects 1 in 3,000 individuals worldwide, with 30%-40% of cases inherited as autosomal dominant (AD). Mutations in RHO (RP4) are the most common cause of ADRP. Because most RHO mutations exert gain-of-function or dominant-negative effects, conventional gene supplementation is insufficient, requiring mutant allele inactivation. Allele-specific editing is impractical, as each mutation requires a unique therapeutic strategy. We present a mutation-agnostic, RHO-specific approach using adeno-associated viral vector-mediated homology-independent targeted integration (AAV-HITI). Optimized donor DNA design enables targeted integration and efficient transgene expression from the endogenous RHO locus. In a humanized RP4 mouse model harboring the RHO P23H mutant allele alongside an endogenous wild-type mouse Rho allele, AAV-HITI significantly improves retinal structure, function, and visual acuity up to 1 year post-treatment. Comprehensive molecular analyses characterize on-target editing in mouse retina and off-target editing in a human cell line. These findings establish an effective, human-centric AAV-HITI platform for RP4 and support its evaluation in this and other dominant genetic conditions.
PMID:
42727583
Bibliographic data and abstract were imported from PubMed on 12 Sep 2026.
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