Journal Article

DKFZ-2026-02245

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Targeted insertion of an optimized donor DNA is effective in a humanized mouse model of dominant retinitis pigmentosa.

Esposito, F. ; Padmanabhan, A. ; Rhiel, M. ; Lupo, M. ; Marrocco, E. ; Auricchio, S. ; Cundin, X. B. ; Pellecchia, S. ; Cornu, T. I. ; Andrieux, G.DKFZ* ; Llado-Santaeularia, M. ; Surace, E. M. ; Trapani, I. ; Colella, P. ; Gambardella, G. ; Cathomen, T. ; Auricchio, A.

2026
Cell Press Cambridge, MA

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.

Keyword(s): AAV ; HITI ; autosomal dominant retinitis pigmentosa ; genome editing ; homology-independent targeted integration ; retina ; rhodopsin

Note: #DKTKZFB9# / epub

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Freiburg (FR01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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Database coverage:
; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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