Downregulation of rhodopsin is an effective therapeutic strategy in ameliorating peripherin-2-associated inherited retinal disorders.

Autor: Rutan Woods CT; Department of Biomedical Engineering, University of Houston, Houston, TX, 77204, USA., Makia MS; Department of Biomedical Engineering, University of Houston, Houston, TX, 77204, USA., Lewis TR; Department of Ophthalmology, Duke University Medical Center, Durham, NC, 27710, USA., Crane R; Department of Biomedical Engineering, University of Houston, Houston, TX, 77204, USA., Zeibak S; Department of Biomedical Engineering, University of Houston, Houston, TX, 77204, USA., Yu P; Department of Biomedical Engineering, University of Houston, Houston, TX, 77204, USA., Kakakhel M; Department of Biomedical Engineering, University of Houston, Houston, TX, 77204, USA., Castillo CM; Department of Ophthalmology, Duke University Medical Center, Durham, NC, 27710, USA., Arshavsky VY; Department of Ophthalmology, Duke University Medical Center, Durham, NC, 27710, USA., Naash MI; Department of Biomedical Engineering, University of Houston, Houston, TX, 77204, USA. mnaash@central.uh.edu., Al-Ubaidi MR; Department of Biomedical Engineering, University of Houston, Houston, TX, 77204, USA. malubaid@central.uh.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jun 04; Vol. 15 (1), pp. 4756. Date of Electronic Publication: 2024 Jun 04.
DOI: 10.1038/s41467-024-48846-5
Abstrakt: Given the absence of approved treatments for pathogenic variants in Peripherin-2 (PRPH2), it is imperative to identify a universally effective therapeutic target for PRPH2 pathogenic variants. To test the hypothesis that formation of the elongated discs in presence of PRPH2 pathogenic variants is due to the presence of the full complement of rhodopsin in absence of the required amounts of functional PRPH2. Here we demonstrate the therapeutic potential of reducing rhodopsin levels in ameliorating disease phenotype in knockin models for p.Lys154del (c.458-460del) and p.Tyr141Cys (c.422 A > G) in PRPH2. Reducing rhodopsin levels improves physiological function, mitigates the severity of disc abnormalities, and decreases retinal gliosis. Additionally, intravitreal injections of a rhodopsin-specific antisense oligonucleotide successfully enhance the physiological function of photoreceptors and improves the ultrastructure of discs in mutant mice. Presented findings shows that reducing rhodopsin levels is an effective therapeutic strategy for the treatment of inherited retinal degeneration associated with PRPH2 pathogenic variants.
(© 2024. The Author(s).)
Databáze: MEDLINE
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