Mirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosa.

Autor: Orlans HO; Nuffield Laboratory of Ophthalmology, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford, UK. Enquiries@eye.ox.ac.uk.; Moorfields Eye Hospital, London, UK. Enquiries@eye.ox.ac.uk., McClements ME; Nuffield Laboratory of Ophthalmology, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford, UK., Barnard AR; Nuffield Laboratory of Ophthalmology, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford, UK., Martinez-Fernandez de la Camara C; Nuffield Laboratory of Ophthalmology, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford, UK., MacLaren RE; Nuffield Laboratory of Ophthalmology, Level 6, West Wing, John Radcliffe Hospital, Headley Way, Headington, Oxford, UK.; Moorfields Eye Hospital, London, UK.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Aug 16; Vol. 12 (1), pp. 4934. Date of Electronic Publication: 2021 Aug 16.
DOI: 10.1038/s41467-021-25204-3
Abstrakt: Rhodopsin (RHO) gene mutations are a common cause of autosomal dominant retinitis pigmentosa (ADRP). The need to suppress toxic protein expression together with mutational heterogeneity pose challenges for treatment development. Mirtrons are atypical RNA interference effectors that are spliced from transcripts as short introns. Here, we develop a novel mirtron-based knockdown/replacement gene therapy for the mutation-independent treatment of RHO-related ADRP, and demonstrate efficacy in a relevant mammalian model. Splicing and potency of rhodopsin-targeting candidate mirtrons are initially determined, and a mirtron-resistant codon-modified version of the rhodopsin coding sequence is validated in vitro. These elements are then combined within a single adeno-associated virus (AAV) and delivered subretinally in a Rho P23H knock-in mouse model of ADRP. This results in significant mouse-to-human rhodopsin RNA replacement and is associated with a slowing of retinal degeneration. This provides proof of principle that synthetic mirtrons delivered by AAV are capable of reducing disease severity in vivo.
(© 2021. The Author(s).)
Databáze: MEDLINE
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