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

Harry O. Orlans (), Michelle E. McClements, Alun R. Barnard, Cristina Martinez-Fernandez de la Camara and Robert E. MacLaren
Additional contact information
Harry O. Orlans: John Radcliffe Hospital, Headley Way, Headington
Michelle E. McClements: John Radcliffe Hospital, Headley Way, Headington
Alun R. Barnard: John Radcliffe Hospital, Headley Way, Headington
Cristina Martinez-Fernandez de la Camara: John Radcliffe Hospital, Headley Way, Headington
Robert E. MacLaren: John Radcliffe Hospital, Headley Way, Headington

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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 RhoP23H 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.

Date: 2021
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-25204-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25204-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-25204-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().