Journal article
Mirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosa
- 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 Rho<sup>P23H</sup> 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 3.5MB, Terms of use)
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- Publisher copy:
- 10.1038/s41467-021-25204-3
Authors
- Publisher:
- Springer Nature
- Journal:
- Nature Communications More from this journal
- Volume:
- 12
- Issue:
- 1
- Article number:
- 4934
- Place of publication:
- England
- Publication date:
- 2021-08-16
- Acceptance date:
- 2021-07-26
- DOI:
- EISSN:
-
2041-1723
- Pmid:
-
34400638
- Language:
-
English
- Keywords:
- Pubs id:
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1191675
- Local pid:
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pubs:1191675
- Deposit date:
-
2021-11-08
Terms of use
- Copyright holder:
- Orlans et al.
- Copyright date:
- 2021
- Rights statement:
- ©2021 The Author(s). Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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