Mirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosa
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...
| Main Authors: | , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2021
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| _version_ | 1797097160005648384 |
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| author | Orlans, HO McClements, ME Barnard, AR Martinez-Fernandez de la Camara, C MacLaren, RE |
| author_facet | Orlans, HO McClements, ME Barnard, AR Martinez-Fernandez de la Camara, C MacLaren, RE |
| author_sort | Orlans, HO |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T04:51:35Z |
| format | Journal article |
| id | oxford-uuid:d5255281-048a-4e08-ac4a-f0defc618a77 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T04:51:35Z |
| publishDate | 2021 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:d5255281-048a-4e08-ac4a-f0defc618a772022-03-27T08:23:51ZMirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:d5255281-048a-4e08-ac4a-f0defc618a77EnglishSymplectic ElementsSpringer Nature2021Orlans, HOMcClements, MEBarnard, ARMartinez-Fernandez de la Camara, CMacLaren, RERhodopsin (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. |
| spellingShingle | Orlans, HO McClements, ME Barnard, AR Martinez-Fernandez de la Camara, C MacLaren, RE Mirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosa |
| title | Mirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosa |
| title_full | Mirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosa |
| title_fullStr | Mirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosa |
| title_full_unstemmed | Mirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosa |
| title_short | Mirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosa |
| title_sort | mirtron mediated rna knockdown replacement therapy for the treatment of dominant retinitis pigmentosa |
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