A reversible RNA on-switch that controls gene expression of AAV-delivered therapeutics in vivo
| Autor: | Michael Farzan, Zachary J Tickner, Yujun Li, Guocai Zhong, Mai H. Tran, Haimin Wang, Huihui Mou, Tianling Ou, Yiming Yin, Wenhui He, Huitian Diao |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
Genetic enhancement Transgene Biomedical Engineering Bioengineering Applied Microbiology and Biotechnology Article Cell Line 03 medical and health sciences 0302 clinical medicine Genes Reporter Gene expression Animals Humans RNA Catalytic Transgenes Gene 030304 developmental biology Regulation of gene expression 0303 health sciences Mice Inbred BALB C biology Oligonucleotide Ribozyme RNA Genetic Therapy Dependovirus Oligonucleotides Antisense Cell biology Gene Expression Regulation biology.protein Molecular Medicine Female 030217 neurology & neurosurgery Biotechnology |
| Zdroj: | Nature biotechnology |
| ISSN: | 1546-1696 1087-0156 |
| Popis: | Widespread use of gene therapy technologies is limited in part by the lack of small genetic switches with wide dynamic ranges that control transgene expression without the requirement of additional protein components1-5. In this study, we engineered a class of type III hammerhead ribozymes to develop RNA switches that are highly efficient at cis-cleaving mammalian mRNAs and showed that they can be tightly regulated by a steric-blocking antisense oligonucleotide. Our variant ribozymes enabled in vivo regulation of adeno-associated virus (AAV)-delivered transgenes, allowing dose-dependent and up to 223-fold regulation of protein expression over at least 43 weeks. To test the potential of these reversible on-switches in gene therapy for anemia of chronic kidney disease6, we demonstrated regulated expression of physiological levels of erythropoietin with a well-tolerated dose of the inducer oligonucleotide. These small, modular and efficient RNA switches may improve the safety and efficacy of gene therapies and broaden their use. |
| Databáze: | OpenAIRE |
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