An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair.
Journal Article (Journal Article)
The efficacy and safety of gene-therapy strategies for indications like tissue damage hinge on precision; yet, current methods afford little spatial or temporal control of payload delivery. Here, we find that tissue-regeneration enhancer elements (TREEs) isolated from zebrafish can direct targeted, injury-associated gene expression from viral DNA vectors delivered systemically in small and large adult mammalian species. When employed in combination with CRISPR-based epigenome editing tools in mice, zebrafish TREEs stimulated or repressed the expression of endogenous genes after ischemic myocardial infarction. Intravenously delivered recombinant AAV vectors designed with a TREE to direct a constitutively active YAP factor boosted indicators of cardiac regeneration in mice and improved the function of the injured heart. Our findings establish the application of contextual enhancer elements as a potential therapeutic platform for spatiotemporally controlled tissue regeneration in mammals.
Full Text
Duke Authors
- Asokan, Aravind
- Baht, Gurpreet
- Bishawi, Muath
- Bowles, Dawn Elizabeth
- Bursac, Nenad
- Gersbach, Charles
- Karra, Ravi
- Poss, Kenneth Daniel
- Williams, Adam Richard
Cited Authors
- Yan, R; Cigliola, V; Oonk, KA; Petrover, Z; DeLuca, S; Wolfson, DW; Vekstein, A; Mendiola, MA; Devlin, G; Bishawi, M; Gemberling, MP; Sinha, T; Sargent, MA; York, AJ; Shakked, A; DeBenedittis, P; Wendell, DC; Ou, J; Kang, J; Goldman, JA; Baht, GS; Karra, R; Williams, AR; Bowles, DE; Asokan, A; Tzahor, E; Gersbach, CA; Molkentin, JD; Bursac, N; Black, BL; Poss, KD
Published Date
- January 5, 2023
Published In
Volume / Issue
- 30 / 1
Start / End Page
- 96 - 111.e6
PubMed ID
- 36516837
Pubmed Central ID
- PMC9830588
Electronic International Standard Serial Number (EISSN)
- 1875-9777
Digital Object Identifier (DOI)
- 10.1016/j.stem.2022.11.012
Language
- eng
Conference Location
- United States