Journal
CELL STEM CELL
Volume 30, Issue 1, Pages 96-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2022.11.012
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This study found that tissue-regeneration enhancer elements (TREEs) isolated from zebrafish can be used to direct targeted, injury-associated gene expression in small and large mammalian species through systemic delivery of viral DNA vectors. In mice, when used with CRISPR-based epigenome editing tools, zebrafish TREEs can stimulate or repress the expression of endogenous genes after ischemic myocardial infarction. Intravenously delivered recombinant AAV vectors designed with a TREE can enhance indicators of cardiac regeneration and improve the function of the injured heart in mice. These findings establish the potential of contextual enhancer elements as a therapeutic platform for spatiotemporally controlled tissue regeneration in mammals.
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.
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