PUBLICATION
An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair
- Authors
- Yan, R., Cigliola, V., Oonk, K.A., Petrover, Z., DeLuca, S., Wolfson, D.W., Vekstein, A., Mendiola, M.A., Devlin, G., Bishawi, M., Gemberling, M.P., Sinha, T., Sargent, M.A., York, A.J., Shakked, A., DeBenedittis, P., Wendell, D.C., Ou, J., Kang, J., Goldman, J.A., Baht, G.S., Karra, R., Williams, A.R., Bowles, D.E., Asokan, A., Tzahor, E., Gersbach, C.A., Molkentin, J.D., Bursac, N., Black, B.L., Poss, K.D.
- ID
- ZDB-PUB-221216-17
- Date
- 2022
- Source
- Cell Stem Cell 30(1): 96-111.e6 (Journal)
- Registered Authors
- Black, Brian, Gemberling, Matt, Goldman, Joseph, Kang, Junsu, Karra, Ravi, Oonk, Kelsey, Ou, Jianhong, Poss, Kenneth D., Yan, Ruorong
- Keywords
- YAP, cardiomyocyte proliferation, enhancers, gene therapy, heart regeneration, mouse, pig, tissue regeneration, zebrafish
- MeSH Terms
-
- Animals
- Cell Proliferation
- Enhancer Elements, Genetic*
- Genetic Therapy*/methods
- Heart*/physiology
- Mice
- Myocardial Infarction*/genetics
- Myocardial Infarction*/therapy
- Myocytes, Cardiac*/metabolism
- Regeneration*/genetics
- Zebrafish/genetics
- PubMed
- 36516837 Full text @ Cell Stem Cell
Citation
Yan, R., Cigliola, V., Oonk, K.A., Petrover, Z., DeLuca, S., Wolfson, D.W., Vekstein, A., Mendiola, M.A., Devlin, G., Bishawi, M., Gemberling, M.P., Sinha, T., Sargent, M.A., York, A.J., Shakked, A., DeBenedittis, P., Wendell, D.C., Ou, J., Kang, J., Goldman, J.A., Baht, G.S., Karra, R., Williams, A.R., Bowles, D.E., Asokan, A., Tzahor, E., Gersbach, C.A., Molkentin, J.D., Bursac, N., Black, B.L., Poss, K.D. (2022) An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair. Cell Stem Cell. 30(1):96-111.e6.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping