An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair

Ruorong Yan; Valentina Cigliola; Kelsey A. Oonk; Zachary Petrover; Sophia DeLuca; David W. Wolfson; Andrew Vekstein; Michelle A. Mendiola; Garth Devlin; Muath Bishawi; Matthew P. Gemberling; Tanvi Sinha; Michelle A. Sargent; Allen J. York; Avraham Shakked; Paige DeBenedittis; David C. Wendell; Jianhong Ou; Junsu Kang; Joseph A. Goldman; Gurpreet S. Baht; Ravi Karra; Adam R. Williams; Dawn E. Bowles; Aravind Asokan; Eldad Tzahor; Charles A. Gersbach; Jeffery D. Molkentin; Nenad Bursac; Brian L. Black; Kenneth D. Poss

doi:10.1016/j.stem.2022.11.012

An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair

Ruorong Yan, Valentina Cigliola, Kelsey A. Oonk, Zachary Petrover, Sophia DeLuca, David W. Wolfson, Andrew Vekstein, Michelle A. Mendiola, Garth Devlin, Muath Bishawi, Matthew P. Gemberling, Tanvi Sinha, Michelle A. Sargent, Allen J. York, Avraham Shakked, Paige DeBenedittis, David C. Wendell, Jianhong Ou, Junsu Kang, Joseph A. GoldmanGurpreet S. Baht, Ravi Karra, Adam R. Williams, Dawn E. Bowles, Aravind Asokan, Eldad Tzahor, Charles A. Gersbach, Jeffery D. Molkentin, Nenad Bursac, Brian L. Black, Kenneth D. Poss

Department of Molecular Cell Biology

Weizmann Institute of Science

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	96-111.e6
Journal	Cell Stem Cell
Volume	30
Issue number	1
DOIs	https://doi.org/10.1016/j.stem.2022.11.012
State	Published - 5 Jan 2023

Keywords

YAP
cardiomyocyte proliferation
enhancers
gene therapy
heart regeneration
mouse
pig
tissue regeneration
zebrafish

All Science Journal Classification (ASJC) codes

Molecular Medicine
Genetics
Cell Biology

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10.1016/j.stem.2022.11.012

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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., ... Poss, K. D. (2023). An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair. Cell Stem Cell, 30(1), 96-111.e6. https://doi.org/10.1016/j.stem.2022.11.012

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title = "An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair",

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.",

keywords = "YAP, cardiomyocyte proliferation, enhancers, gene therapy, heart regeneration, mouse, pig, tissue regeneration, zebrafish",

author = "Ruorong Yan and Valentina Cigliola and Oonk, \{Kelsey A.\} and Zachary Petrover and Sophia DeLuca and Wolfson, \{David W.\} and Andrew Vekstein and Mendiola, \{Michelle A.\} and Garth Devlin and Muath Bishawi and Gemberling, \{Matthew P.\} and Tanvi Sinha and Sargent, \{Michelle A.\} and York, \{Allen J.\} and Avraham Shakked and Paige DeBenedittis and Wendell, \{David C.\} and Jianhong Ou and Junsu Kang and Goldman, \{Joseph A.\} and Baht, \{Gurpreet S.\} and Ravi Karra and Williams, \{Adam R.\} and Bowles, \{Dawn E.\} and Aravind Asokan and Eldad Tzahor and Gersbach, \{Charles A.\} and Molkentin, \{Jeffery D.\} and Nenad Bursac and Black, \{Brian L.\} and Poss, \{Kenneth D.\}",

note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",

year = "2023",

month = jan,

day = "5",

doi = "10.1016/j.stem.2022.11.012",

language = "الإنجليزيّة",

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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 2023, 'An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair', Cell Stem Cell, vol. 30, no. 1, pp. 96-111.e6. https://doi.org/10.1016/j.stem.2022.11.012

TY - JOUR

T1 - An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair

AU - Yan, Ruorong

AU - Cigliola, Valentina

AU - Oonk, Kelsey A.

AU - Petrover, Zachary

AU - DeLuca, Sophia

AU - Wolfson, David W.

AU - Vekstein, Andrew

AU - Mendiola, Michelle A.

AU - Devlin, Garth

AU - Bishawi, Muath

AU - Gemberling, Matthew P.

AU - Sinha, Tanvi

AU - Sargent, Michelle A.

AU - York, Allen J.

AU - Shakked, Avraham

AU - DeBenedittis, Paige

AU - Wendell, David C.

AU - Ou, Jianhong

AU - Kang, Junsu

AU - Goldman, Joseph A.

AU - Baht, Gurpreet S.

AU - Karra, Ravi

AU - Williams, Adam R.

AU - Bowles, Dawn E.

AU - Asokan, Aravind

AU - Tzahor, Eldad

AU - Gersbach, Charles A.

AU - Molkentin, Jeffery D.

AU - Bursac, Nenad

AU - Black, Brian L.

AU - Poss, Kenneth D.

PY - 2023/1/5

Y1 - 2023/1/5

N2 - 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.

AB - 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.

KW - YAP

KW - cardiomyocyte proliferation

KW - enhancers

KW - gene therapy

KW - heart regeneration

KW - mouse

KW - pig

KW - tissue regeneration

KW - zebrafish

UR - http://www.scopus.com/inward/record.url?scp=85144814837&partnerID=8YFLogxK

U2 - 10.1016/j.stem.2022.11.012

DO - 10.1016/j.stem.2022.11.012

M3 - مقالة

C2 - 36516837

SN - 1934-5909

VL - 30

SP - 96-111.e6

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 1

ER -

An enhancer-based gene-therapy strategy for spatiotemporal control of cargoes during tissue repair

Abstract

Keywords

All Science Journal Classification (ASJC) codes

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