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. 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

Duke University
Weizmann Institute of Science
University of California at San Francisco
University of Cincinnati
University of Wisconsin-Madison
Ohio State University

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

56 Scopus citations

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
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2022 Elsevier Inc.

Funding

We thank Duke DLAR staff for mouse and swine care; Duke Cardiovascular Physiology Core, J. Stowell, and S. Degan for performing mouse MI surgeries; B. Varelas for plasmid; C. Bryant and N. Lee for technical help; Duke Zebrafish Core for zebrafish care; and F. Sun and M. Pronobis for comments on the manuscript. R.Y. was supported by an American Heart Association (AHA) postdoctoral fellowship ( 17POST33660087 ). V.C. was supported by Early ( P2GEP3_175016 ) and Advanced ( P400PM_186709 ) Postdoc Mobility fellowships from the Swiss National Science Foundation . S.D. was supported by predoctoral fellowships from AHA ( 903369 ) and NIH ( F31 HL162460 ). J.K. acknowledges support from National Institutes of Health ( R01 HL151522 ) and AHA ( AHA16SDG30020001 ). J.A.G. acknowledges support from AHA ( AHA117SDG33660922 ). G.S.B. acknowledges support from the Claude D. Pepper Older Americans Independence Center Pilot Award ( P30AG028716 ) and NIH ( R21 AG067245 ). R.K. acknowledges support from Transforming Duke Health (TDH) and NIH ( R01 HL157277 ). C.A.G. acknowledges support from NIH ( U01AI146356 , UM1HG013053 , RM1HG011123 , R33DA041878 ), National Science Foundation ( EFMA-1830957 ), the Duke-Coulter Translational Partnership , and an Allen Distinguished Investigator Award . N.B. acknowledges support from NIH ( U01 HL134764 and R01 HL126524 ), TDH , and Fondation Leducq . B.L.B. acknowledges support from NIH ( R01 HL146366 and R01 DK119621 ). K.D.P. acknowledges support from NIH (R35 HL150713 and R01 HL136182 ), AHA , TDH , and Fondation Leducq .

Funders	Funder number
Claude D. Pepper Older Americans Independence Center	P30AG028716, R01 HL157277, RM1HG011123, UM1HG013053, R21 AG067245, U01AI146356, R33DA041878
TDH
National Science Foundation	EFMA-1830957, R01 HL126524, U01 HL134764
National Institutes of Health	AHA16SDG30020001, AHA117SDG33660922, F31 HL162460, R01 HL151522
American Heart Association	17POST33660087, P400PM_186709, P2GEP3_175016
Fondation Leducq	R01 HL136182, R01 DK119621, R01 HL146366, R35 HL150713
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	903369

Keywords

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

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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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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.",

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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.\}",

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year = "2023",

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day = "5",

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

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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

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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 - https://www.scopus.com/pages/publications/85144814837

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C2 - 36516837

AN - SCOPUS:85144814837

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

Bibliographical note

Funding

Keywords

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