Enhancer-directed gene delivery for digit regeneration based on conserved epidermal factors
Instructing regeneration of complex structures in mammals remains an unsolved problem. Gene therapy offers a compelling approach to foster endogenous regeneration by delivering therapeutic gene products to specific cells post injury. We identified a conserved regeneration-linked epidermal transcriptional program in mouse digit regeneration centered on the SP6 and SP8 transcription factors, involving inflammatory responses from osteoclasts. We engineered AAVs harboring a zebrafish tissue regeneration enhancer to direct FGF8 expression in the epidermis after amputation. This enhancer directed delivery partially rescued impaired digit regeneration in <i>Sp6</i> and <i>Sp8</i> conditional knockout mice and accelerated regrowth in wildtype digits. Our work links developmental signaling to adult regeneration and establishes a modular, injury site specific gene therapy framework that enables new interventions for limb healing.
Authors
- Anton F. Ehrhardt (ORCID: https://orcid.org/0000-0003-3942-5578)
- Tim M. Curtis (ORCID: https://orcid.org/0000-0003-1543-2781)
- Aravind Asokan (ORCID: https://orcid.org/0000-0001-5563-4877)
- Grant Darner
- Joshua D. Currie (ORCID: https://orcid.org/0000-0001-7402-4265)
- Smita Bhatia (ORCID: https://orcid.org/0000-0002-7755-5683)
- Kendall Reitz (ORCID: https://orcid.org/0009-0001-2500-5786)
- Colin Milligan (ORCID: https://orcid.org/0000-0003-4965-5609)
- Trevor Gonzalez (ORCID: https://orcid.org/0000-0002-2242-4483)
- Thomas Dvergsten
- David W. Wolfson (ORCID: https://orcid.org/0000-0003-3850-3925)
- Kenneth D. Poss (ORCID: https://orcid.org/0000-0002-6743-5709)
- Sydney Jeffs (ORCID: https://orcid.org/0000-0002-1761-8566)
- Jianhong Ou (ORCID: https://orcid.org/0000-0002-8652-2488)
- Erin Brush (ORCID: https://orcid.org/0000-0002-3743-3534)
- Madeleine B. Landau (ORCID: https://orcid.org/0009-0007-7315-8326)
- David A. Brown (ORCID: https://orcid.org/0009-0005-9805-0632)
- Melissa Tran
- Katja K. Koll
- Rochelle Bitolas
- David S. Salven
- Leslie A. Slota-Burtt
- Isabel Snee
- Elena Singer-Freeman
Institutions
- Tulane University (US)
- University of Wisconsin System (US)
- University of Wisconsin–Madison (US)
- Duke University (US)
- Georgetown University (US)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- Morgridge Institute for Research (US)
- Berufsgenossenschaftliche Unfallklinik Ludwigshafen (DE)
- Klinikum Ludwigshafen (DE)
- Wake Forest University (US)
- Heidelberg University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-02
- DOI
- https://doi.org/10.64898/2025.12.01.691633
- Primary Topic
- Developmental Biology and Gene Regulation
- Type
- article
- Field-Weighted Citation Impact
- 0.00