Alginate hydrogel polymers enable efficient delivery of a vascular-targeted AAV vector into aortic tissue

Anca Remes; Dima Ibrahim Basha; Thomas Puehler; Christopher Borowski; Susanne Hille; Laura Kummer; Andreas H Wagner; Markus Hecker; Jasmin Soethoff; Georg Lutter; Derk Frank; Rawa Arif; Norbert Frey; Marcin Zaradzki; Oliver J Müller

doi:10.1016/j.omtm.2021.02.017

Alginate hydrogel polymers enable efficient delivery of a vascular-targeted AAV vector into aortic tissue

Mol Ther Methods Clin Dev. 2021 Feb 24:21:83-93. doi: 10.1016/j.omtm.2021.02.017. eCollection 2021 Jun 11.

Authors

Anca Remes^{1

2}, Dima Ibrahim Basha^{1

2}, Thomas Puehler^{2

3}, Christopher Borowski^{1

2}, Susanne Hille^{1

2}, Laura Kummer⁴, Andreas H Wagner⁵, Markus Hecker⁵, Jasmin Soethoff⁶, Georg Lutter^{2

3}, Derk Frank^{1

2}, Rawa Arif⁶, Norbert Frey^{1

2

7}, Marcin Zaradzki⁶, Oliver J Müller^{1

2}

Affiliations

¹ Department of Internal Medicine III, University of Kiel, Kiel, Germany.
² German Centre for Cardiovascular Research, Partner Site Hamburg/Kiel/Lübeck, Germany.
³ Department of Cardiac and Vascular Surgery, University of Kiel, Kiel, Germany.
⁴ Department of Anesthesiology, University Hospital Heidelberg, Heidelberg, Germany.
⁵ Department of Cardiovascular Physiology, Heidelberg University, Heidelberg, Germany.
⁶ Department of Cardiac Surgery, University Hospital Heidelberg, Heidelberg, Germany.
⁷ Internal Medicine III, University Hospital Heidelberg, Heidelberg, Germany.

Abstract

Gene therapeutic approaches to aortic diseases require efficient vectors and delivery systems for transduction of endothelial cells (ECs) and smooth muscle cells (SMCs). Here, we developed a novel strategy to efficiently deliver a previously described vascular-specific adeno-associated viral (AAV) vector to the abdominal aorta by application of alginate hydrogels. To efficiently transduce ECs and SMCs, we used AAV9 vectors with a modified capsid (AAV9SLR) encoding enhanced green fluorescent protein (EGFP), as wild-type AAV vectors do not transduce ECs and SMCs well. AAV9SLR vectors were embedded into a solution containing sodium alginate and polymerized into hydrogels. Gels were surgically implanted around the adventitia of the infrarenal abdominal aorta of adult mice. Three weeks after surgery, an almost complete transduction of both the endothelium and tunica media adjacent to the gel was demonstrated in tissue sections. Hydrogel-mediated delivery resulted in induction of neutralizing antibodies but did not cause inflammatory responses in serum or the aortic wall. To further determine the translational potential, aortic tissue from patients was embedded ex vivo into AAV9SLR-containing hydrogel, and efficient transduction could be confirmed. These findings demonstrate that alginate hydrogel harboring a vascular-targeting AAV9SLR vector allows efficient local transduction of the aortic wall.

Keywords: AAV vector; adeno-associated virus; alginate hydrogel; aorta; endothelial cells; gene therapy; smooth muscle cells; vascular disease; vascular gene transfer; vascular system.