Protein-Engineered Hydrogels for Gene Transplantation for Myocardial Infarction

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PROJECT SUMMARY/ABSTRACT Nearly one million Americans experience a myocardial infarction (MI) annually. Minimally invasive, local delivery of drugs, cells, genes, and/or growth factors are promising regenerative therapies for MI; however, delivery to the contracting heart remains an unmet challenge. To be a clinically viable option, biomaterials must be catheter injectable, must provide rapid and robust gelation to prevent extrusion out of the beating myocardium, and must permit controlled release of a therapeutic dosage of payload. Unfortunately, most catheter-injectable materials are weak gels that are extruded during myocardial contraction. As an alternative, I propose gels formed via biocompatible, dynamic covalent chemistry (DCC) crosslinks that are reversible yet strong, resulting in injectable gels with the mechanical integrity necessary to be retained in contractile tissue. Specifically, these gels are composed of recombinant, elastin-like proteins and chemically modified hyaluronic acid. These components are crosslinked together through DCC hydrazone bonds to form enzymatically degradable gels that are fully chemically defined for future FDA studies. In Aim 1, a family of 12 gels will be synthesized, mechanically characterized, and evaluated in vitro and in vivo for easy catheter injection and retention in the contracting heart. In Aim 2, a regenerative payload, minicircle genes encoding stromal cell-derived factor-1α, will be tethered to the injectable gel via DNA hybridization with peptide nucleic acid-peptides to achieve sustained, long-term release. In Aim 3, the gel formulation with optimized in vivo retention and sustained gene release will be evaluated for therapeutic potential in a preclinical rat MI model. This Career Development Award would enable me to enhance my strong background in biomaterials chemistry and gene delivery with new expertise in cardiovascular biology, preclinical models of ischemic cardiomyopathy, and translational bioengineering. My career development plan includes (1) formal coursework in regenerative medicine and cardiovascular biology and disease, (2) technical training in recombinant biomaterials, minicircle genes, and preclinical MI models, (3) close co-mentorship by two outstanding scientists (a bioengineer and a surgeon) with a strong track-record of successful training and collaboration, and (4) career guidance by an Advisory Committee that reflects a diversity of career experiences and fields. To prepare for my transition to independence, I devised a plan in consultation with my co-mentors to further increase and strengthen my professional network, to become polished and confident in my oral research presentations, and to gain invaluable grant-writing skills. This plan leverages the outstanding resources available within the Stanford Cardiovascular Institute and the Stanford School of Engineering with national and international events. During the last year of this award, I will prepare and submit application packets for the position of tenure-track Assistant Professor in Bioengineering. My long-term goal is to lead a translational bioengineering lab that develops regenerative therapies for cardiovascular diseases and to serve as a role model for young black scientists.