Event

PhD Dissertation Defense: Yahya Cheema

Thursday, May 28, 2026
12:00 p.m.
AJC 5104 (5th floor conference room)
Debbie Chu
301 405 8268
dgchu@umd.edu

Title: Investigating the Extracellular Matrix and Protein Corona as Physiological Barriers to Adeno-Associated Viral Gene Delivery

Committee members:

Dr. Gregg A. Duncan, Chair
Dr. Matthew T. Wolf
Dr. Sylvina Matysiak
Dr. Sara Molinari
Dr. James Culver, Dean’s Representative

Abstract:

Adeno-associated viral vectors (AAV) have emerged as a leading viral gene delivery system with multiple serotypes that are effective at transducing (infecting) diverse tissue environments.  Despite its wide use, AAV systemic delivery efficiency remains an area that can be greatly improved, as systemic delivery of AAV often results in poor biodistribution in target tissues and unwanted off-target effects within patients, which necessitates the use of higher doses of AAV viral vectors, leading to higher therapeutic costs and negative side effects. Key components of this biodistribution are the presence of the extracellular matrix (ECM) of the tissue microenvironment which poses a significant barrier to the distribution of AAV in target organs, and the formation of a protein corona on AAV viral vectors, which may influence the distribution and transduction efficiency of AAV viral vectors, subsequently impacting delivery of therapeutic genetic cargo. The overall objective of this dissertation is to advance the understanding of the influence of the extracellular matrix microenvironment on AAV diffusive and transduction abilities and evaluating the influence of human serum-derived protein corona formation on AAV transport and infectious behavior. Our objective includes further evaluating the feasibility of leveraging these interactions for localized, controlled-release gene delivery through ECM hydrogel platforms. We hypothesized that both the AAV serotype and ECM composition, as well as the formation of the human serum-protein corona on AAV vectors impacts AAV transport and gene delivery. We further hypothesized that the intrinsic AAV-ECM interactions could be leveraged to improve vector retention, resulting in localized delivery and effective transduction in vitro. Our first aim was to determine the influence of the ECM from lung, liver, and small intestine submucosa tissue on AAV2, AAV6, and AAV8 serotypes on AAV transport and transduction through in vitro ECM incorporated models. We found that all AAV serotypes displayed reduced diffusivity through ECM in all tissue types and that AAV transduction in ECM incorporated in vitro models was significantly reduced in both 2D and 3D culture. We then assessed the influence of a human serum-derived protein corona on AAV behavior by characterizing serum-incubated AAV vectors and their transport and gene delivery in dECM incorporated in vitro models. We observed that a human serum-derived protein corona significantly influences AAV diffusion and transduction in vitro, and that the combined effects of protein corona formation and ECM microenvironment on AAV6 transport and cellular interaction significantly impacts vector transduction ability. Finally, we investigated the feasibility of using ECM hydrogels as a localized controlled-release platform for AAV gene delivery and found that the intrinsic binding of AAV to the ECM can be functionally leveraged to enhance controlled release applications in gene therapy. This work provides additional insight into the impact of physiological barriers to the transport and transduction of AAV viral vectors within the tissue microenvironment, as well as additional considerations for the design of efficient AAV-based gene therapeutics.