mRNA Delivery of Gene Therapy using Extracellular Vesicles Produces Better Immune Response than AAV and LNP Delivery
January 20, 2025
Researchers at Stanford University School of Medicine and Shenzhen Bay Laboratory recently announced the publication of a first-of-its-kind study comparing a novel, non-viral gene therapy delivered by extracellular vesicles (EV) with adeno-associated virus (AAV) and liponanoparticle (LNP).
Recent clinical trials of VEGF-A gene therapy, delivered by viral vectors, have produced lackluster results and heightened the need for alternative delivery strategies. The study, “VEGF- A mRNA EVs for treatment of ischemic injury,” recently published in the European Heart Journal, aimed to compare the in vivo delivery and efficacy of VEGF-A using adeno-associated virus (AAV) DNA, lipid nanoparticles (LNP) mRNA, and EV mRNA.
The head-to-head study concluded that EV mRNA offers efficient, dose-dependent delivery of VEGF-A mRNA and protein formation with low immunogenicity, resulting in new vessel formation in mice with ischemic vascular disease and offering greater therapeutic benefits when compared to AAV and LNP delivery. EVs loaded with VEGF-A mRNA were more effective at improving lower limb blood flow, wound healing, and cardiac function in mouse models.
“We are very pleased with the results of this study, which show that non-viral EV mRNA may offer an effective and potentially safer path for delivering angiogenic gene therapy to ischemic tissue,” said Patricia Nguyen, MD, Associate Professor in the Department of Cardiovascular Medicine, Stanford University, and member of the Cardiovascular Institute.
Extracellular Vesicle (EV) delivery of VEGF-A mRNA was shown to have low immunogenicity and to improve cardiac function.
EVs are naturally occurring structures, formed by cells, that transport molecules and nucleic acids in the body. They can be modified to carry mRNA, giving them the benefits of innate biocompatibility without triggering a strong immune response.
EVs may result in higher immune tolerance when compared to other gene therapy vehicles, allowing for serial dosing of therapy without the potential for added toxicity. In the study, delivery of VEGF-A by EVs was characterized by both a low innate and low adaptive immune response. By comparison: delivery via AAV elicited a strong innate and strong adaptive immune response; delivery via LNP elicited a strong innate and low adaptive immune response.
“We now know that EVs have wider applications for non-viral gene therapy delivery, where low immunogenicity and repeat dosing can produce optimal outcomes,” said Andrew Lee, MD, PhD, of Shenzhen Bay Laboratory. “This study opens the door to exploring more of these applications, including current therapies, like AAV-based gene therapy for muscular dystrophy, which have struggled to achieve efficacy at safe doses due to their viral immunogenicity and need better methods of delivery. We look forward to seeing more studies conducted on EV mRNA as a novel and effective delivery modality, beyond cardiovascular disease.”
Dr. Patricia Nguyen