Engineering immuno-evading adeno-associated virus vectors for gene therapy

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 DESCRIPTION (provided by applicant): Gene therapy with adeno-associated virus (AAV) has emerged as a promising treatment option for a variety of diseases, including those afflicting the cardiovascular system. Unfortunately, humoral immune responses against the AAV capsid prevent the ability to re-administer the viral vector as needed. In addition to the anti- AAV capsi antibody responses, tissue targeting is another major hurdle to effective cardiac gene therapy. Previously, we designed a Protease-Activatable Virus (PAV) based on AAV that is stimulated by overexpressed matrix metalloproteinases (MMPs) in diseased tissues. Although the PAVs may enable more targeted delivery to sites of disease, they will also suffer from antibody responses against the capsid just like the unengineered vectors. To overcome this problem, I hypothesize that genetically inserting a `self-peptide' into the PAV capsid (PAV-SP) will minimize phagocytic uptake, ultimately decreasing neutralizing antibody production. The aims of this fellowship project are the following: 1) genetically clone and structurally characterize PAV-SP and 2) functionally characterize PAV-SP with in vitro models.