The Vandenberghe laboratory deconstructs viral evolution to improve viral vector design and use in gene therapy. We aim to more profoundly understand capsid structure-function relationships and use this information to select and engineer gene therapy vectors for clinical indications. For many of these studies, we use the ssDNA mammalian adeno-associated virus (AAV) as a model. AAV is not only one of the smallest and simplest mammalian viruses, it has also captivated the world of gene therapy as AAV, with remarkable efficiency and safety, is able to deliver and transduce genetic cargo into therapeutic target tissues such as the retina, cochlea, liver, and CNS. AAVs come in many flavors that were originally distinguished based on serology, but now are more and more phylogenetically and structurally defined. Different AAVs demonstrate very distinct phenotypes (tropism, receptor use, host response, assembly, etc.) as a wild type virus or replication-defective vector. We are interested in functionally and structurally understanding the mechanism of these stark differences from the perspective of virus as well as host. One avenue towards this goal is to study the evolutionary biology of this virus, and use mathematical, statistical, and systems approaches in combination with empirical and molecular methods to shed light on the structure-function relationship of these small, yet intricately complex infectious protein assemblies.

We aim at integrating these findings into improved technologies for therapeutic gene transfer, and use these findings and novel reagents toward building innovative therapies for diseases with unmet need, with a particular focus on blinding and hearing disorders.