We are focused on engineering technologies to enable transformative, new medicines, particularly,
Our approach hinges on engineering viruses and genomic elements, including
[Parvoviruses] often truncated to “parvo”, which is both the common name in English casually applied to all the viruses in the Parvoviridae taxonomic family, and also the taxonomic name of the Parvovirus genus within the Parvoviridae family. Parvoviruses are typically linear, non-segmented single-stranded DNA viruses, with an average genome size of 5,000 nucleotides. Parvoviruses are some of the smallest viruses (from the latin word parvus, meaning small) and are 18-26 nm in diameter (~ Wikipedia]
Adeno-Associated Viruses (AAV) are non-pathogenic, helper-dependent members of the parvovirus family and currently being evaluated in human gene therapy clinical trials. We are interested in understanding the biology of AAV as well as developing a synthetic AAV toolkit for the clinic. To achieve such, we utilize a broad spectrum of techniques and resources including gene synthesis, structural modeling, protein engineering, cell biology, microscopy, high throughput screening, genome editing tools and transgenic animal models.
The AAV Genome: Manipulation of genomic material packaged within viruses is critical towards vector development for gene therapy applications. Towards this end, we are interested in (a) incorporation of novel RNA-based regulatory elements in viral vector genomes, (b) integration of CRISPR-based genome engineering tools with AAV vectors and (c) exploring the possibility whether viruses can package larger and/or structurally modified genomes.
The AAV Capsid: Among the smallest known viruses at a diameter of 25nm, the icosahedral AAV shell is comprised of 60 protein subunits and encapsidates a single-stranded DNA genome. We are interested in understanding the biology of the AAV capsid at the molecular level. For instance, how does the capsid self-assemble and disassemble? What receptors does AAV utilize to infect different cells? How do receptors interact with specific amino acid residues to form footprints on the capsid surface and how does this determine tissue tropism and antigenicity? To answer these questions, we utilize an ever-expanding synthetic AAV toolkit generated through a combination of rational and combinatorial mutagenesis.
Applications: Natural and engineered AAV strains can be utilized in a broad spectrum of gene therapy, silencing and genome editing applications. We are currently developing vectors for therapeutic gene transfer in diseases affecting cardiac, pulmonary and neuro/muscular organ systems. In conjunction with these efforts, we also carry out studies focused on biodistribution, toxicity and systemic transport mechanisms of AAV vectors in transgenic mouse models. Our ultimate goal is to generate lead candidates for gene therapy clinical trials.