The Medicine by Design Global Speaker Series invites established and emerging international leaders in regenerative medicine to engage with our extraordinary community of researchers and clinicians.
Medicine by Design, in partnership with the Ontario Institute for Regenerative Medicine, is pleased to welcome David Schaffer, PhD, Professor of Chemical and Biomolecular Engineering, Bioengineering, Molecular and Cell Biology, and the Helen Wills Neuroscience Institute, and director of the Berkeley Stem Cell Center at the University of California, Berkeley. The title of his talk is Directed Evolution of New Viruses for Therapeutic Gene Delivery.
For those unable to attend in person, the event will be available through live stream webcasting. (Link will be live shortly before the event.)
Gene therapy has experienced an increasing number of successful human clinical trials, particularly ones using delivery vehicles or vectors based on adeno-associated viruses (AAV). These include trials for hemophilia B, Leber’s congenital amaurosis (LCA2), spinal muscular atrophy, and lipoprotein lipase deficiency (LPLD). As a result, AAV is the basis for a clinically approved gene therapy product to treat LPLD in the European Union, and an AAV gene therapy will likely receive FDA approval this year for LCA2. AAV is thus capable of safe and therapeutic gene delivery to some cell targets. However, vectors in general face a number of challenges that limit their efficacy, not surprisingly since the parent viruses upon which these vectors are based were not evolved by nature for our convenience to use as human therapeutics. For most applications there is insufficient mechanistic knowledge of underlying virus structure-function relationships to empower rational design to improve such vectors.
As an alternative approach, we were the first to develop and have since been implementing directed evolution – involving the iterative genetic diversification of a viral genome and functional selection for desired properties – to address a number of problems with AAV. Genetic diversification has included the random diversification of peptide sequences at defined locations in the capsid, random point mutagenesis of the cap gene, and recombination of cap genes from a number of parental serotypes to create random chimeras. Using a range of in vitro and in vivo strategies to select the resulting large (~108) libraries for improved function, we have evolved AAVs for evasion of neutralizing antibodies, enhanced biodistribution and spread within a target tissue, greatly improved delivery efficiency, and targeted delivery in vitro and in vivo, thereby substantially improving the vectors’ capacity to meet human therapeutic needs.