(352d) Invited Speaker: Directed Evolution of New Viruses for Enhanced Gene Delivery

Viral vectors – composed of protein biopolymer capsids surrounding a recombinant genome –  offer a number of advantageous properties including the potential for safe and efficient gene delivery in vivo.  However, they also face a number of challenges – including inefficient delivery to some therapeutically valuable cell types, difficulty with targeted delivery, and an inability to overcome some tissue transport barriers in vivo – all which arguably stem from the fact that they did not naturally evolve to be utilized as human therapeutics.  Rational design approaches have generated vectors with enhancements in efficiency and selectivity of gene delivery.  However, in many cases there is insufficient knowledge of viral infection mechanisms and structure-function relationships that underlie gene transfer challenges to empower rational design efforts to improve the gene delivery properties of viral proteins.  As a complementary approach, we have been developing directed evolution – the iterative generation of large libraries genetic mutants and selection for enhanced properties – as an approach to create new viruses with useful properties for gene therapy.  For example, adeno-associated virus (AAV) vectors have enjoyed recent success in several clinical trials, and we have evolved AAV for the ability to transduce nonpermissive cells in vitro and in vivo, cross tissue barriers to gene delivery, target delivery to specific cell types, and evade pre-existing immunity.  Furthermore, we have engineered retroviral vectors for both targeted delivery and safe harbor integration into the human genome.  Directed evolution thus represents a powerful approach for engineering ‘designer’ viruses with enhanced gene delivery properties and therapeutic potential.