There has been an increasing number of successful gene therapy clinical trials, leading to regulatory approvals of numerous gene therapy products, in particular ones based on the adeno-associated virus (AAV).  That said, vectors based on natural versions of AAV face a number of delivery challenges that limit their efficacy and will thus preclude the extension of these successes to the majority of human diseases.  These delivery limitations arise since the parent viruses upon which these vectors are based were not evolved by nature for our convenience to use as human therapeutics.  We have been developing and implementing a high throughput approach termed directed evolution – involving the iterative genetic diversification of a viral genome and functional selection for desired properties – to engineer highly optimized variants of AAV for a broad range of cell and tissue targets.

In parallel, the advent of genome editing technologies such as the CRISPR/Cas9 system raise the possibility of using gene delivery not only for gene replacement but for repair or knockout of endogenous genes.  We have thus been combining engineered AAVs with CRISPR/Cas9 for a range of applications, in particular, to treat central nervous system disorders.  The integration of these new technologies – Cas9 cargo with AAV delivery – can enable a broad range of basic and therapeutic applications.

Learning Objectives:

1. To gain an understanding of how preclinical and clinical research in gene therapy is leading to strong advances and clinical approvals

2. To discuss how improvements in delivery technologies, such as engineered AAV delivery vectors, are still needed to fully unlock the potential of gene therapy and genome editing