Gene therapy has experienced an increasing number of successful human clinical trials, leading to 6 FDA approved products using delivery vectors based on adeno-associated viruses (AAV). These successes were possible due to the identification of specific disease targets for which natural variants of AAV were sufficient. However, vectors face a number of barriers and shortcomings that preclude their extension to most human diseases, including limited delivery efficiency to target cells, pre-existing antibodies against AAVs, suboptimal biodistribution, limited spread within tissues, and/or an inability to target delivery to specific cells. These barriers are not surprising, since the parent viruses upon which vectors are based were not evolved by nature for our convenience to use as human therapeutics.
David Schaffer,
University of California, Berkeley
Unfortunately, for most applications, there is insufficient mechanistic knowledge of underlying virus structure-function relationships to empower rational design improvements. As an alternative, for over two decades we have been implementing directed evolution – the iterative genetic diversification of the viral genome and functional selection for desired properties – to engineer highly optimized, next generation AAV variants for efficient and targeted delivery to any cell or tissue target. We have genetically diversified AAV using a broad range of approaches from fully random (e.g. error prone PCR) to computationally guided (e.g. by machine learning). The resulting large (~109) libraries are then functionally selected for substantially enhanced delivery, yielding AAVs capable of highly efficient therapeutic gene delivery. Our variants have been effective in both animal models and in >10 human clinical trials to date, and results from both will be discussed.
David Schaffer is the Hubbard Howe Professor of Chemical and Biomolecular Engineering, Bioengineering, and Molecular and Cell Biology at the University of California, Berkeley, and he also serves as the executive director of QB3 and the director of the Bakar Labs and Bakar Fellows Program. He completed his B.S. in chemical engineering at Stanford University in 1993, his Ph.D. in chemical engineering at MIT in 1998, and a postdoctoral fellowship at the Salk Institute for Biological Studies in 1999 before joining Berkeley in 1999. There, he applies engineering principles to optimize gene and stem cell therapies, work that includes developing the concept of applying directed evolution to engineer targeted and efficient viral gene therapy vectors as well as new technologies to investigate and control stem cell function.
He has published >250 papers, has advised >100 graduate students and postdoctoral fellows, is an inventor on >50 issued patents, and developed technologies that are being used in >10 human clinical trials. In addition, he has co-founded seven companies from his lab, including 4D Molecular Therapeutics (NASDAQ FDMT), Ignite Immunotherapies (acquired by Pfizer) and Rewrite (acquired by Intellia).
Finally, he has received recognitions including the National Academy of Engineering, National Academy of Inventors, Daniel I.C. Wong Award for Excellence in Biochemical Engineering, Andreas Acrivos Professional Progress Award, the American Institute of Chemical Engineers Pharmaceutical and Bioengineering Award, the American Chemical Society Marvin Johnson Award, the Biomedical Engineering Society Rita Shaffer Young Investigator Award, and others.