Therapeutic gene delivery is increasingly succeeding in clinical trials, and vehicles or vectors based on viruses offer the potential for safe and efficient gene transfer.
For example, the majority of the human population has been previously exposed to adeno-associated viruses (AAV), which are not associated with any disease. Vector nanoparticles based on AAV have shown positive results in clinical trials for hemophilia, Parkinson’s disease, and Leber’s congenital amaurosis.
Despite this promise, several challenges impede broader implementation of AAV gene therapy, including the pre-existing exposure and immunity to these human viruses, low gene delivery efficiency to a number of therapeutically relevant cell and tissue types, a lack of targeted delivery to specific cell types, and an inability to overcome physical and cellular barriers to gene transfer in vivo.
These challenges arise since the demands we place on AAV vectors are often different from or even at odds with the properties nature endowed to their parent viruses. In addition, there is insufficient mechanistic knowledge of virus structure-function relationships to empower rational design with the capacity to engineer improved properties.
We have therefore developed viral directed evolution – the iterative generation of large, diverse libraries of viral mutants and selection for variants with specific properties of interest – as a biomimetic approach to create new “designer” viruses that address these shortcomings. This approach has made strong progress in creating or “synthesizing” novel AAV variants with advantageous in vitro and in vivo gene delivery properties, as well as strong clinical potential.
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Prof. Schaffer is Director of the Berkeley Stem Cell Center
http://stemcellcenter.berkeley.edu/
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