Powered by synthetic biology, Pierce Ogden makes ALL possible mutations to an adeno-associated virus (AAV) outer shell and rapidly screens them to dissect their attributes. Pierce discusses the technological advances that make this breakthrough screen possible and the novel properties that were discovered. AAVs are rapidly becoming the prefered way to perform gene therapy, correcting cells that carry disease-causing mutations through genetic modification. This technology forms the basis for company Dyno Therapeutics.

About the Author

• Pierce performed this work as a postdoc at Harvard University in the lab of Professor George Church. Professor Church is one of the founding fathers of synthetic biology and the lab is renowned for developing high throughput methods to design, build, and test bioengineered parts.
• In his role as Co-Founder & CSO at Manifold Bio, Pierce utilizes his multiplexing expertise to uncover the design principles of protein therapeutics and make new drugs faster than ever before.

Key Takeaways

• Gene therapy uses genetic information as a drug, correcting cells that carry disease-causing mutations.
• The inability to deliver these genes to the correct cells limits the widespread adoption of gene therapy.
• Adeno-associated viruses (AAVs) are an extremely promising way to deliver DNA to human cells. Their outer shell, or capsid, can be engineered for increased safety, specificity, and shelf-life.
• Using advances in DNA synthesis technology, all possible single mutations to the AAV capsid are generated.
• With a DNA barcode read through next generation sequencing, this AAV library was simultaneously tested cheaply and quickly to find mutations with improved properties.
• Increased thermal stability, evasion of immune responses, and specificity toward the brain were all found. 

Translation

• Pierce demonstrates that smart usage of our synthetic biology toolbox can allow millions of protein variants to be tested simultaneously, in direct opposition to the “tested in parallel” model that has dominated high-throughput biology.
• Manifold Bio takes this idea of DNA barcodes coupled with simultaneous screening and points it toward the field of protein therapeutics.

First Author: Pierce Ogden

Paper: Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design. Science, 2020.

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