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Directed evolution of AAV delivery systems for clinical gene therapy

Published on July 31, 2023   44 min

A selection of talks on Immunology & Inflammation

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0:00
Hi, I'm David Schaffer. I'm a professor of chemical and biomolecular engineering, bioengineering, and molecular and cell biology at the University of California at Berkeley, where I also serve as the director of two institutes, QB3 as well as Bakar Labs. Today, it's my pleasure to be sharing with you some of our work and perspectives in the directed evolution of AAV delivery systems for clinical gene therapy.
0:24
I'd like to start with what really motivates us and gets us out of bed every morning, which is that regardless of which tissue you look at in the human body, there are very, unfortunately, long-term chronic degenerative disorders that kill off particular populations of cells, gradually undermine the function of those tissues, and rob patients their quality of life. Using the central nervous system as an example, there are a couple of different categories of diseases. There are monogenic disorders, where you can sequence a specific gene in the genome to find the mutation that's responsible for a given disease, and that includes lysosomal storage diseases, as well as Huntington's. In addition, there more complex idiopathic disorders, such as Alzheimer's and Parkinson's, that are due to a combination of genetics, as well as experience and environment. Regardless, however, the underlying cause, we really need to identify novel therapeutics to be able to spare the life as well as quality of life of patients suffering from these conditions.
1:18
To do so, we feel it's useful to roll all the way back to a very basic tenet of biology, specifically the central dogma that holds that information is stored at the level of DNA, transcribed into RNA and translated into protein. RNA and protein make up the functional arms of biology, and information, of course, is stored at DNA.
1:40
For us, each one of these levels of information represents a potential drug target. The majority of pharmaceuticals used in the clinic these days target at the level of proteins, where small molecules float around to find a hydrophobic collapse within an enzyme typically, and inhibit or modify the activity of that molecule. By contrast, monoclonal antibodies float around on the outside of cells and again, typically, bind to a protein and inhibit its function. It's also possible to drug at the level of RNA. There are several FDA-approved RNA interference drugs, which degrade specific messages. Antisense drugs are also approved. And finally, of course, we know very well from Pfizer and Moderna that messenger RNA itself can be a therapeutic modality. My career really revolves at the level of drugging DNA as a molecule. If you're adding a new gene to a genome, that's gene therapy. If you're changing the sequence of an existing gene, that's a genome edit. Finally, if you're adding an entirely new genome to a tissue, that's cell therapy. What's potentially promising and transformative about drugging at the level of DNA is that, unlike small molecules and proteins, DNA can become a permanent part of an organ or a tissue, so you can think about one and done. Single administration, long-term therapeutic benefit.

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Directed evolution of AAV delivery systems for clinical gene therapy

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