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Directed evolution of novel adeno-associated viral vectors for gene therapy

Published on August 5, 2014 Archived on July 31, 2023   52 min

A selection of talks on Ophthalmology

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0:00
This is David Schaffer. I'm a professor at the University of California at Berkeley in Chemical and Biomolecular Engineering, Bioengineering, and the Helen Wills Neuroscience Institute, as well as director of the Berkeley Stem Cell Center. In addition, I'm co-founder of the company, 4D Molecular Therapeutics. And I'm going to be talking about directed evolution of novel adeno-associated viral vectors for gene therapy.
0:23
So if we assess the current status of the field of gene therapy, which can be defined as the introduction or delivery of genetic material to the cells of an individual for therapeutic benefit. There have been a number-- an increasing number of successes over the past few years, and these include bona fide clinical successes for the treatment of Leber's congenital amaurosis, hemophilia B, as well as familial lipoprotein lipase deficiency and x-linked adrenoleukodystrophy. Now the first three indications I mentioned were made possible through adeno-associated viral vector technology, which has been increasingly successful as we mentioned over the past few years. Despite all of these successes however, a number of disease targets are still beyond the reach of current gene transfer technology. And that technology must be made better, which is the focus of my talk today.
1:09
So if we zoom into more detail next slide on adeno-associated virus, we see that this virus has a relatively simple genome. It simply contains two Cis elements-- the inverted terminal repeats that flank the genome. And the genome only has two genes that are open reading frames-- REP, which encodes several proteins, as well as CAP, which encodes three proteins, as well as a fourth protein and an alternative reading frame. Now this virus encodes as I mentioned several versions or several variants of the cap protein-- 60 copies of which will self assemble to create this beautiful icosahedral structure-- and the rep protein which is responsible for mediating the replication as well as of other functions of the viral genome will then load this capsid with it's viral genome payload for cargo. So this virus is non-pathogenic. It's never been associated with human disease. It's among the smallest of viruses both in terms of genome size at around 4.9 kilobases of information, as well as the dimensions of the particle-- around 25 nanometers in size. And a number of natural variants of the virus have been isolated, which typically have variations in the amino-acid sequence or identity on these exposed loop regions that you can see on the viral capsid structure.

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Directed evolution of novel adeno-associated viral vectors for gene therapy

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