Researchers discover genes that could explain the Browning ability of white fat
Dr. Vandenberghe says delivering AAV genetic therapies to a cell is like crossing a ravine using monkey bars on a jungle gym. Each bar is a cellular factor that the AAV relies on to eventually make it into the nucleus of the cell. Notably, a few years ago, researchers from Stanford identified one important crossbar in a highly conserved AAV entry receptor called AAVR.
"Our new study identifies a second necessary cellular co-factor that might enable us to better design these vectors for specific purposes," said Dr. Vandenberghe. Findings May Propel Genetic Therapy Field Forward
In the current study, researchers used a genome-wide CRISPR screening tool to look at 100,000 genes and determine which cells played a role in AAV targeting. They identified GPR108 as a highly conserved entry factor that was required for entry of all AAV variants tested except for one, the highly divergent AAV5. GPR108 was shown to be critical for most AAVs that are currently being studied clinically, including AAVs used in the two FDA-approved gene therapies.
These findings were found in both in vitro and in vivo mouse models, further providing a mechanistic understanding to help explain and predict how AAV gene therapies target tissues and cells, said lead study author Amanda M. Dudek, PhD, who completed this research at Mass. Eye and Ear and is now a postdoctoral researcher at Stanford University.
"Our study shines some light on the mechanistic role of GPR108 in AAV entry. With this knowledge, scientists can further increase their understanding of AAV gene therapy safety, gene targeting and other properties of this novel class of drugs," said Dudek.
Dr. Vandenberghe's team plans to further study this mechanism and the biology of AAVs with the hope of optimizing these vectors for therapies. Their team is working on developing vectors that target specific genetic eye diseases, such as retinitis pigmentosa and Usher syndrome.
Gene-based therapies for eye diseases are a major focus of our research mission at Massachusetts Eye and Ear, where our goal is to end blindness. This latest work by Dr. Vandenberghe and colleagues is a major breakthrough in our understanding of viral vectors, and will guide further development of this promising class of AAV therapies. Joan W. Miller, MD, Chief of Ophthalmology at Massachusetts Eye and Ear and Massachusetts General Hospital and Chair of Ophthalmology and David Glendenning Cogan Professor of Ophthalmology at Harvard Medical School Source: Journal reference:
Dudek, A. M. et al . (2020) GPR108 Is a Highly Conserved AAV Entry Factor. Molecular Therapy . doi.org/10.1016/j.ymthe.2019.11.005
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