USH2020: Gene Therapy for Usher Syndrome Type 1F
July 10, 2020
David P. Corey, PhD, Harvard Medical School
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Usher syndrome type 1F is caused by mutations in the PCDH15 gene, which encodes the protocadherin-15 protein. Gene addition by means of viral vectors such as AAV has successfully treated hereditary sensory disorders in humans and in animal models, and might also be attractive for Usher 1F. However the capacity of AAV is limited to about 4700 letters of DNA, and the DNA that encodes PCDH15 is about 6000 letters. This talk describes an effort to engineer a smaller but still functional PCDH15 so that its DNA will fit in AAV. In a mouse model of Usher 1F, an AAV vector carrying DNA for this "mini-PCDH15" can almost completely prevent deafness. A mini-PCDH15 is also being tested in a zebrafish model of Usher 1F, to see if it can prevent blindness.
Dr. David Corey has studied proteins of the hair-cell mechanotransduction complex with methods ranging from single-cell electrophysiology to single-molecule force spectroscopy to biochemistry to cryo-EM. His laboratory is now focused on how mutations in some of these proteins lead to hereditary deafness, and how gene therapy can treat deafness. With Dr. Artur Indzhykulian (Massachusetts Eye and Ear), he has developed strategies for gene therapy for Usher syndrome 1F. With Dr. Casey Maquire (Massachusetts General Hospital), he has also developed more efficient viral vectors to deliver therapeutic genes to specific cell types in the cochlea.