GM2 gangliosidosis future treatments 2

Published on June 29, 2017   19 min

Other Talks in the Series: Protein Epidemiology

Hello, my name is Brian Mark. I'm an associate professor of microbiology at the University Manitoba. This is the second half of a talk on the Future Treatments for GM2 Gangliosidosis.
For the remainder of my talk, I'm now going to describe recent research that has exploited the features of self-complementary adeno-associated virus 9 and its variant AAV 9.47 to correct both Sandhoff and Tay-Sachs disease in most models. The following lists key challenges that one faces when attempting to deliver HexA using self-complementary adeno-associated virus. The heterodimeric nature of HexA makes gene delivery challenging since the amount of DNA that is needed to encode both the Alpha and Beta subunit of HexA are about 1600 and 1700 base pairs respectively. The two genes, together, thus exceeds the packaging capacity of self-complementary adeno-associated virus. Not to mention the additional DNA that is needed to encode the promoter and enhancer elements that provide robust gene expression. Packaging only a deficient subunit into self-complementary adeno-associated virus would limit the level of HexA to the endogenous partnering subunit which would reduce the potential benefit of cross-correction. Over expression of fully recombinant HexA would maximize secretion and cross-correction thus both subunits should be packaged into the delivery virus. Finally, co-administering two separate self-complementary adeno-associated viral vectors and coding HexA and HexB would reduce transduction efficiency since cells would need to be transduced with both viruses in order to express fully recombinant HexA. The solution to the limited size of the transgene that can be packaged into