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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.
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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
