Intrathecal Delivery of a Human Bicistronic Hexosaminidase Vector to Correct Sandhoff Disease in a Murine Model: A Dose-Response Study

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Ryckman, Alex
GM2 Gangliosidosis , Sandhoff disease , Tay Sachs disease , Gene therapy , AAV , Viral Vector
GM2 gangliosidosis is a group of lysosomal storage disorders including Tay-Sachs disease (TSD), Sandhoff disease (SD), and the AB variant of GM2 gangliosidosis. TSD and SD are characterized by reduced or absent levels of the hydrolase β-hexosaminidase A (Hex A). Normally, the heterodimer Hex A hydrolyzes GM2 ganglioside into GM3, however if Hex A activity drops below the threshold of 10-15%, GM2 pathologically accumulates within the central nervous system. This is caused by mutation to either the gene HEXA or HEXB, which encode the α- and β-subunit of Hex A, respectively. As such, afflicted individuals experience rapid neurological decline resulting in death by 4 years of age in infantile cases. Currently, there have been no approved treatments capable of slowing or stopping disease progression in GM2 gangliosidosis and thus clinicians must rely on symptom management for treatment. Recently, a novel bicistronic gene therapy carrying both HEXA and HEXB, has illustrated promising results in mouse models of SD. Treated mice experienced significant reduction in GM2 storage, increased levels of Hex A, and marked improvement of their behavioral phenotype including doubling their lifespan, as compared with controls. Overall, the bicistronic vector provided long-term correction of SD in these mice. The current study aims to identify an optimal dosage of the bicistronic gene therapy vector for translation into the clinic. Three dosages of the bicistronic vector have been analyzed: high-dose (2.5e11vector genomes/mouse), medium-dose (1.25e11vg/mouse), and low-dose (0.625e11vg/mouse). The overall data suggests the high-dose performed the best, where the high-dose mice lived to an average of 53.6 weeks of age, more than 3x their lifespan as compared to SD controls. These results may have direct implications in deciding a human equivalent dose in a clinical trial for GM2 gangliosidosis.
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