In vivo gene therapy for Tay-Sachs and Sandhoff diseases by utilizing AAV9 vector encoding modified HEXB

Tay-Sachs disease (TSD) and Sandhoff disease (SD) are autosomal recessive GM2 gangliosidoses, caused by the gene mutations of HEXA and HEXB encoding the α and β-subunits of lysosomal β-hexosaminidase (Hex), respectively. These incurable diseases associate with the HexA (αβ heterodimer) deficiency and excessive accumulation of GM2 gangliosides (GM2) in brains of the patients and neurological manifestations. Although high incidence of TSD in Ashkenazy-Jewish populations is well known, there are 12 of Japanese TSD patients at present. We constructed an adeno-associated viral vector (AAV9/3-modHEXB) encoding the modified HEXB to produce the modified HexB composed of homodimeric β-subunits carrying 9 amino acid residues substituted to those of the α-type involving GM2 degradation. We demonstrated that the intracerebroventricular and intravenous administration of AAV9/3-modHEXB to SD model mice could restore the GM2-degrading activity, reduce the GM2 accumulated in the brains, repress the motor dysfunctions and prolong the life span. We also found that the neuronal cells induced from iPS cells derived from a TSD patient secreted the human active modHexB after treatment with AAV9/3-modHEXB, suggesting the “cross-correction” effect. From these findings, the in vivo gene therapy by utilizing AAV9/3-modHEXB will be expected as a novel low-antigenic treatment especially for TSD.