Increased phosphorylation of HexM improves lysosomal uptake and potential for managing GM2 gangliosidoses.

ABSTRACT: Tay-Sachs and Sandhoff diseases are genetic disorders resulting from mutations in HEXA or HEXB, which code for the α- and β-subunits of the heterodimer β-hexosaminidase A (HexA), respectively. Loss of HexA activity results in the accumulation of GM2 ganglioside (GM2) in neuronal lysosomes, culminating in neurodegeneration and death, often by age 4. Previously, we combined critical features of the α- and β-subunits of HexA into a single subunit to create a homodimeric enzyme known as HexM. HexM is twice as active as HexA and degrades GM2 in vivo, making it a candidate for enzyme replacement therapy (ERT). Here we show HexM production is scalable to meet ERT requirements and we describe an approach that enhances its cellular uptake via co-expression with an engineered Gl

SUBMITTER: Benzie G 

PROVIDER: S-EPMC10074939 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature