hyperfunctional β-galactosidase gene therapy

hyperfunctional β-galactosidase gene therapy is an experimental hematopoietic stem cell gene therapy (HSC-GT) designed for the treatment of GM1 gangliosidosis, a lethal lysosomal storage disease caused by deficiency of the β-galactosidase (β-gal) enzyme. The therapy utilizes a self-inactivating (SIN) lentiviral vector to transduce autologous hematopoietic stem and progenitor cells (HSPCs) with a codon-optimized, hyperfunctional variant of the human GLB1 gene. This engineered enzyme variant is modeled after the murine isoform to achieve significantly higher enzymatic activity (approximately 6-fold higher than wild-type human β-gal) while maintaining physiological protein-protein interactions in human cells. The approach aims to achieve metabolic cross-correction of the central nervous system through the infiltration of gene-modified, donor-derived myeloid and microglial cells that act as a local source of the therapeutic enzyme, thereby reducing lysosomal storage and neuroinflammation.