Lentiviral hematopoietic stem cell gene therapy ameliorates GM1-gangliosidosis in mice.

Lysosomal storage diseases (LSDs) are >70 devasting diseases causing progressive neurodegeneration and systemic symptoms. Hematopoietic stem cell (HSC) gene therapy (GT), i.e., the autologous transplantation of genetically corrected HSCs by lentiviral transduction, has shown transformative efficacy in multiple neurodegenerative LSDs so far. We developed a translational HSC GT approach for GM1-gangliosidosis, a neurodegenerative LSD due to β-galactosidase (β-gal) deficiency, based on a lentiviral vector expressing either the human or the murine therapeutic enzyme. Cells were administered by a standard intravenous injection, or by an innovative, combined systemic and local cell delivery to enhance the GT efficacy. In the murine model of the disease, GT broadly restored enzymatic activity and reduced the lysosomal storage in the brain, ameliorated the neuromuscular phenotype, and increased animal survival. Combined cell-delivery GT with the human enzyme, or standard intravenous GT with the murine β-gal were similarly effective in mitigating disease phenotype, indicating a substantial therapeutic potential of the approach for a future clinical translation.