GM2 Gangliosidosis
https://www.nature.com/articles/s41591-025-03822-4#Sec11
Tay–Sachs and Sandhoff diseases are devastating childhood brain disorders caused by a lack of an enzyme called hexosaminidase A (HexA). Without HexA, fatty molecules called GM2 gangliosides build up in the brain and spinal cord, leading to progressive loss of movement, feeding difficulties, seizures, and early death. Currently, there are no effective treatments. This study tested a new gene therapy that uses two specially engineered viruses (rAAVrh8 vectors) to deliver working copies of the HEXA and HEXB genes into brain cells. These genes produce the two protein parts that together form the HexA enzyme. By restoring HexA, the therapy aims to clear GM2 and slow the disease. Nine children with Tay–Sachs or Sandhoff disease (six infantile, three juvenile) were treated in this early-phase clinical trial. The treatment was given directly into the thalamus and into the fluid surrounding the brain and spinal cord. Results showed encouraging signs: enzyme activity increased, GM2 levels fell, and brain scans suggested new nerve connections were forming. Infantile patients experienced slower disease progression, were able to keep feeding by mouth for longer, and had fewer or less severe seizures. However, the therapy was less safe in older, juvenile patients, who developed worsening movement problems, leading researchers to continue the trial only in infants. While effects peaked around three months and then declined, the study shows that gene therapy can alter the course of GM2 diseases. These findings provide hope and valuable insights for designing future treatments.