Gene therapy for G_M1 gangliosidosis: challenges of translational medicine

G_M1 gangliosidosis is an autosomal recessive lysosomal storage disorder with an estimated incidence of between 1 in 100,000 and 1 in 200,000 (1). Clinical features are predominantly those of a neurodegenerative disorder due to G_M1 ganglioside deposition in the central nervous system (CNS). Other clinical features include hepatosplenomegaly, coarse facial features and skeletal dysostosis. The underlying biochemical abnormality is a deficiency of β-galactosidase whose level of activity is inversely proportional to disease severity. While the disease is relatively heterogeneous three clinical subtypes are recognised. In the severe infantile form enzyme activity may be 0.07-1.3% of normal and clinical signs emerge between birth and 6 months of age. The clinical signs are a combination of a neurolipidosis (i.e., neurodegeneration and macular cherry-red spots) and a mucopolysaccharidosis (i.e., organomegaly, dysostosis and coarse facial features). The infantile form is characterised by a rapidly progressive course with severe CNS degeneration and death by 1-2 years of age commonly due to aspiration pneumonia or cardiomyopathy. The juvenile form is associated with enzyme activity in the order of 0.3-4.8% of normal and presents between 7 months and 3 years of age. It is characterised by psychomotor retardation with the other features of the infantile form being present in variable degrees. Disease progression is slower than the infantile form and death typically occurs before the second decade of life. The adult form occurs in those with an enzyme activity in the region of 5-10% of normal and is characterised by normal early neurological development with symptom onset between 3-30 years of age. Characteristic features are of a slowly progressive dementia, parkinsonism and dystonia. There is marked phenotypic variability in the adult form and the age of death varies widely. The diagnosis can be made by measuring β-galactosidase activity in peripheral blood leucocytes or by β-galactosidase gene (GLB1) molecular testing. Over 100 mutations have been reported in GLB1 (1) and there is no clear correlation between genotype and phenotype.