Research ArticleGene Therapy

Sustained Normalization of Neurological Disease after Intracranial Gene Therapy in a Feline Model

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Science Translational Medicine  09 Apr 2014:
Vol. 6, Issue 231, pp. 231ra48
DOI: 10.1126/scitranslmed.3007733

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Gene Therapy for a Lysosomal Storage Disease

GM1 gangliosidosis results from defects in the lysosomal enzyme β-galactosidase (β-gal) and subsequent accumulation of GM1 ganglioside, which causes neurodegeneration and premature death. Although no effective treatment exists, encouraging gene therapy data from the GM1 mouse model warranted an evaluation of the feasibility for human clinical application in a large animal model. In a new study, McCurdy et al. injected an adeno-associated viral vector encoding feline β-gal bilaterally into two brain targets (thalamus and deep cerebellar nuclei) of cats with GM1 gangliosidosis. Sixteen weeks after injection, β-gal activity and GM1 storage were normalized throughout the central nervous system of the animals, with accompanying increases in enzyme activity in cerebrospinal fluid and liver. In long-term studies, the mean survival of 12 treated cats with GM1 gangliosidosis was >38 months, compared to 8 months for untreated cats. A minority of cats that progressed to the humane endpoint had low β-gal activity in the spinal cord, yet still lived >2.5 times longer than untreated animals. Most of the treated GM1 cats demonstrated subtle or no gait abnormalities, and magnetic resonance imaging showed normalization of brain architecture up to at least 32 months of age. Long-term correction of the disease phenotype in cats with GM1 gangliosidosis suggests that gene therapy may be useful for treating the human disorder.