7T MRI predicts amelioration of neurodegeneration in the brain after AAV gene therapy

Abstract GM1 gangliosidosis is a fatal neurodegenerative lysosomal storage disease that occurs most commonly in young children, with no effective treatment available. Long-term follow up of GM1 cats treated by bilateral thalamic and deep cerebellar nuclei injection of AAV mediated gene therapy has increased lifespan to 8 years of age, compared to an untreated lifespan of ∼8 months. Due to risks associated with cerebellar injection in humans, the lateral ventricle was tested as a replacement route to deliver an AAVrh8 vector expressing feline β-galactosidase (β-gal), the defective enzyme in GM1 gangliosidosis. Treatment via the thalamus and lateral ventricle corrected storage, myelination, astrogliosis and neuronal morphology in areas where β-gal was effectively delivered. Oligodendrocyte number increased, but only in areas where myelination was corrected. Reduced AAV and β-gal distribution were noted in the cerebellum with subsequent increases in storage, demyelination, astrogliosis and neuronal degeneration. These postmortem findings were correlated with endpoint MRI and MR spectroscopy. Compared to the moderate dose with which most cats were treated, a higher AAV dose produced superior survival, currently 6.5 years. Thus, MRI and MRS can predict therapeutic efficacy of AAV gene therapy and non-invasively monitor cellular events within the GM1 brain.