361. IV Gene Therapy Corrects Feline GM1 Gangliosidosis Long Term

Abstract

GM1 gangliosidosis is a fatal neurodegenerative disease that affects all ages. Intracranial injection of adeno-associated viral (AAV) gene therapy has resulted in a >6 fold increase in lifespan. While untreated GM1 cats live to 8.0±0.6 months, many treated cats are still alive at 5-6 years of age (Sci Transl Med 2014. 6, 231). To bypass the invasiveness of brain injection, AAV9 at 1.5e13 vg/kg was injected into the cephalic vein in two GM1 cats at one month of age. Currently over 2 years of age (Fig. 1AFig. 1A), IV treated cats have been followed with biomarkers derived from blood, urine, cerebrospinal fluid (CSF), electrodiagnostics, abdominal ultrasound, 7T magnetic resonance imaging (MRI), and MR spectroscopy. Neurologic abnormalities are limited to mild hindlimb muscle atrophy and fine ear tremors, with remarkable preservation of brain architecture (Fig. 1BFig. 1B). Evaluation of CSF showed complete normalization (p<0.05) of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) compared to untreated GM1 cats (Fig 1. CFig 1. C). The defective lysosomal enzyme, β-galactosidase, was increased to ~15 fold normal levels in CSF (Fig. 1DFig. 1D). MR spectroscopy revealed correction of brain metabolites associated with microgliosis (myoinositol; Ins), neuroaxonal loss (N-acetylaspartate; NAA) and demyelination (glycerophosphocholine and phosphocholine; GPC+PCh) (Fig. 1EFig. 1E), and metabolite levels correlated with clinical signs (R2 = 0.66, 0.50 and 0.63, respectively). No evidence of tumorigenesis or peripheral toxicity has been noted. Intravenous administration of AAV gene therapy shows promise as an alternative for intracranial administration, although further experiments are required to determine maximum survival.Figure 1Effect of IV gene therapy in the GM1 cat. A) Survival curve of GM1+AAV cats. B) 7T T2 weighted MRI of normal, GM1 and GM1+AAV treated cats. C) CSF levels of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH). D) CSF levels of the therepeutic enzyme β-galactosidease (β-gal). D) MR spectroscopy of the feline brain * p<0.05 and **p<0.01 from normal; l p<0.05 and l p<0.01 from GM1 cats.View Large Image | Download PowerPoint Slide