13. Post-Symptomatic Intrathecal Infusion of AAV1 Results in Reversal of Storage Lesions Throughout the Brain in the Cat Model of Alpha-Mannnosidosis Leading To Clinical Improvement

Abstract

Lysosomal storage diseases (LSDs) are debilitating neurometabolic disorders for which long-term effective therapies have not been developed for most. A critical barrier to progress in the successful treatment of LSDs is an approach that will allow sustained delivery of the missing lysosomal enzyme to the brain in a quantity sufficient to prevent neuropathology. Intrathecal injection of AAVs has been shown to mediate transduction of neuronal and glial cells in the brain and spinal cord of large animals, and it has recently been reported that AAV9 infusion into the cerebrospinal fluid (CSF) of MPS I cats improves histopathological lesions, but no evidence of improvement in clinical signs were reported. We tested the efficacy of post-symptomatic intrathecal delivery of AAV1 to the brain via the cisterna magna in alpha-mannosidosis (AMD) affected cats. Lysosomal alpha-mannosidase (LAMAN) activity in the CSF was consistently above untreated AMD cat control values. The lifespan of the treated cats was significantly extended compared to untreated cats and the onset of clinical symptoms were delayed and reduced in severity. We have previously shown that magnetic resonance spectroscopy (MRS) detects a large peak of accumulated oligosaccharides in the AMD brain of live animals, and it was significantly decreased in the treated cat brains. Post-mortem histopathology showed resolution of lysosomal storage lesions in most regions of the brain, including the cerebral cortex, caudate nucleus, hippocampus, cerebellum and choroid plexus, and LAMAN enzymatic activity was above levels of untreated tissues. Our results demonstrate that a single intrathecal injection of AAV1 expressing feline alpha-mannosidase gene (fMANB) into the CSF was able to mediate widespread neuronal transduction of the brain and meaningful clinical improvement. Thus, intrathecal gene delivery by AAV1 appears to be a viable strategy for a long lasting treatment for the whole brain in AMD and, based on the widespread gene distribution, should be applicable to many of the neurotropic LSDs as well as other neurogenetic disorders.