605. Cerebrospinal Fluid for Delivery of AAV Gene Therapy in GM1 Gangliosidosis

Abstract

GM1 gangliosidosis, a hereditary lysosomal storage disease caused by a deficiency of lysosomal β-galactosidase, is characterized by rapidly progressing and fatal neurologic disease. The most common form of GM1 affects children and is fatal by approximately 4 years of age. Currently, there is no effective treatment for GM1 gangliosidosis beyond palliative or supportive care. There are several naturally occurring models of GM1 gangliosidosis, including a well-characterized feline model that closely reproduces human disease progression and facilitates testing of experimental therapies for clinical application. Adeno-associated viral (AAV) therapy has proven effective in GM1 cats, with a greater than 6 fold increase in lifespan after thalamic and deep cerebellar nuclei injections. Prior to initiation of human clinical trials, CSF delivery was evaluated to circumvent the risk of cerebellar parenchymal injection and to improve cortical biodistribution. AAVrh10 was delivered at a total dose of 1e12 vector genomes/kg body weight via 3 routes: cisterna magna (CM), bilateral intracerebroventricular (ICV), or lumbar cistern (LC). Cats were followed for 4 weeks post injection, after which biodistribution of enzyme and vector were assessed. After LC injection, enzyme was limited to the spinal cord, where it reached a maximum of 0.7 fold normal. As expected, the highest vector concentration was limited to the lumbar spinal cord. This indicates limited cranial flow of vector from the lumbar cistern of injected cats, minimizing the efficacy of lumbar delivery. Delivery by the CM led to 0.4 fold - 1.5 fold normal levels of enzyme activity in the spinal cord and up to 2.1 fold the cerebellum and thalamic regions. Following CM injection, vector distributed well to the caudal region of the cerebrum, all of the cerebellum, and throughout the spinal cord. Enzyme activity after ICV injections showed increases from 0.2 fold - 0.8 fold normal in the spinal cord and 0.1 fold - 0.5 fold in the brain. ICV injections led to vector distribution throughout the cerebrum as well as the spinal cord. CSF delivery via cisterna magna, ICV, or lumbar injection is substantially less invasive than cerebellar injection. Based on the results presented here, CM or ICV injection may prove beneficial in clinical trials. Additionally, combining cisterna magna and ICV injection of vector could further enhance therapeutic effect.View Large Image | Download PowerPoint Slide