Niemann-Pick disease type C1 (NPC1 disease) is a hereditary disorder characterized by the lysosomal storage of cholesterol and sphingolipids, and clinical signs of progressive cerebellar ataxia, dementia, vertical supranuclear gaze palsy, dysphagia, and early death. There are no FDA-approved therapies for NPC1 disease. Repeated intracisterna magna (IC) administration of 2-hydroxypropyl-beta-cyclodextrin (HPCD) in cats with NPC1 disease prevented the onset of cerebellar ataxia, prevented Purkinje cell death, normalized cerebellocortical and cerebrocortical cholesterol and gangliosides concentrations, and increased survival time. These preclinical data advanced IC HPCD into clinical trials where efficacy has been demonstrated. However, HPCD must be administered IC every two weeks for the duration of the patient?s life and results in progressive dose-limiting ototoxicity, highlighting a clear need for less invasive and safer therapies for these patients. We hypothesize that optimization of IC gene therapy using an AAV9 vector to deliver NPC1 to the brain will effectively prevent NPC1 disease-associated cerebellar ataxia and Purkinje cell pathology without repeated lifelong injections and without ototoxicity. We also hypothesize that intracarotid (IV) administration of a novel AAV serotype to cats can deliver NPC1 to the basal ganglia and brainstem, regions which are untreated by IC administration of HPCD or AAV9, and are responsible for dystonia, vertical supranuclear gaze palsy, and dysphagia. Therefore, in the proposed studies we will assess methods to optimize AAV9-mediated transduction of the greatest number of Purkinje cells (Aim 1), evaluate the efficacy of AAV9-NPC1 administration to treat clinical, biochemical, and histologic aspects of NPC1-associated cerebellar disease (Aim 2), and evaluate the efficacy of intracarotid AAV-NPC1 administration to treat extracerebellar regions responsible for dementia (cerebral cortex), dystonia (basal ganglia), and vertical supranuclear gaze palsy and dysphagia (brainstem) (Aim 3). These proof-of-concept studies will be the first to optimize the delivery of a non-diffusible membrane-bound protein to Purkinje cells, thereby advancing gene therapy for many other genetic diseases affecting Purkinje cells including spinocerebellar ataxias. Moreover, these studies will be the first to develop a one-time therapy for NPC1 disease that treats both cerebellar and extracerebellar disease and results in no ototoxicity.
Niemann-Pick disease type C1 (NPC1 disease) is a hereditary disorder characterized by the lysosomal storage of cholesterol and sphingolipids, and clinical signs of progressive cerebellar ataxia, dementia, vertical supranuclear gaze palsy, dysphagia, and early death. Despite the identification of causative mutations and a partial understanding of the function of the lysosomal membrane-bound NPC1 protein, there are no FDA- approved therapies for NPC1 disease. This study will be the first to develop gene therapy approaches that will allow widespread correction of NPC1-associated disease in the brain of a large animal model and will provide proof of concept for advancement of this strategy to the clinics.
