Niemann-Pick type C disease (NPC) is an autosomal recessive lysosomal storage disease occurring in 1 out of 89,000 individuals, with no available FDA approved treatment. Our long-term goal is to identify safe and effective therapeutics for NPC patients. In this application, we begin to develop a therapeutic strategy based on synthetic high-density lipoprotein (sHDL) nanoparticles capable of removing stored cholesterol from NPC mutant cells, since this is a unifying and key pathologic feature of disease. These sHDL nanoparticles have already been translated to the clinic for treatment of cardiovascular disease and were found to be safe at doses up to 100 mg/kg. The objective of this application is to select the best nanoparticles for cholesterol removal from NPC mutant cells and to improve brain-targeting ability. The selected nanoparticles will be tested in vivo in an established mouse model of NPC (Npc1 I1061T mice). This work builds upon our strong preliminary data showing that treatment of primary fibroblasts isolated from NPC patients with sHDL results in a significant and robust reversal of lipid storage. Moreover, we have found that the dose-dependent rescue of cholesterol storage is sensitive to the lipid and peptide composition of sHDL nanoparticles, enabling us to identify compounds with a range of therapeutic potency. We also found that sHDL nanoparticles are capable of removing excess cholesterol from neurons in cerebellar slice cultures from Npc1 I1061T mice. The sHDL nanoparticles were found in the brain after systemic administration and distributed throughout brain tissues after intracranial doses. In vivo testing will be conducted in an existing mouse model for which there are established, quantifiable behavioral, biochemical and pathologic endpoints. Preliminary studies demonstrate that sHDL administration to these mice results in target engagement and rescues of peripheral phenotypes. We now seek strategies to enhance the rescue of central nervous system (CNS) disease. This project will be completed by a unique, multidisciplinary team of scientists with complementary expertise in sHDL discovery and development (Schwendeman), and lysosomal diseases and neuropathology (Lieberman). To accomplish our goals, we will optimize sHDL cholesterol efflux capacity and blood brain barrier penetration in vitro, and test for improvement in cholesterol mobilization and brain accumulation of selected sHDL in vivo (Aim 1). Additionally, we will determine the extent to which sHDL nanoparticles rescue disease in Npc1 I1061T mice (Aim 2). We expect that these studies will allow for selection of brain-targeted sHDL for further testing in larger animal models of NPC and potentially for clinical translation.
Synthetic high-density lipoprotein nanoparticles will be optimized to treat Niemann-Pick Type C disease. Cholesterol removal from cells, brain targeting and abilities of nanoparticles to reverse disease symptoms, delay the onset of the disease and prolong survival will be evaluated.