This proposal studies two fatal, neurological lysosomal storage diseases, Type A/B and Type C Niemann-Pick disease (NPA/B and NPC, respectively). NPA/B is due to an inherited deficiency of the enzyme acid sphingomyelinase (ASM), leading to the accumulation of the sphingolipid, sphingomyelin (SPM), in cells and tissues of affected patients. In contrast, ~95% of patients with NPC have a defect in the cholesterol transport protein, NPC1, leading to a primary defect in cholesterol storage. Despite their distinct genetic and protein defects, the pathological and clinical presentation of NPA/B and NPC overlap. For example, ~50% of NPA/B patients and all patients with NPC suffer from debilitating and life-threatening central nervous system (CNS) complications, and no effective therapies exist. To address this important unmet medical need, in preliminary studies we have generated a range of data supporting the use of a novel endocannabinoid (ECB)-based treatment for these disorders. For example, we have found that inhibitors of the enzyme fatty acid amide hydrolase (FAAH), which elevate several ECBs, significantly lowered SPM in cultured neurons and tissues of Type A/B NPD mice, leading to CNS improvements and extension of lifespan. We also found a significant down-regulation of the type-1 cannabinoid receptor (CB1R) expression on the surface of neurons from these mice and in brain tissue from a patient with NPA, due to entrapment of the receptor within the lysosome. This abnormality was corrected by FAAH inhibition. Similarly, treatment of NPC mouse neurons with FAAH inhibitors led to a reduction of both SPM and cholesterol, and there was a down-regulation of CB1R expression on the surface of these cells as well. Based on these preliminary findings, we propose that FAAH inhibition could be a novel and highly effective treatment for the CNS disease in both NPA/B and NPC, and that repurposing existing FAAH inhibitors that cross the blood brain barrier might be rapidly translatable to patients. To pursue this goal and further understand the relatedness of these disorders, three specific aims are proposed: 1) Characterize the molecular mechanism(s) underpinning the protective effects of FAAH inhibition in NPA/B cells and mice; 2) Investigate the function of the ECB system in NPC, and further explore FAAH inhibition as a potential treatment for this disease, and; 3) Use system biology and multi-omic approaches to compare the pathways and networks impacted in NPA/B and NPC, and to obtain a global picture of the molecular changes resulting from FAAH inhibition. We also hope to provide further insights regarding the relatedness of these ultra rare diseases to common neurologic diseases with which they share significant CNS pathology, including Alzheimer's and Parkinson's disease.