# Endocannabinoid-Based Treatment for the Neurologic Niemann-Pick Diseases

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2022 · $540,046

## Abstract

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.

## Key facts

- **NIH application ID:** 10499992
- **Project number:** 1R01HD109312-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** EDWARD H. SCHUCHMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $540,046
- **Award type:** 1
- **Project period:** 2022-09-09 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499992

## Citation

> US National Institutes of Health, RePORTER application 10499992, Endocannabinoid-Based Treatment for the Neurologic Niemann-Pick Diseases (1R01HD109312-01). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10499992. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*