Endocannabinoid system enhancement for the treatment of sphingolipid storage disorders


The endocannabinoid system is composed of a class of unique lipidic mediators including 2-arachidonoyl glycerol (2-AG) and anandamide (N-arachidonoyl ethanolamine, AEA), the metabolic enzymes for their synthesis and degradation along with the two G protein-coupled cannabinoid receptors (CB1 and CB2). The system controls several aspects of the development and function of neurons, it also associated with synaptic communication in some pathophysiological events. In addition, the endocannabinoid system plays a significant role in anti-inflammatory, prohomeostatic and neuroprotective functions. These qualities have made researchers explore the therapeutic potential of endocannabinoid modulation in treating neurological disorders. Studies have shown that membrane lipids are relevant to endocannabinoid function, it is therefore important to understand their relation in details.

Acid sphingomyelinase deficiency (ASMD) is a neurological disorder that results in neurodegeneration, cellular accumulation of the sphingolipid sphingomyelin and early death. The infantile neurovisceral form of acid sphingomyelinase deficiency (ASMD also known as acute neuronopathic ASMD or Niemann–Pick type A) is fatal. Various studies have been conducted to identify therapeutic approaches that are beneficial for patients with this disorder; however, they have mostly been inadequate for the neuronopathic forms.

In a new research paper published in the Journal EMBO Molecular Medicine, Spanish scientists from the Centro Biologia Molecular Severo Ochoa (CSIC-UAM): Dr. Adrián Bartoll, Ana Toledano-Zaragoza and Dr. María Dolores Ledesma explored the therapeutic benefits of enhancing the endocannabinoid system in a mouse lacking the acid sphingomyelinase (ASM-KO) that mimics the neurovisceral form of ASMD. Their findings revealed a pathophysiological crosstalk between the endocannabinoid system and neuronal sphingomyelin and the therapeutic benefits of enhancing the endocannabinoid system in ASMD and other sphingolipid storage disorders such as Niemann Pick type C. The research was conducted in collaboration with Dr. Josefina Casas (IQAC-CSIC), Professor Manuel Guzmán (Complutense University) and Professor Edward Schuchman from the Icahn School of Medicine at Mount Sinai in the United State and supported by the patient association Wylder Nation Foundation.

CB1 and CB2 receptors mediate endocannabinoid signaling in the mammalian brain. Therefore, the authors first characterized the CB1 receptor anomalies in the brains of an infantile neurovisceral ASMD patient and ASM-KO mice with a focus on the analysis of the cerebellum, because it is the most affected brain area in the disease. The levels of CB2 mRNA and protein were unchanged between ASM-KO mice and the wild type littermates. In contrast, there was a reduction in the mRNA and protein levels of CB1 in the cerebellum and other brain areas of the ASM-KO mice compared to wild type littermates. CB1 protein reduction was also observed in neurons of an ASMD-affected patient.

The research team found that a reduction in the expression of CB1 in ASM-KO neurons correlated with elevated levels of sphingomyelin and an increase in the delivery of CB1 to lysosomes, leading to its degradation. They also noticed that sphingomyelin levels in cultured ASM-KO neurons were reduced by enhancing endocannabinoid signaling. CB1 activation via the inhibition of the endocannabinoid -degrading enzyme fatty acid amide hydrolase in ASM-KO neurons led to the activation of neutral sphingomyelinase and degradation of sphingomyelin without any associated cell toxicity.

It was interesting to notice that chronic oral treatment with a fatty acid amide hydrolase inhibitor starting at early stages of the disease (6 weeks of age), improved the behavior of ASM-KO mice, increased neuronal survival, reduced brain sphingomyelin levels and inflammation and extended their lifespan. The authors also confirmed the safety profile for the treatment even in advanced stages of the disease in ASM-KO mice. The administration of fatty acid amide hydrolase inhibitor  was beneficial in cells and mice affected by Niemann–Pick disease type C (NPC), another sphingolipid storage disease, where CB1 receptor is also pathologically downregulated.

In nutshell, the authors showed for the first time the various impacts of the endocannabinoid system in neurovisceral ASMD and in NPC that can be viewed as both pathological and beneficial. Their findings provide further proof that endocannabinoid enhancing interventions are a suitable novel treatment option for fatal sphingolipid storage disorders.

Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling - Medicine Innovates
A. Neurons in ASMD and NPC accumulate sphingomyelin leading to reduced plasma membrane levels of the endocannabinoid receptor CB1 and its blockage and degradation in lysosomes. On the other hand, CB1 may activate the Neutral sphingomyelinase inducing sphingomyelin degradation.
B. Inhibition of the endocannabinoid-degrading enzyme FAAH in the context of ASMD and NPC increases endocannabinoid levels. This stimulates CB1 and sphingomyelin degradation through the neutral sphingomyelinase ameliorating the pathological phenotype.

About the author

Dr. Maria Dolores Ledesma is staff scientist of the Spanish Research Council and Group leader at the Centro Biologia Molecular Severo Ochoa (Madrid, Spain). Research interest in her laboratory is in the role of lipids in neuronal physiology and pathology. The study of this kind of molecules has been traditionally neglected due to lack of tools. Still, neuronal physiology heavily relies on membranes of which lipids are major components and lipid imbalances cause severe neurological diseases. Using mouse models in which the metabolism of cholesterol and sphingomyelin has been genetically altered, we want to understand the contribution of these abundant lipids to relevant cellular processes in neurons. These include synaptic function, calcium homeostasis or autophagy. To this aim we use biochemical, cell biology, electrophysiology and behaviour assays. These mice mimic fatal lysosomal storage disorders such as acid sphingomyelinase deficiency (ASMD) and Niemann Pick type C (NPC).

An important goal in Ledesma laboratory is dissecting the pathological mechanisms in these diseases and validating therapeutic strategies at the preclinical stage. This fosters the contact with clinicians and patient associations. One of them, The Wylder Nation Foundation, inspired and financed the study showing the involvement of the endocannabinoid system in the pathology and therapy of ASMD and NPC.

About the author

Dr. Edward H. Schuchman is the Genetic Disease Foundation-Francis Crick Professor of Genetics & Genomic Sciences at the Icahn School of Medicine at Mount Sinai. His research career has spanned over 30 years and is focused on the understanding the pathophysiology of lysosomal storage disorders and developing new treatments. Among his accomplishments, Dr. Schuchman’s laboratory was the first to isolate the gene encoding acid sphingomyelinase (ASM), the enzyme deficient in Types A and B Niemann-Pick disease, leading to the identification of the first mutations causing the disease, the first genotype/phenotype correlations and gene-based screening for the disorder, construction of the first mouse model and production of the first recombinant ASM, and development of the first enzyme replacement therapy for this disorder.

His laboratory also was the first to isolate the gene encoding acid ceramidase, the enzyme deficient in Farber disease, and he co-founded a company in 2013 to develop acid ceramidase-based therapies for this and other genetic diseases. This company was sold to a NY-based pharmaceutical company in 2016 for further clinical development. Among his other interests are the mucopolysaccharidoses (MPS), leading to the identification and evaluation of a repurposed drug for these disorders (pentosan polysulfate, PPS). PPS has successfully completed phase 1/2 clinical trials in MPS I and MPS II patients and is currently undergoing further clinical testing. Dr. Schuchman has been continuously funded by the NIH and other organizations for his work and is currently the recipient of a prestigious NIH MERIT award.

He has published over 250 peer-reviewed scientific articles and has authored over 50 book chapters. Over the years Dr. Schuchman has received numerous awards for his research, including the NY Intellectual Property Inventor of the Year (2013), Inventor of the Year at Mount Sinai (2019), and Election as a Distinguished Fellow to the National Academy of Inventors (2020). He serves on the Scientific Advisory Board for numerous organizations, including the Wylder Nation Foundation and National Niemann-Pick Disease Foundation (NNPDF), where a research fellowship is offered in his name.


Bartoll A, Toledano-Zaragoza A, Casas J, Guzmán M, Schuchman EH, Ledesma MD. Inhibition of fatty acid amide hydrolase prevents pathology in neurovisceral acid sphingomyelinase deficiency by rescuing defective endocannabinoid signaling. EMBO Mol Med. 2020 Nov 6;12(11):e11776.

Go To EMBO Mol Med