Abstract
Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients.
Highlights
IntroductionFarber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase (human AC, murine Ac) deficiency [1]
Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation
Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease
Summary
Farber disease (FD) is a rare lysosomal storage disorder resulting from acid ceramidase (human AC, murine Ac) deficiency [1]. AC deficiency in FD results in an accumulation of lysosomal ceramide [4], which is considered the cause of the disease. FD clinically presents with a triad of deformed joints, subcutaneous nodules, and progressive hoarseness [5]. It can resemble juvenile idiopathic arthritis in infancy, which is why a number of FD patients are misdiagnosed at first [6,7,8]. Subtypes I and IV include severely affected patients who rarely survive past two years of age and exhibit lung involvement (type I and IV), neurological deficits (type I) and hepatosplenomegaly (type IV). The pathophysiology is still poorly understood, in part owing to the very low incidence rate
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