TY  - GEN
A1  - Beckmann, Nadine
A1  - Becker, Katrin Anne
A1  - Kadow, Stephanie
A1  - Schumacher, Fabian
A1  - Kramer, Melanie
A1  - Kühn, Claudine
A1  - Schulz-Schaeffer, Walter J.
A1  - Edwards, Michael J.
A1  - Kleuser, Burkhard
A1  - Gulbins, Erich
A1  - Carpinteiro, Alexander
T1  - Acid sphingomyelinase deficiency ameliorates Farber disease
T2  - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe
N2  - 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
T3  - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 1087 
KW  - Farber disease
KW  - lysosomal storage disorders
KW  - acid ceramidase
KW  - acid sphingomyelinase
KW  - amitriptyline
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-441282
SN  - 1866-8372
IS  - 1087
ER  -