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Titel: Acid Sphingomyelinase Deficiency Ameliorates Farber Disease
VerfasserIn: Beckmann, Nadine
Becker, Katrin Anne
Kadow, Stephanie
Schumacher, Fabian
Kramer, Melanie
Kühn, Claudine
Schulz-Schaeffer, Walter J.
Edwards, Michael J.
Kleuser, Burkhard
Gulbins, Erich
Carpinteiro, Alexander
Sprache: Englisch
Titel: International Journal of Molecular Sciences
Bandnummer: 20
Heft: 24
Verlag/Plattform: MDPI
Erscheinungsjahr: 2019
Freie Schlagwörter: Farber disease
lysosomal storage disorders
acid ceramidase
acid sphingomyelinase
amitriptyline
DDC-Sachgruppe: 610 Medizin, Gesundheit
Dokumenttyp: Journalartikel / Zeitschriftenartikel
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.
DOI der Erstveröffentlichung: 10.3390/ijms20246253
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-301123
hdl:20.500.11880/30190
http://dx.doi.org/10.22028/D291-30112
ISSN: 1422-0067
Datum des Eintrags: 11-Dez-2020
Bezeichnung des in Beziehung stehenden Objekts: Supplementary Materials
In Beziehung stehendes Objekt: http://www.mdpi.com/1422-0067/20/24/6253/s1
Fakultät: M - Medizinische Fakultät
Fachrichtung: M - Medizinische und Klinische Psychologie
Professur: M - Prof. Dr. Walter Schulz-Schaeffer
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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