{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:16:29Z","timestamp":1790691389262,"version":"4.1.0"},"reference-count":55,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2019,12,11]],"date-time":"2019-12-11T00:00:00Z","timestamp":1576022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["GU 335-35\/1"],"award-info":[{"award-number":["GU 335-35\/1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["GRK 2098"],"award-info":[{"award-number":["GRK 2098"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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\u2019t 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.<\/jats:p>","DOI":"10.3390\/ijms20246253","type":"journal-article","created":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T03:20:16Z","timestamp":1576120816000},"page":"6253","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Acid Sphingomyelinase Deficiency Ameliorates Farber Disease"],"prefix":"10.3390","volume":"20","author":[{"given":"Nadine","family":"Beckmann","sequence":"first","affiliation":[{"name":"Department of Molecular Biology, University of Duisburg-Essen, Hufelandstra\u00dfe 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6317-7298","authenticated-orcid":false,"given":"Katrin Anne","family":"Becker","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Duisburg-Essen, Hufelandstra\u00dfe 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6430-1230","authenticated-orcid":false,"given":"Stephanie","family":"Kadow","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Duisburg-Essen, Hufelandstra\u00dfe 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8703-3275","authenticated-orcid":false,"given":"Fabian","family":"Schumacher","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Duisburg-Essen, Hufelandstra\u00dfe 55, 45147 Essen, Germany"},{"name":"Department of Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Kramer","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Duisburg-Essen, Hufelandstra\u00dfe 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudine","family":"K\u00fchn","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Duisburg-Essen, Hufelandstra\u00dfe 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter J.","family":"Schulz-Schaeffer","sequence":"additional","affiliation":[{"name":"Insitute of Neuropathology, University of the Saarland, Kirrberger Str. 100, 66421 Homburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Edwards","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Cincinnati, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1888-9595","authenticated-orcid":false,"given":"Burkhard","family":"Kleuser","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erich","family":"Gulbins","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Duisburg-Essen, Hufelandstra\u00dfe 55, 45147 Essen, Germany"},{"name":"Department of Surgery, University of Cincinnati, 231 Albert Sabin Way, ML 0558, Cincinnati, OH 45229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Carpinteiro","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Duisburg-Essen, Hufelandstra\u00dfe 55, 45147 Essen, Germany"},{"name":"Department of Hematology, University Hospital Essen, Hufelandstra\u00dfe 55, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1126\/science.178.4065.1100","article-title":"Ceramidase Deficiency in Farber\u2019s Disease (Lipogranulomatosis)","volume":"178","author":"Sugita","year":"1972","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.jbior.2016.10.002","article-title":"Ceramidases, Roles in Sphingolipid Metabolism and in Health and Disease","volume":"63","author":"Coant","year":"2017","journal-title":"Adv. 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