Hematopoietic stem cell transplantation leads to biochemical and functional correction in two mouse models of acid ceramidase deficiency. Mol Ther 2024 Oct 02;32(10):3402-3421
Date
08/07/2024Pubmed ID
39108096Pubmed Central ID
PMC11489543DOI
10.1016/j.ymthe.2024.08.004Scopus ID
2-s2.0-85205740497 (requires institutional sign-in at Scopus site) 7 CitationsAbstract
Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions are caused by mutations in the ASAH1 gene, clinical presentations differ considerably. FD patients usually die in childhood, while SMA-PME patients can live until adulthood. There is no treatment for FD or SMA-PME. Hematopoietic stem cell transplantation (HSCT) and gene therapy strategies for the treatment of ACDase deficiency are being investigated. We have previously generated and characterized mouse models of both FD and SMA-PME that recapitulate the symptoms described in patients. Here, we show that HSCT improves lifespan, behavior, hematopoietic system anomalies, and plasma cytokine levels and significantly reduces histiocytic infiltration and ceramide accumulation throughout the tissues investigated, including the CNS, in both models of ACDase-deficient mice. HSCT was also successful in preventing lesion development and significant demyelination of the spinal cord seen in SMA-PME mice. Importantly, we note that only early and generally pre-symptomatic treatment was effective, and kidney impairment was not improved in either model.
Author List
Rybova J, Sundararajan T, Kuchar L, Dlugi TA, Ruzicka P, McKillop WM, Medin JAAuthors
Theresa A. Dlugi PhD Research Scientist I in the Obstetrics and Gynecology department at Medical College of WisconsinJeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Acid CeramidaseAnimals
Ceramides
Disease Models, Animal
Farber Lipogranulomatosis
Hematopoietic Stem Cell Transplantation
Humans
Mice
Mice, Knockout
Myoclonic Epilepsies, Progressive
Spinal Cord
