BMT Doubles The Lifespan Of A Mouse Model Of Farber Disease and Corrects Hematopoietic Defects

Farber disease (FD) is a rare and severe inherited metabolic disorder with childhood lethality and no known cure. Farber patients have mutations in ASAH1, which codes for the protein acid ceramidase (ACDase). ACDase degrades ceramide; it is an essential and ubiquitous hydrolase. Clinical signs of FD include hepatosplenomegaly, granulomas, and histiocytosis. Some FD patients have been reported to have monocytosis and leukocytosis; some also present with neurological impairments. Allogeneic bone marrow transplantation (BMT) has had modest success in treating Farber patients, however it fails in patients with neurological manifestations of the disease. To better understand and improve on BMT for Farber disease, we performed syngeneic BMTs in a mouse model of Farber disease that we have recently generated. In our model a mutation from a patient with dramatically reduced ACDase activity was introduced into the analogous loci in the mouse genome. Our mouse model faithfully recapitulates the clinical signs of FD: mice homozygous for the Asah1 P361R mutation (Hom) show robust and systemic ceramide accumulation, lifespans reduced to 7-13 weeks, growth retardation, hepatosplenomegaly, thymomegaly, and wide-spread histiocytosis. Peripheral blood monocytosis and leukocytosis are evident as are neurological manifestations. Hematopoietic organs are particularly affected, with the spleen, thymus, and lymph nodes of Hom Farber mice all being enlarged compared to wild-type (WT) and heterozygous (Het) littermates. These organs are enlarged because they, along with the bone marrow, are massively infiltrated by foamy histiocytes (manuscript in preparation). In this present study we transplanted bone marrow from 4-5 week-old WT donor mice (pre-treated with 5-fluorouracil to enhance hematopoietic stem cell recovery) into 4-5 week-old Hom mice that were myeloablated with radiation. BMT doubled the lifespan of Hom mice to 21 weeks. Weight loss was also reduced, with Hom mice more closely approaching the weight of WT and Het mice. Hematopoietic organ enlargement was minimalized: spleen and lymph node sizes were significantly reduced and thymii were no longer visible. The prevention of hematopoietic organ enlargement was likely due to a drastic reduction in histiocysosis: much fewer foamy macrophages were found in the organs. Additionally, peripheral blood monocytosis and leukocytosis were prevented. This study demonstrates that BMT is efficacious in the treatment of the peripheral complications of Farber disease, yet it is not a permanent cure especially when the disease has neurological implications. It reveals the specific beneficial effects of BMT on hematopoietic organs in this novel mouse model of FD. Future studies will look at enhancing BMT outcomes in FD by transducing donor hematopoietic stem/progenitor cells with recombinant lentiviral vectors encoding WT ACDase. This combination of BMT and gene therapy in lysosomal storage disorders is clinically relevant as it could be translated for use in FD patients, following future clinical implementation for other disorders of this class, such as Fabry disease, for example.