RARE DISEASE
Farber disease
Farber disease
Farber disease
Synonyms: Acid ceramidase deficiency, Farber lipogranulomatosis
Synonyms: Acid ceramidase deficiency, Farber lipogranulomatosis
Synonyms: Acid ceramidase deficiency, Farber lipogranulomatosis
Drug discovery
2
drugs
With orphan designations
Overview
Farber disease is a rare autosomal recessive lysosomal storage disorder caused by ASAH1 gene mutations, leading to acid ceramidase deficiency and ceramide accumulation. The classic triad includes subcutaneous nodules, painful joint deformities, and hoarse voice, with onset typically in infancy. Progressive symptoms involve respiratory, neurological, and systemic inflammation. Severe cases result in early mortality, while milder forms may extend survival into adolescence or adulthood. Diagnosis relies on clinical evaluation, enzyme activity assays, and genetic testing. No disease-modifying therapies exist, and management focuses on palliative care [1][6][9][12].
Burden
High morbidity: Chronic pain, respiratory failure, and mobility loss due to contractures [1][14][17].
Mortality: Severe forms (e.g., type 1) often fatal by age 2–3; attenuated forms may extend survival to teens/adulthood [2][9][17].
Quality-of-life impact: Requires multidisciplinary care for physical disability and systemic complications [14][17].
Therapies
Palliative care: Corticosteroids, pain management, tracheostomy, and surgery for granuloma removal [3][9][17].
Hematopoietic stem cell transplantation (HSCT): Shows promise in improving joint/nodular symptoms in non-neurological cases [5][6][15].
Investigational therapies: Enzyme replacement (e.g., ACG-801) and gene therapy in preclinical/early clinical trials [3][8][13][18].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare skin diseases, rare transplant-related disorders
Research Papers
72 drug discovery papers about Farber disease, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
72 drug discovery papers about Farber disease, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2024-11-21 | Endocannabinoid receptor 2 is a potential biomarker and therapeutic target for the lysosomal storage disorders.
Herein, we studied the expression of endocannabinoid receptor 2 (CB2R), a known inflammation mediator, in several lysosomal storage disorder (LSD) animal models and evaluated it as a potential biomarker and therapeutic target for these diseases. CB2R was highly elevated in the plasma of Farber disease and mucopolysaccharidosis (MPS) type IIIA mice, followed by Fabry disease and MPS type I mice. Mice with acid sphingomyelinase-deficient Niemann-Pick disease (ASMD) and rats with MPS type VI exhibited little or no plasma CB2R elevation. High-level expression of CB2R was also observed in tissues of Farber and MPS IIIA mice. Treatment of MPS IIIIA patient cells with CB2R agonists led to a reduction of CB2R and monocyte chemoattractant protein-1 (MCP-1), a chemotactic factor that is elevated in this LSD. Treatment of MPS IIIA mice with one of these agonists (JWH133) led to a reduction of plasma and tissue CB2R and MCP-1, a reduction of glial fibrillary acidic protein (GFAP) in the brain, and an improvement in hanging test performance. JWH133 treatment of Farber disease mice also led to a reduction of MCP-1 in tissues and plasma, and treatment of these mice by enzyme replacement therapy (ERT) led to a reduction of plasma CB2R, indicating its potential to monitor treatment response. Overall, these findings suggest that CB2R should be further examined as a potential therapeutic target for the LSDs and may also be a useful biomarker to monitor the impact of therapies.
2024-04-10 | Adiponectin overexpression improves metabolic abnormalities caused by acid ceramidase deficiency but does not prolong lifespan in a mouse model of Farber Disease.
Farber Disease is a debilitating and lethal childhood disease of ceramide accumulation caused by acid ceramidase deficiency. The potent induction of a ligand-gated neutral ceramidase activity promoted by adiponectin may provide sufficient lowering of ceramides to allow for the treatment of Farber Disease. In vitro, adiponectin or adiponectin receptor agonist treatments lowered total ceramide concentrations in human fibroblasts from a patient with Farber Disease. However, adiponectin overexpression in a Farber Disease mouse model did not improve lifespan or immune infiltration. Intriguingly, mice heterozygous for the Farber Disease mutation were more prone to glucose intolerance and insulin resistance when fed a high-fat diet, and adiponectin overexpression protected from these metabolic perturbations. These studies suggest that adiponectin evokes a ceramidase activity that is not reliant on the functional expression of acid ceramidase, but indicates that additional strategies are required to ameliorate outcomes of Farber Disease.
2024-02-17 | A fluorogenic substrate for the detection of lipid amidases in intact cells
Lipid amidases of therapeutic relevance include acid ceramidase (AC), N-acylethanolamine-hydrolyzing acid amidase, and fatty acid amide hydrolase (FAAH). Although fluorogenic substrates have been developed for the three enzymes and high-throughput methods for screening have been reported, a platform for the specific detection of these enzyme activities in intact cells is lacking. In this article, we report on the coumarinic 1-deoxydihydroceramide RBM1-151, a 1-deoxy derivative and vinilog of RBM14-C12, as a novel substrate of amidases. This compound is hydrolyzed by AC (
2022-11-25 | Cell-intrinsic ceramides determine T cell function during melanoma progression
Acid sphingomyelinase (Asm) and acid ceramidase (Ac) are parts of the sphingolipid metabolism. Asm hydrolyzes sphingomyelin to ceramide, which is further metabolized to sphingosine by Ac. Ceramide generates ceramide-enriched platforms that are involved in receptor clustering within cellular membranes. However, the impact of cell-intrinsic ceramide on T cell function is not well characterized. By using T cell-specific Asm- or Ac-deficient mice, with reduced or elevated ceramide levels in T cells, we identified ceramide to play a crucial role in T cell function in vitro and in vivo. T cell-specific ablation of Asm in Smpd1 fl/fl /Cd4 cre/+ (Asm/CD4cre) mice resulted in enhanced tumor progression associated with impaired T cell responses, whereas Asah1 fl/fl /Cd4 cre/+ (Ac/CD4cre) mice showed reduced tumor growth rates and elevated T cell activation compared to the respective controls upon tumor transplantation. Further in vitro analysis revealed that decreased ceramide content supports CD4 + regulatory T cell differentiation and interferes with cytotoxic activity of CD8 + T cells. In contrast, elevated ceramide concentration in CD8 + T cells from Ac/CD4cre mice was associated with enhanced cytotoxic activity. Strikingly, ceramide co-localized with the T cell receptor (TCR) and CD3 in the membrane of stimulated T cells and phosphorylation of TCR signaling molecules was elevated in Ac-deficient T cells. Hence, our results indicate that modulation of ceramide levels, by interfering with the Asm or Ac activity has an effect on T cell differentiation and function and might therefore represent a novel therapeutic strategy for the treatment of T cell-dependent diseases such as tumorigenesis.
2022-03-10 | The acid ceramidase/ceramide axis controls parasitemia in Plasmodium yoelii-infected mice by regulating erythropoiesis
Abstract Acid ceramidase (Ac) is part of the sphingolipid metabolism and responsible for the degradation of ceramide. As bioactive molecule, ceramide is involved in the regulation of many cellular processes. However, the impact of cell-intrinsic Ac activity and ceramide on the course of Plasmodium infection remains elusive. Here, we use Ac-deficient mice with ubiquitously increased ceramide levels to elucidate the role of endogenous Ac activity in a murine malaria model. Interestingly, ablation of Ac leads to alleviated parasitemia associated with decreased T cell responses in the early phase of Plasmodium yoelii ( P. yoelii ) infection. Mechanistically, we identified dysregulated erythropoiesis with reduced numbers of reticulocytes, the preferred host cells of P. yoelii , in Ac-deficient mice. Furthermore, we demonstrate that administration of the Ac inhibitor carmofur to wild type mice has similar effects on P. yoelii infection and erythropoiesis. Notably, therapeutic carmofur treatment after manifestation of P. yoelii infection is efficient in reducing parasitemia. Hence, our results provide evidence for the involvement of Ac and ceramide in controlling P. yoelii infection by regulating red blood cell development.
cell therapies
2024-08-07 | Hematopoietic stem cell transplantation leads to biochemical and functional correction in two mouse models of acid ceramidase deficiency.
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.
2019-02-27 | Allogeneic hematopoietic cell transplantation in Farber disease
Abstract Background Farber disease (FD) is a rare, lysosomal storage disorder caused by deficient acid ceramidase activity. FD has long been considered a fatal disorder with death in the first three decades of life resulting either from respiratory insufficiency as a consequence of airway involvement or from progressive neurodegeneration because of nervous system involvement. Peripheral symptoms associated with FD, including inflammatory joint disease, have been described to improve relatively rapidly after hematopoietic cell transplantation (HCT). Aims To evaluate the disease‐specific status and limitations in the long‐term follow‐up after HCT, investigate genotype/phenotype correlations and the benefit of allogeneic HCT in FD patients with nervous system involvement. Patients and methods Transplant‐ and disease‐related information of ten FD patients was obtained by using a questionnaire, physicians' letters and additional telephone surveys. ASAH1 gene mutations were identified to search for genotype/phenotype correlations. Results After mainly busulfan‐based preparative regimens, all patients engrafted with one late graft loss. The inflammatory symptoms resolved completely in all patients. Abnormal neurologic findings were present pre‐transplant in 4/10 patients, post‐transplant in 6/10 patients. Mutational analyses revealed new mutations in the ASAH1 gene and a broad diversity of phenotypes without a genotype/phenotype correlation. With a median follow‐up of 10.4 years, overall survival was 80% with two transplant‐related deaths. Conclusion Allogeneic HCT leads to complete and persistent resolution of the inflammatory aspects in FD patients. It appears to have no beneficial effect on progression of nervous system involvement. New mutations in the acid ceramidase gene were identified. A genotype/phenotype correlation could not be established.
2019-02-01 | Lentiviral-modified T Rapa cells as 'micropharmacies' for lysosomal diseases
Transgene-augmented cell therapies are a promising strategy for the treatment of amenable Lysosomal Storage Disorderls (LSDs). Most overexpressed lysosomal enzymes can be secreted from vector-modified cells and taken up by uncorrected cells, a process termed “cross-correction”. Our lab is currently evaluating a treatment for Fabry disease using transduced CD34+ hematopoietic stem and progenitor cells (HSPCs) in a phase I trial (NCT02800070). These HSPCs are modified ex vivo with a recombinant lentivirus to engineer overexpression of α-galactosidase A (α-gal A). Transduced HSPCs are reinfused into the Fabry patient and differentiate into leukocytes that secrete α-gal A long-term. However, HSPC collection requires both a hospital stay and a drug regimen for cell mobilization. HSPC engraftment also requires a chemotherapy-based conditioning protocol (even for 'mild' myeloablation - as in our case). An alternative hematopoietic cell population that can be readily obtained without mobilization and engrafted with less conditioning may therefore be more desirable for the systemic delivery of therapeutic cargo - such as lysosomal hydrolases. T cells can be obtained from peripheral blood without mobilization and expanded exponentially in culture. T cells can also secrete high levels of protein. When treated with rapamycin in defined ex vivo conditions, ‘T Rapa’ cells acquire an anti-apoptotic and pro-engraftment phenotype. These T Rapa cells engraft with minimal conditioning. Autologous transduced CD4+ T Rapa cells have potential to deliver enzyme systemically as “circulating micropharmacies”. Our data shows that T Rapa cells manufactured from Fabry patients can be stably transduced and secrete α-gal A in vitro. Secreted α-gal A can be taken up by fibroblasts. α-Gal A activity was also detected in the plasma of xenografted NOD/SCID/Fabry mice substrate was reduced. We are concomitantly testing the potential for T Rapa cells to secrete enzymes for treating other LSDs, such as Gaucher disease, Farber disease, and Pompe disease.
2018-11-14 | Favorable outcome of allogenic hematopoietic stem cell transplantation in farber disease
Farber disease is a rare autosomal recessively inherited disorder caused by acid ceramidase deficiency. Painful subcutaneous skin nodules, progressive joint stiffness, and laryngeal involvement leading to a progressive hoarseness are the main characteristics of the disease. We report favorable outcome of hematopoietic stem cell transplantation after 24 months of follow up in a 2.7-years-old girl with Farber’s disease who was transplanted from her 49-years-old maternal grandfather resulting in resolution of her symptoms. Hematopoetic stem cell transplantation could provide sufficient amount of enzyme and accordingly diminish or stabilize the symptoms in these patients.
2015-09-15 | Nervous system involvement in Farber disease
Abstract A 30 months‐old boy with Farber disease developed nystagmus 12 months after hematopoietic stem cell transplantation (HSCT). At 40 months, gait ataxia was evident, and brain MRI showed increased size of pericerebellar sulci and 4th ventricle. EMG showed denervation in the tongue and upper limb muscles, consistent with motor neuron disease. HSCT improves the peripheral manifestations of Farber disease, but may not prevent the progressive neurological deterioration.
gene therapies
2023-04-20 | rAAV-mediated over-expression of acid ceramidase prevents retinopathy in a mouse model of Farber lipogranulomatosis.
Farber disease (FD) is a rare monogenic lysosomal storage disorder caused by mutations in ASAH1 that results in a deficiency of acid ceramidase (ACDase) activity and the abnormal systemic accumulation of ceramide species, leading to multi-system organ failure involving neurological decline and retinopathy. Here we describe the effects of rAAV-mediated ASAH1 over-expression on the progression of retinopathy in a mouse model of FD (Asah1P361R/P361R) and its littermate controls (Asah1+/+ and Asah1+/P361R). Using a combination of non-invasive multimodal imaging, electrophysiology, post-mortem histology and mass spectrometry we demonstrate that ASAH1 over-expression significantly reduces central retinal thickening, ceramide accumulation, macrophage activation and limits fundus hyper-reflectivity and auto-fluorescence in FD mice, indicating rAAV-mediated over-expression of biologically active ACDase protein is able to rescue the anatomical retinal phenotype of Farber disease. Unexpectedly, ACDase over-expression in Asah1+/+ and Asah1+/P361R control eyes was observed to induce abnormal fundus hyper-reflectivity, auto-fluorescence and retinal thickening that closely resembles a FD phenotype. This study represents the first evidence of a gene therapy for Farber disease-related retinopathy. Importantly, the described gene therapy approach could be used to preserve vision in FD patients synergistically with broader enzyme replacement strategies aimed at preserving life.
2020-03-17 | Altering Sphingolipid Metabolism Attenuates Cell Death and Inflammatory Response After Myocardial Infarction
Sphingolipids have recently emerged as a biomarker of recurrence and mortality after myocardial infarction (MI). The increased ceramide levels in mammalian heart tissues during acute MI, as demonstrated by several groups, is associated with higher cell death rates in the left ventricle and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze proapoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase to produce the prosurvival molecule sphingosine-1-phosphate. We hypothesized that Acid Ceramidase (AC) overexpression would counteract the negative effects of elevated ceramide and promote cell survival, thereby providing cardioprotection after MI. We performed transcriptomic, sphingolipid, and protein analyses to evaluate sphingolipid metabolism and signaling post-MI. We investigated the effect of altering ceramide metabolism through a loss (chemical inhibitors) or gain (modified mRNA [modRNA]) of AC function post hypoxia or MI. We found that several genes involved in de novo ceramide synthesis were upregulated and that ceramide (C16, C20, C20:1, and C24) levels had significantly increased 24 hours after MI. AC inhibition after hypoxia or MI resulted in reduced AC activity and increased cell death. By contrast, enhancing AC activity via AC modRNA treatment increased cell survival after hypoxia or MI. AC modRNA-treated mice had significantly better heart function, longer survival, and smaller scar size than control mice 28 days post-MI. We attributed the improvement in heart function post-MI after AC modRNA delivery to decreased ceramide levels, lower cell death rates, and changes in the composition of the immune cell population in the left ventricle manifested by lowered abundance of proinflammatory detrimental neutrophils. Our findings suggest that transiently altering sphingolipid metabolism through AC overexpression is sufficient and necessary to induce cardioprotection post-MI, thereby highlighting the therapeutic potential of AC modRNA in ischemic heart disease.
2019-03-18 | Acid ceramidase deficiency: Farber disease and SMA-PME.
Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber disease (FD) and a rare epileptic disorder called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Both disorders are caused by mutations in the ASAH1 gene that encodes the lysosomal hydrolase that breaks down the bioactive lipid ceramide. To date, there have been fewer than 200 reported cases of FD and SMA-PME in the literature. Typical textbook manifestations of classical FD include the formation of subcutaneous nodules, accumulation of joint contractures, and development of a hoarse voice. In reality, however, the clinical presentation is much broader. Patients may develop severe pathologies leading to death in infancy or may develop attenuated forms of the disorder wherein they are often misdiagnosed or not diagnosed until adulthood. A clinical variability also exists for SMA-PME, in which patients develop progressive muscle weakness and seizures. Currently, there is no known cure for FD or for SMA-PME. The main treatment is symptom management. In rare cases, treatment may include surgery or hematopoietic stem cell transplantation. Research using disease models has provided insights into the pathology as well as the role of ACDase in the development of these conditions. Recent studies have highlighted possible biomarkers for an effective diagnosis of ACDase deficiency. Ongoing work is being conducted to evaluate the use of recombinant human ACDase (rhACDase) for the treatment of FD. Finally, gene therapy strategies for the treatment of ACDase deficiency are actively being pursued. This review highlights the broad clinical definition and outlines key studies that have improved our understanding of inherited ACDase deficiency-related conditions.
2017-11-21 | Spinal muscular atrophy with progressive myoclonic epilepsy linked to mutations in ASAH1
Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), a rare disorder caused by mutation in the ASAH1 gene, is characterized by progressive muscle weakness and intractable epilepsy. The literature about SMA-PME is very rare and most of the time limited to case reports. Mutation in the ASAH1 gene is also found in another rare syndrome which is Farber disease. We report a case of a 13.5-year-old girl with SMA-PME associated with ASAH1 gene mutation. She presented with progressive muscle weakness, tremor, seizure, and cognitive impairment. Clinical features and electrophysiological investigations revealed a motor neuron disease and generalized epilepsy. The marked difference in disease manifestations may explain why Farber and SMA-PME diseases were not suspected of being allelic conditions. SMA-PME cases with ASAH1 mutation could be treated using therapeutic studies regarding Farber disease. In patients with undefined PME or lower motor neuron disease cases, ASAH1 mutation scans should be studied.
2015-08-01 | Targeted Induction of Ceramide Degradation Leads to Improved Systemic Metabolism and Reduced Hepatic Steatosis
Sphingolipids have garnered attention for their role in insulin resistance and lipotoxic cell death. We have developed transgenic mice inducibly expressing acid ceramidase that display a reduction in ceramides in adult mouse tissues. Hepatic overexpression of acid ceramidase prevents hepatic steatosis and prompts improvements in insulin action in liver and adipose tissue upon exposure to high-fat diet. Conversely, overexpression of acid ceramidase within adipose tissue also prevents hepatic steatosis and systemic insulin resistance. Induction of ceramidase activity in either tissue promotes a lowering of hepatic ceramides and reduced activation of the ceramide-activated protein kinase C isoform PKCζ, though the induction of ceramidase activity in the adipocyte prompts more rapid resolution of hepatic steatosis than overexpression of the enzyme directly in the liver. Collectively, our observations suggest the existence of a rapidly acting “cross-talk” between liver and adipose tissue sphingolipids, critically regulating glucose metabolism and hepatic lipid uptake.
proteins
2024-11-18 | [Therapeutic perspectives for lysosomal storage disorders caused by acid ceramidase deficiency].
Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are two ultra-rare lysosomal storage disorders resulting from loss-of-function mutations in the ASAH1 gene encoding for acid ceramidase (ACDase). ACDase deficiency leads to the intracellular accumulation of ceramides with an inflammatory response in tissues. These two diseases manifest differently but are part of a clinical continuum with variable severity affecting the nervous system and/or peripheral tissues, including the neuromuscular system. To date, no specific or curative treatments are available for patients affected by acid ceramidase deficiency. Here, we summarize the clinical features, enzyme function, mouse models and therapeutic perspectives for these allelic diseases.
other
2025-08-08 | Farber's Lipogranulomatosis: Multimodal Therapy With Tocilizumab and Consolidative HSCT Improves Assessment, and Long-Term Outcome.
Farber's lipogranulomatosis (FL) is an autosomal recessive lipid storage disorder, arising as a consequence of genetic acid ceramidase deficiency. Clinically, it presents as severe arthritis, voice hoarseness, and widespread, painful subcutaneous nodules (SCN). For those without CNS involvement, haematopoietic stem cell transplant provides a viable option for the improvement of both respiratory and musculoskeletal morbidity. A better understanding of macrophage-driven inflammation in FL has resulted in targeted medical therapies such as Tocilizumab being utilized in FL patients. Since FL is a rare disease, minimal guidance on how treatment modalities should be utilized is available. We describe the case of a girl with FL presenting at 15 months with severe pain, swelling, and deformity of predominantly the small joints secondary to SCNs. Critical airway narrowing from laryngeal nodules necessitated tracheostomy. Regression of motor skills was also apparent. Fortnightly tocilizumab infusions improved pain and irritability, allowing neurological evaluation and tracheostomy decannulation. It did not halt the progression of SCNs. Therefore, we completed a 10/10 matched family donor haematopoietic stem cell transplant. Post-transplant, she is stable neurologically, with resolution of her SCN, and her cognition, performance status, and well-being are considerably improved by transplant.
small molecules
2024-11-21 | Endocannabinoid receptor 2 is a potential biomarker and therapeutic target for the lysosomal storage disorders.
Herein, we studied the expression of endocannabinoid receptor 2 (CB2R), a known inflammation mediator, in several lysosomal storage disorder (LSD) animal models and evaluated it as a potential biomarker and therapeutic target for these diseases. CB2R was highly elevated in the plasma of Farber disease and mucopolysaccharidosis (MPS) type IIIA mice, followed by Fabry disease and MPS type I mice. Mice with acid sphingomyelinase-deficient Niemann-Pick disease (ASMD) and rats with MPS type VI exhibited little or no plasma CB2R elevation. High-level expression of CB2R was also observed in tissues of Farber and MPS IIIA mice. Treatment of MPS IIIIA patient cells with CB2R agonists led to a reduction of CB2R and monocyte chemoattractant protein-1 (MCP-1), a chemotactic factor that is elevated in this LSD. Treatment of MPS IIIA mice with one of these agonists (JWH133) led to a reduction of plasma and tissue CB2R and MCP-1, a reduction of glial fibrillary acidic protein (GFAP) in the brain, and an improvement in hanging test performance. JWH133 treatment of Farber disease mice also led to a reduction of MCP-1 in tissues and plasma, and treatment of these mice by enzyme replacement therapy (ERT) led to a reduction of plasma CB2R, indicating its potential to monitor treatment response. Overall, these findings suggest that CB2R should be further examined as a potential therapeutic target for the LSDs and may also be a useful biomarker to monitor the impact of therapies.
2024-04-10 | Adiponectin overexpression improves metabolic abnormalities caused by acid ceramidase deficiency but does not prolong lifespan in a mouse model of Farber Disease.
Farber Disease is a debilitating and lethal childhood disease of ceramide accumulation caused by acid ceramidase deficiency. The potent induction of a ligand-gated neutral ceramidase activity promoted by adiponectin may provide sufficient lowering of ceramides to allow for the treatment of Farber Disease. In vitro, adiponectin or adiponectin receptor agonist treatments lowered total ceramide concentrations in human fibroblasts from a patient with Farber Disease. However, adiponectin overexpression in a Farber Disease mouse model did not improve lifespan or immune infiltration. Intriguingly, mice heterozygous for the Farber Disease mutation were more prone to glucose intolerance and insulin resistance when fed a high-fat diet, and adiponectin overexpression protected from these metabolic perturbations. These studies suggest that adiponectin evokes a ceramidase activity that is not reliant on the functional expression of acid ceramidase, but indicates that additional strategies are required to ameliorate outcomes of Farber Disease.
2024-02-17 | A fluorogenic substrate for the detection of lipid amidases in intact cells
Lipid amidases of therapeutic relevance include acid ceramidase (AC), N-acylethanolamine-hydrolyzing acid amidase, and fatty acid amide hydrolase (FAAH). Although fluorogenic substrates have been developed for the three enzymes and high-throughput methods for screening have been reported, a platform for the specific detection of these enzyme activities in intact cells is lacking. In this article, we report on the coumarinic 1-deoxydihydroceramide RBM1-151, a 1-deoxy derivative and vinilog of RBM14-C12, as a novel substrate of amidases. This compound is hydrolyzed by AC (
2022-11-25 | Cell-intrinsic ceramides determine T cell function during melanoma progression
Acid sphingomyelinase (Asm) and acid ceramidase (Ac) are parts of the sphingolipid metabolism. Asm hydrolyzes sphingomyelin to ceramide, which is further metabolized to sphingosine by Ac. Ceramide generates ceramide-enriched platforms that are involved in receptor clustering within cellular membranes. However, the impact of cell-intrinsic ceramide on T cell function is not well characterized. By using T cell-specific Asm- or Ac-deficient mice, with reduced or elevated ceramide levels in T cells, we identified ceramide to play a crucial role in T cell function in vitro and in vivo. T cell-specific ablation of Asm in Smpd1 fl/fl /Cd4 cre/+ (Asm/CD4cre) mice resulted in enhanced tumor progression associated with impaired T cell responses, whereas Asah1 fl/fl /Cd4 cre/+ (Ac/CD4cre) mice showed reduced tumor growth rates and elevated T cell activation compared to the respective controls upon tumor transplantation. Further in vitro analysis revealed that decreased ceramide content supports CD4 + regulatory T cell differentiation and interferes with cytotoxic activity of CD8 + T cells. In contrast, elevated ceramide concentration in CD8 + T cells from Ac/CD4cre mice was associated with enhanced cytotoxic activity. Strikingly, ceramide co-localized with the T cell receptor (TCR) and CD3 in the membrane of stimulated T cells and phosphorylation of TCR signaling molecules was elevated in Ac-deficient T cells. Hence, our results indicate that modulation of ceramide levels, by interfering with the Asm or Ac activity has an effect on T cell differentiation and function and might therefore represent a novel therapeutic strategy for the treatment of T cell-dependent diseases such as tumorigenesis.
2022-03-10 | The acid ceramidase/ceramide axis controls parasitemia in Plasmodium yoelii-infected mice by regulating erythropoiesis
Abstract Acid ceramidase (Ac) is part of the sphingolipid metabolism and responsible for the degradation of ceramide. As bioactive molecule, ceramide is involved in the regulation of many cellular processes. However, the impact of cell-intrinsic Ac activity and ceramide on the course of Plasmodium infection remains elusive. Here, we use Ac-deficient mice with ubiquitously increased ceramide levels to elucidate the role of endogenous Ac activity in a murine malaria model. Interestingly, ablation of Ac leads to alleviated parasitemia associated with decreased T cell responses in the early phase of Plasmodium yoelii ( P. yoelii ) infection. Mechanistically, we identified dysregulated erythropoiesis with reduced numbers of reticulocytes, the preferred host cells of P. yoelii , in Ac-deficient mice. Furthermore, we demonstrate that administration of the Ac inhibitor carmofur to wild type mice has similar effects on P. yoelii infection and erythropoiesis. Notably, therapeutic carmofur treatment after manifestation of P. yoelii infection is efficient in reducing parasitemia. Hence, our results provide evidence for the involvement of Ac and ceramide in controlling P. yoelii infection by regulating red blood cell development.
cell therapies
2024-08-07 | Hematopoietic stem cell transplantation leads to biochemical and functional correction in two mouse models of acid ceramidase deficiency.
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.
2019-02-27 | Allogeneic hematopoietic cell transplantation in Farber disease
Abstract Background Farber disease (FD) is a rare, lysosomal storage disorder caused by deficient acid ceramidase activity. FD has long been considered a fatal disorder with death in the first three decades of life resulting either from respiratory insufficiency as a consequence of airway involvement or from progressive neurodegeneration because of nervous system involvement. Peripheral symptoms associated with FD, including inflammatory joint disease, have been described to improve relatively rapidly after hematopoietic cell transplantation (HCT). Aims To evaluate the disease‐specific status and limitations in the long‐term follow‐up after HCT, investigate genotype/phenotype correlations and the benefit of allogeneic HCT in FD patients with nervous system involvement. Patients and methods Transplant‐ and disease‐related information of ten FD patients was obtained by using a questionnaire, physicians' letters and additional telephone surveys. ASAH1 gene mutations were identified to search for genotype/phenotype correlations. Results After mainly busulfan‐based preparative regimens, all patients engrafted with one late graft loss. The inflammatory symptoms resolved completely in all patients. Abnormal neurologic findings were present pre‐transplant in 4/10 patients, post‐transplant in 6/10 patients. Mutational analyses revealed new mutations in the ASAH1 gene and a broad diversity of phenotypes without a genotype/phenotype correlation. With a median follow‐up of 10.4 years, overall survival was 80% with two transplant‐related deaths. Conclusion Allogeneic HCT leads to complete and persistent resolution of the inflammatory aspects in FD patients. It appears to have no beneficial effect on progression of nervous system involvement. New mutations in the acid ceramidase gene were identified. A genotype/phenotype correlation could not be established.
2019-02-01 | Lentiviral-modified T Rapa cells as 'micropharmacies' for lysosomal diseases
Transgene-augmented cell therapies are a promising strategy for the treatment of amenable Lysosomal Storage Disorderls (LSDs). Most overexpressed lysosomal enzymes can be secreted from vector-modified cells and taken up by uncorrected cells, a process termed “cross-correction”. Our lab is currently evaluating a treatment for Fabry disease using transduced CD34+ hematopoietic stem and progenitor cells (HSPCs) in a phase I trial (NCT02800070). These HSPCs are modified ex vivo with a recombinant lentivirus to engineer overexpression of α-galactosidase A (α-gal A). Transduced HSPCs are reinfused into the Fabry patient and differentiate into leukocytes that secrete α-gal A long-term. However, HSPC collection requires both a hospital stay and a drug regimen for cell mobilization. HSPC engraftment also requires a chemotherapy-based conditioning protocol (even for 'mild' myeloablation - as in our case). An alternative hematopoietic cell population that can be readily obtained without mobilization and engrafted with less conditioning may therefore be more desirable for the systemic delivery of therapeutic cargo - such as lysosomal hydrolases. T cells can be obtained from peripheral blood without mobilization and expanded exponentially in culture. T cells can also secrete high levels of protein. When treated with rapamycin in defined ex vivo conditions, ‘T Rapa’ cells acquire an anti-apoptotic and pro-engraftment phenotype. These T Rapa cells engraft with minimal conditioning. Autologous transduced CD4+ T Rapa cells have potential to deliver enzyme systemically as “circulating micropharmacies”. Our data shows that T Rapa cells manufactured from Fabry patients can be stably transduced and secrete α-gal A in vitro. Secreted α-gal A can be taken up by fibroblasts. α-Gal A activity was also detected in the plasma of xenografted NOD/SCID/Fabry mice substrate was reduced. We are concomitantly testing the potential for T Rapa cells to secrete enzymes for treating other LSDs, such as Gaucher disease, Farber disease, and Pompe disease.
2018-11-14 | Favorable outcome of allogenic hematopoietic stem cell transplantation in farber disease
Farber disease is a rare autosomal recessively inherited disorder caused by acid ceramidase deficiency. Painful subcutaneous skin nodules, progressive joint stiffness, and laryngeal involvement leading to a progressive hoarseness are the main characteristics of the disease. We report favorable outcome of hematopoietic stem cell transplantation after 24 months of follow up in a 2.7-years-old girl with Farber’s disease who was transplanted from her 49-years-old maternal grandfather resulting in resolution of her symptoms. Hematopoetic stem cell transplantation could provide sufficient amount of enzyme and accordingly diminish or stabilize the symptoms in these patients.
2015-09-15 | Nervous system involvement in Farber disease
Abstract A 30 months‐old boy with Farber disease developed nystagmus 12 months after hematopoietic stem cell transplantation (HSCT). At 40 months, gait ataxia was evident, and brain MRI showed increased size of pericerebellar sulci and 4th ventricle. EMG showed denervation in the tongue and upper limb muscles, consistent with motor neuron disease. HSCT improves the peripheral manifestations of Farber disease, but may not prevent the progressive neurological deterioration.
gene therapies
2023-04-20 | rAAV-mediated over-expression of acid ceramidase prevents retinopathy in a mouse model of Farber lipogranulomatosis.
Farber disease (FD) is a rare monogenic lysosomal storage disorder caused by mutations in ASAH1 that results in a deficiency of acid ceramidase (ACDase) activity and the abnormal systemic accumulation of ceramide species, leading to multi-system organ failure involving neurological decline and retinopathy. Here we describe the effects of rAAV-mediated ASAH1 over-expression on the progression of retinopathy in a mouse model of FD (Asah1P361R/P361R) and its littermate controls (Asah1+/+ and Asah1+/P361R). Using a combination of non-invasive multimodal imaging, electrophysiology, post-mortem histology and mass spectrometry we demonstrate that ASAH1 over-expression significantly reduces central retinal thickening, ceramide accumulation, macrophage activation and limits fundus hyper-reflectivity and auto-fluorescence in FD mice, indicating rAAV-mediated over-expression of biologically active ACDase protein is able to rescue the anatomical retinal phenotype of Farber disease. Unexpectedly, ACDase over-expression in Asah1+/+ and Asah1+/P361R control eyes was observed to induce abnormal fundus hyper-reflectivity, auto-fluorescence and retinal thickening that closely resembles a FD phenotype. This study represents the first evidence of a gene therapy for Farber disease-related retinopathy. Importantly, the described gene therapy approach could be used to preserve vision in FD patients synergistically with broader enzyme replacement strategies aimed at preserving life.
2020-03-17 | Altering Sphingolipid Metabolism Attenuates Cell Death and Inflammatory Response After Myocardial Infarction
Sphingolipids have recently emerged as a biomarker of recurrence and mortality after myocardial infarction (MI). The increased ceramide levels in mammalian heart tissues during acute MI, as demonstrated by several groups, is associated with higher cell death rates in the left ventricle and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze proapoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase to produce the prosurvival molecule sphingosine-1-phosphate. We hypothesized that Acid Ceramidase (AC) overexpression would counteract the negative effects of elevated ceramide and promote cell survival, thereby providing cardioprotection after MI. We performed transcriptomic, sphingolipid, and protein analyses to evaluate sphingolipid metabolism and signaling post-MI. We investigated the effect of altering ceramide metabolism through a loss (chemical inhibitors) or gain (modified mRNA [modRNA]) of AC function post hypoxia or MI. We found that several genes involved in de novo ceramide synthesis were upregulated and that ceramide (C16, C20, C20:1, and C24) levels had significantly increased 24 hours after MI. AC inhibition after hypoxia or MI resulted in reduced AC activity and increased cell death. By contrast, enhancing AC activity via AC modRNA treatment increased cell survival after hypoxia or MI. AC modRNA-treated mice had significantly better heart function, longer survival, and smaller scar size than control mice 28 days post-MI. We attributed the improvement in heart function post-MI after AC modRNA delivery to decreased ceramide levels, lower cell death rates, and changes in the composition of the immune cell population in the left ventricle manifested by lowered abundance of proinflammatory detrimental neutrophils. Our findings suggest that transiently altering sphingolipid metabolism through AC overexpression is sufficient and necessary to induce cardioprotection post-MI, thereby highlighting the therapeutic potential of AC modRNA in ischemic heart disease.
2019-03-18 | Acid ceramidase deficiency: Farber disease and SMA-PME.
Acid ceramidase (ACDase) deficiency is a spectrum of disorders that includes a rare lysosomal storage disorder called Farber disease (FD) and a rare epileptic disorder called spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME). Both disorders are caused by mutations in the ASAH1 gene that encodes the lysosomal hydrolase that breaks down the bioactive lipid ceramide. To date, there have been fewer than 200 reported cases of FD and SMA-PME in the literature. Typical textbook manifestations of classical FD include the formation of subcutaneous nodules, accumulation of joint contractures, and development of a hoarse voice. In reality, however, the clinical presentation is much broader. Patients may develop severe pathologies leading to death in infancy or may develop attenuated forms of the disorder wherein they are often misdiagnosed or not diagnosed until adulthood. A clinical variability also exists for SMA-PME, in which patients develop progressive muscle weakness and seizures. Currently, there is no known cure for FD or for SMA-PME. The main treatment is symptom management. In rare cases, treatment may include surgery or hematopoietic stem cell transplantation. Research using disease models has provided insights into the pathology as well as the role of ACDase in the development of these conditions. Recent studies have highlighted possible biomarkers for an effective diagnosis of ACDase deficiency. Ongoing work is being conducted to evaluate the use of recombinant human ACDase (rhACDase) for the treatment of FD. Finally, gene therapy strategies for the treatment of ACDase deficiency are actively being pursued. This review highlights the broad clinical definition and outlines key studies that have improved our understanding of inherited ACDase deficiency-related conditions.
2017-11-21 | Spinal muscular atrophy with progressive myoclonic epilepsy linked to mutations in ASAH1
Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME), a rare disorder caused by mutation in the ASAH1 gene, is characterized by progressive muscle weakness and intractable epilepsy. The literature about SMA-PME is very rare and most of the time limited to case reports. Mutation in the ASAH1 gene is also found in another rare syndrome which is Farber disease. We report a case of a 13.5-year-old girl with SMA-PME associated with ASAH1 gene mutation. She presented with progressive muscle weakness, tremor, seizure, and cognitive impairment. Clinical features and electrophysiological investigations revealed a motor neuron disease and generalized epilepsy. The marked difference in disease manifestations may explain why Farber and SMA-PME diseases were not suspected of being allelic conditions. SMA-PME cases with ASAH1 mutation could be treated using therapeutic studies regarding Farber disease. In patients with undefined PME or lower motor neuron disease cases, ASAH1 mutation scans should be studied.
2015-08-01 | Targeted Induction of Ceramide Degradation Leads to Improved Systemic Metabolism and Reduced Hepatic Steatosis
Sphingolipids have garnered attention for their role in insulin resistance and lipotoxic cell death. We have developed transgenic mice inducibly expressing acid ceramidase that display a reduction in ceramides in adult mouse tissues. Hepatic overexpression of acid ceramidase prevents hepatic steatosis and prompts improvements in insulin action in liver and adipose tissue upon exposure to high-fat diet. Conversely, overexpression of acid ceramidase within adipose tissue also prevents hepatic steatosis and systemic insulin resistance. Induction of ceramidase activity in either tissue promotes a lowering of hepatic ceramides and reduced activation of the ceramide-activated protein kinase C isoform PKCζ, though the induction of ceramidase activity in the adipocyte prompts more rapid resolution of hepatic steatosis than overexpression of the enzyme directly in the liver. Collectively, our observations suggest the existence of a rapidly acting “cross-talk” between liver and adipose tissue sphingolipids, critically regulating glucose metabolism and hepatic lipid uptake.
proteins
2024-11-18 | [Therapeutic perspectives for lysosomal storage disorders caused by acid ceramidase deficiency].
Farber disease and spinal muscular atrophy with progressive myoclonic epilepsy are two ultra-rare lysosomal storage disorders resulting from loss-of-function mutations in the ASAH1 gene encoding for acid ceramidase (ACDase). ACDase deficiency leads to the intracellular accumulation of ceramides with an inflammatory response in tissues. These two diseases manifest differently but are part of a clinical continuum with variable severity affecting the nervous system and/or peripheral tissues, including the neuromuscular system. To date, no specific or curative treatments are available for patients affected by acid ceramidase deficiency. Here, we summarize the clinical features, enzyme function, mouse models and therapeutic perspectives for these allelic diseases.
other
2025-08-08 | Farber's Lipogranulomatosis: Multimodal Therapy With Tocilizumab and Consolidative HSCT Improves Assessment, and Long-Term Outcome.
Farber's lipogranulomatosis (FL) is an autosomal recessive lipid storage disorder, arising as a consequence of genetic acid ceramidase deficiency. Clinically, it presents as severe arthritis, voice hoarseness, and widespread, painful subcutaneous nodules (SCN). For those without CNS involvement, haematopoietic stem cell transplant provides a viable option for the improvement of both respiratory and musculoskeletal morbidity. A better understanding of macrophage-driven inflammation in FL has resulted in targeted medical therapies such as Tocilizumab being utilized in FL patients. Since FL is a rare disease, minimal guidance on how treatment modalities should be utilized is available. We describe the case of a girl with FL presenting at 15 months with severe pain, swelling, and deformity of predominantly the small joints secondary to SCNs. Critical airway narrowing from laryngeal nodules necessitated tracheostomy. Regression of motor skills was also apparent. Fortnightly tocilizumab infusions improved pain and irritability, allowing neurological evaluation and tracheostomy decannulation. It did not halt the progression of SCNs. Therefore, we completed a 10/10 matched family donor haematopoietic stem cell transplant. Post-transplant, she is stable neurologically, with resolution of her SCN, and her cognition, performance status, and well-being are considerably improved by transplant.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Farber disease.
2 orphan drug designations for Farber disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Recombinant human acid ceramidase | proteins | EMA | 2014-02-21 | — | Granzer Regulatory Consulting & Services GmbH |
recombinant human acid ceramidase | proteins | FDA | 2013-12-24 | — | Aceragen, Inc. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.