RARE DISEASE
Wolman disease
Wolman disease
Wolman disease
Drug discovery
1
drug
With orphan designation
Overview
Wolman disease is a severe infantile form of lysosomal acid lipase deficiency (LAL-D) caused by autosomal recessive mutations in the LIPA gene [1][6][9]. It manifests in the first weeks of life with hepatosplenomegaly, adrenal calcifications, steatorrhea, vomiting, and failure to thrive due to systemic lipid accumulation [1][6][9]. Untreated, it progresses rapidly to liver failure and death by 12 months [1][6][9]. Diagnosis is confirmed via lysosomal acid lipase enzyme assay or genetic testing [6][13][14].
Burden
Mortality: >90% mortality by age 1 without therapy [1][6][9].
Multi-organ impact: Liver fibrosis, adrenal insufficiency, malnutrition, and systemic inflammation [1][6][12].
Healthcare burden: High costs of ERT, frequent hospitalizations, and multidisciplinary care needs [7][10][14].
Early diagnosis via newborn screening (where available) and prompt ERT initiation are critical to alter prognosis [1][13][14].
Therapies
Enzyme replacement therapy: Sebelipase alfa (FDA/EMA-approved), improves survival when initiated early [3][5][11][14].
Supportive care: Low-fat diet, parenteral nutrition, lipid-lowering agents, and adrenal hormone replacement [3][7][9].
Hematopoietic stem cell transplant: Limited utility due to procedural risks; often reserved for refractory cases [3][7].
Categories: rare endocrine diseases, rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
100 drug discovery papers about Wolman disease, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
100 drug discovery papers about Wolman disease, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-19 | Secreted enzyme uptake masks the in vivo phenotype of macrophage-specific lysosomal acid lipase deletion.
Lysosomal acid lipase (LAL) is so far the only known intracellular enzyme that is capable of hydrolyzing triglycerides and cholesteryl esters at an acidic pH inside the lysosome. Mutations in the LAL-encoding Lipa gene cause a rare autosomal recessive lysosomal storage disorder in humans with massive lipid accumulation. In mice, the loss of systemic LAL is associated with severe lipid accumulation, particularly in the liver and small intestine, accompanied by infiltration of lipid-filled CD68+-TREM2+ macrophages. We hypothesize that macrophages are among the key players in LAL deficiency and are responsible for lipid accumulation in the affected tissues. We generated macrophage (mac)- and macrophage/enterocyte-specific (mac/int-) LAL KO mice and performed morphological, histopathological, and functional analyses under chow- and high-fat/high-cholesterol diet-fed conditions. We observed that neither macLAL-KO nor mac/int-LAL KO mice replicated the phenotype of whole-body LAL KO mice, as lipoprotein secretion, lipid absorption, and lipid accumulation remained unaffected. However, the absence of macrophage LAL ameliorated diet-induced obesity in both mouse lines. Notably, the lipid accumulation observed in the lysosomes of macrophages from whole-body LAL KO mice was absent in macrophages from macLAL-KO mice, attributable to residual LAL enzyme activity despite genetic ablation. Treatment of macrophages from whole-body LAL KO mice with conditioned medium of hepatocytes from macLAL-KO mice effectively prevented lipid accumulation. These findings suggest that LAL secreted from hepatocytes, macrophages, and possibly other cell types in vivo corrects the phenotype of cell type-specific LAL deficiency, a key insight for guiding future gene therapy strategies.
2025-12-22 | Human iPSC-derived liver organoids model multicellular tissue responses and therapeutic rescue in Wolman disease
Wolman disease (WD), the severe infantile form of lysosomal acid lipase deficiency, is a rare metabolic disorder caused by inactivating mutations in the LIPA gene. Although WD is characterized by profound hepatic dysfunction, experimental human systems capable of modelling multicellular liver pathology and supporting therapeutic testing remain limited. Here, we generated an isogenic human model of WD by introducing LIPA loss-of-function mutations into induced pluripotent stem cells and differentiating them into multicellular human liver organoids (HLO). LIPA-deficient HLO preserved hepatic lineage specification while recapitulating key biochemical and cellular features of WD, including loss of LIPA activity, lysosomal expansion, lipid accumulation, and activation of inflammatory and fibrogenic programs. Single-cell RNA sequencing resolved cell-type-specific disease states across hepatocyte-, stromal-, and biliary-like populations, revealing the emergence of a reactive biliary program consistent with ductular reaction, a complex tissue response associated with chronic liver injury. Importantly, this reactive biliary phenotype was supported by targeted gene-expression analysis in WD liver organoids and independently validated in liver tissue from mouse models and WD patients. Isolated LIPA-deficient cholangiocyte organoids failed to reproduce the DR-associated program, indicating that this response depends on multicellular interactions within the hepatic microenvironment rather than on biliary cell-autonomous dysfunction alone. Consistently, hepatocyte-directed AAV-mediated restoration of LIPA expression attenuated metabolic stress, inflammatory and fibrogenic programs, and suppressed ductular reaction both in organoids and in vivo. Together, these findings establish multicellular human liver organoids as a physiologically relevant platform for modelling emergent tissue-level responses in WD and for evaluating therapeutic rescue strategies in a human context.
2025-09-13 | The lysosomal acid lipase deficiency spectrum from infancy to adulthood: a multidisciplinary experience.
Lysosomal acid lipase (LAL) deficiency, an ultrarare autosomal recessive disorder related to LIPA gene variants, presents two clinical phenotypes: Wolman's disease (WD), which occurs early with severe presentation, and Cholesteryl Ester Storage Disease (CESD) with a milder and variable course mainly affecting lipid metabolism and liver function. Misdiagnosis risk, treatment effectiveness and long-term outcome are significant issues. Enzyme replacement therapy (ERT) represents the only effective choice in WD. This study aims to address diagnostic and therapeutic challenges and to explore the long-term effects of lipid-lowering therapy (LLT) in CESD. We retrospectively analyzed data collected over the last 30 years from seven LAL deficiency (LAL-D) patients, 2 WD infants and 5 CESD children and adults, including biochemical analysis, LAL enzyme activity, LIPA gene variants, carotid intima-media thickness and liver assessments by ultrasound, magnetic resonance imaging, transient elastography and biopsy. The variability of first clinical presentation delayed the diagnosis of CESD (from 4 to 52 years). WD twin infants presented with severe liver and gastrointestinal symptoms and died before 9 months of age. Ezetimibe treatment led to LDL-C and ALT improvement in 4/5 CESD patients (LDL-C 19 %, ALT 21.6 % mean decreases) without progression of liver fibrosis in the mid-to long-term follow-up. LAL-D mimics hyperlipidemias and liver disorders making a definitive diagnosis mandatory. Patients with CESD presentation should benefit from first level treatment with LLT before considering ERT which represents the option in case of unresponsiveness or symptoms progression while it represents the elective therapy for WD.
2026-04-19 | Secreted enzyme uptake masks the in vivo phenotype of macrophage-specific lysosomal acid lipase deletion.
Lysosomal acid lipase (LAL) is so far the only known intracellular enzyme that is capable of hydrolyzing triglycerides and cholesteryl esters at an acidic pH inside the lysosome. Mutations in the LAL-encoding Lipa gene cause a rare autosomal recessive lysosomal storage disorder in humans with massive lipid accumulation. In mice, the loss of systemic LAL is associated with severe lipid accumulation, particularly in the liver and small intestine, accompanied by infiltration of lipid-filled CD68+-TREM2+ macrophages. We hypothesize that macrophages are among the key players in LAL deficiency and are responsible for lipid accumulation in the affected tissues. We generated macrophage (mac)- and macrophage/enterocyte-specific (mac/int-) LAL KO mice and performed morphological, histopathological, and functional analyses under chow- and high-fat/high-cholesterol diet-fed conditions. We observed that neither macLAL-KO nor mac/int-LAL KO mice replicated the phenotype of whole-body LAL KO mice, as lipoprotein secretion, lipid absorption, and lipid accumulation remained unaffected. However, the absence of macrophage LAL ameliorated diet-induced obesity in both mouse lines. Notably, the lipid accumulation observed in the lysosomes of macrophages from whole-body LAL KO mice was absent in macrophages from macLAL-KO mice, attributable to residual LAL enzyme activity despite genetic ablation. Treatment of macrophages from whole-body LAL KO mice with conditioned medium of hepatocytes from macLAL-KO mice effectively prevented lipid accumulation. These findings suggest that LAL secreted from hepatocytes, macrophages, and possibly other cell types in vivo corrects the phenotype of cell type-specific LAL deficiency, a key insight for guiding future gene therapy strategies.
2025-12-22 | Human iPSC-derived liver organoids model multicellular tissue responses and therapeutic rescue in Wolman disease
Wolman disease (WD), the severe infantile form of lysosomal acid lipase deficiency, is a rare metabolic disorder caused by inactivating mutations in the LIPA gene. Although WD is characterized by profound hepatic dysfunction, experimental human systems capable of modelling multicellular liver pathology and supporting therapeutic testing remain limited. Here, we generated an isogenic human model of WD by introducing LIPA loss-of-function mutations into induced pluripotent stem cells and differentiating them into multicellular human liver organoids (HLO). LIPA-deficient HLO preserved hepatic lineage specification while recapitulating key biochemical and cellular features of WD, including loss of LIPA activity, lysosomal expansion, lipid accumulation, and activation of inflammatory and fibrogenic programs. Single-cell RNA sequencing resolved cell-type-specific disease states across hepatocyte-, stromal-, and biliary-like populations, revealing the emergence of a reactive biliary program consistent with ductular reaction, a complex tissue response associated with chronic liver injury. Importantly, this reactive biliary phenotype was supported by targeted gene-expression analysis in WD liver organoids and independently validated in liver tissue from mouse models and WD patients. Isolated LIPA-deficient cholangiocyte organoids failed to reproduce the DR-associated program, indicating that this response depends on multicellular interactions within the hepatic microenvironment rather than on biliary cell-autonomous dysfunction alone. Consistently, hepatocyte-directed AAV-mediated restoration of LIPA expression attenuated metabolic stress, inflammatory and fibrogenic programs, and suppressed ductular reaction both in organoids and in vivo. Together, these findings establish multicellular human liver organoids as a physiologically relevant platform for modelling emergent tissue-level responses in WD and for evaluating therapeutic rescue strategies in a human context.
2025-09-13 | The lysosomal acid lipase deficiency spectrum from infancy to adulthood: a multidisciplinary experience.
Lysosomal acid lipase (LAL) deficiency, an ultrarare autosomal recessive disorder related to LIPA gene variants, presents two clinical phenotypes: Wolman's disease (WD), which occurs early with severe presentation, and Cholesteryl Ester Storage Disease (CESD) with a milder and variable course mainly affecting lipid metabolism and liver function. Misdiagnosis risk, treatment effectiveness and long-term outcome are significant issues. Enzyme replacement therapy (ERT) represents the only effective choice in WD. This study aims to address diagnostic and therapeutic challenges and to explore the long-term effects of lipid-lowering therapy (LLT) in CESD. We retrospectively analyzed data collected over the last 30 years from seven LAL deficiency (LAL-D) patients, 2 WD infants and 5 CESD children and adults, including biochemical analysis, LAL enzyme activity, LIPA gene variants, carotid intima-media thickness and liver assessments by ultrasound, magnetic resonance imaging, transient elastography and biopsy. The variability of first clinical presentation delayed the diagnosis of CESD (from 4 to 52 years). WD twin infants presented with severe liver and gastrointestinal symptoms and died before 9 months of age. Ezetimibe treatment led to LDL-C and ALT improvement in 4/5 CESD patients (LDL-C 19 %, ALT 21.6 % mean decreases) without progression of liver fibrosis in the mid-to long-term follow-up. LAL-D mimics hyperlipidemias and liver disorders making a definitive diagnosis mandatory. Patients with CESD presentation should benefit from first level treatment with LLT before considering ERT which represents the option in case of unresponsiveness or symptoms progression while it represents the elective therapy for WD.
Access all drug discovery articles and probability of success in trials forecasts:
Access all drug discovery articles and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Wolman disease.
1 orphan drug designation for Wolman disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Recombinant human lysosomal acid lipase or cholesteryl ester hydrolase | proteins | FDA | 2005-07-14 | — | Lysosomal Acid Lipase, LLC |
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.