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:
categories:
Small molecules
cell therapies
2025-07-30 | Deletion of CH25H and LIPA Genes in Human Abolishes Biosynthesis of 25-Hydroxycholesterol but not of 7α,25-Dihydroxysterols and Enhances Non-enzymatic Cholesterol Oxidation: Metabolic Changes are Partially Reversed by Hematopoietic Stem Cell Transplant ‡
Abstract The CH25H ( cholesterol 25-hyroxylase ) and LIPA ( lipase A, lysosomal acid type ) genes are contiguous genes on chromosome 10. CH25H is translated to cholesterol 25-hydroxylase which generates 25- hydroxycholesterol (25-HC) from cholesterol, while LIPA codes for lysosomal acid lipase (LAL) which hydrolyses cholesteryl esters in the endosome – lysosome compartment. Here we report the effect on the oxysterol pattern in plasma of the homozygous deletion of these two genes and their restoration by allogeneic hematopoietic stem cell transplant (HSCT). In the absence of CH25H , 25-HC is not detected in plasma, but surprisingly, 7α,25-dihydroxysterols are present, indicating their formation by a second sterol 25-hydroxylase. As with the isolated deletion of LIPA seen in Wolman disease, patients with the homozygous contiguous deletion show high levels of cholesterol autoxidation products in plasma. HSCT of patients with the contiguous deletion restores both 25-HC and autoxidation products to normal levels following an initial burst in autoxidation soon after transplant.
2019-06-18 | A decade of excellent transplant survival in children with inherited metabolic diseases: A report from a single metabolic transplant centre in Europe
Hematopoietic cell transplantation (HCT) confers a long-term disease-modifying therapy for transplant-permissive inherited metabolic diseases (IMDs). We examined the overall survival (OS) and engrafted survival (ES) of children with IMDs, who received first HCT at Royal Manchester Children's hospital from 1985 to 2016. A total of 137 children with IMDs were included in this analysis (historical cohort [1985-2006], n＝65; current cohort [2007-2016], n＝72). Primary diagnoses included mucopolysaccharidoses (81%), X-linked adrenoleukodystrophy (6%), metachromatic leukodystrophy (4%), mannosidosis (3%), Wolman disease (2%), and other conditions (4%). The five-year OS has increased from 65% (95% confidence interval [CI], 52%-76%) in the historical cohort to 91% (95% CI, 81%-96%) in the current cohort (P<0.001). Moreover, the five-year ES, which was 64% (95 CI%, 56%-72%) for the entire cohort, has doubled from 41% (95% CI, 29%-53%) in the historical cohort to 85% (95% CI, 75%-92%) in the current cohort (P<0.001). The proportion of patients with graft failure has decreased from 37% in the historical cohort to 8% in the current cohort (P<0.001). In patients who received a second transplant, 13 out of 20 patients (65%) in the historical cohort and all four in the current cohort were alive and engrafted. Of 82 survivors followed-up at Manchester, 80% and 20% had full and mixed chimerism, respectively. Although this study was restricted to a single center, our findings show that HCT is an increasingly safe procedure and provides long-lasting endogenous enzyme replacement therapy for children with IMDs in the modern era of HCT.
2018-02-03 | A Decade of Low Transplant-Related Morbidity and Mortality in Children with Inherited Metabolic Diseases: A Report From a Single Metabolic Transplant Centre in the Europe
Hematopoietic cell transplantation (HCT) confers a long-term disease-modifying therapy for transplant-permissive inherited metabolic diseases (IMD). We examined the outcome of children with IMD received first HCT at Royal Manchester ChildrenÕs hospital from 1985 to 2016, a national metabolic transplant center in the United Kingdom. Cox proportional-hazard models were used to examine the predictors for overall survival. 137 children with IMD were included in this analysis (historical cohort (1985-2006), n = 65; current cohort (2007-2016), n = 72). Primary diagnoses were mucopolysaccharidoses (MPS, n = 112, 81%; MPS IH, n = 103, MPS II, n = 1, MPS III = 2, MPS VI = 6), X-linked adrenoleukodystrophy (XALD, n = 8, 6%), metachromatic leukodystrophy (n = 5, 4%), alpha mannosidosis (n = 4, 3%), Wolman disease (n = 3, 2%) and others (n = 5, 4%). The median age at transplant was 14.4 (range 1.6-220.7) months. Fifty-four children (40%) received relative donor HCT (marrow, n = 43 (78%), apheresis, n = 11 (20%) and cord blood (CB) = 2 (2%)) while 83 (60%) had unrelated donor HCT (marrow, n = 31 (37%), apheresis, n = 9 (11%) and CB, n = 43 (52%)). The estimated 5-year OS improved from 65% (95% CI, 53-76%) in the historical cohort to 91% (95%CI, 81-96%) in the current cohort (P < .001). Male (HR .35, 95%CI, .15-.81, P = .01) and grade III-IV GVHD (HR 5.10, 95%CI, 1.72-15.14, P = .003) were predictors for overall survival. In current cohort, none of the pre-transplant factors, transplant factors and transplant related complications were associated with OS. The estimated 5-year OS in children transplanted in the current cohort was 100% for XALD (n = 5), 98% (95% CI, 83%-98%) for MPS IH (n = 55) and 75% (95% CI, 42-92%) for other IMD. The estimated one-year TRM reduced from 23% (95% CI, 13-40%) in the historical cohort to 7% (95% CI, 3-18%) for current cohort (P = .006). The estimated 5-year engrafted survival (ES) has doubled from 41% (95% CI, 29-53%) in the historical cohort to 86% (95% CI, 75-92%) in the current cohort (P < .001). The proportion of patients with graft failure has decreased from 37% in the historical cohort to 8% in the current cohort (P < .001). Thirteen out of 18 patients (71%) in the historical cohort and all four patients (100%) in the current cohort receiving a second transplant were alive-and-engrafted. Of 82 survivors followed up at Manchester, 80% had full chimerism (_95% donor chimerism) while 20% had mixed chimerism (20-94% donor chimerism). Despite the limitation of a single centre, our findings reiterated the observation of HCT is a safe and life-long therapy for children with IMD. The outcome of a second transplant is good.
2013-03-20 | Unfavorable outcome of hematopoietic stem cell transplantation in two siblings with Wolman disease due to graft failure and hepatic complications
Wolman disease (WD) is a fatal storage disease caused by the deficiency of the lysosomal enzyme acid lipase. Only 3 cases of successful treatment by hematopoietic stem cell transplantation (HSCT), are reported. We report a case of two brothers with WD who were treated with HSCT, but both died from hepatic complications. Together they exemplify the obstacles to successful HSCT in WD. We suggest that different strategies should be investigated in order to offer treatment for this disease.
2010-02-01 | A Pilot Study Of Reduced Intensity Conditioning (RIC) With Busulfan, Fludarabine And Alemtuzumab (BFA) Prior To Allogeneic Stem Cell Transplantation (ALLOSCT) In Children And Adolescent (C&A) Recipients
AlloSCT following conditioning with fludarabine, busulfan, and alemtuzumab (BFA) in adult pts with AML/MDS was safe and permitted durable donor engraftment (Ho et al, Blood, 2004). There is a paucity of data of RIC with fludarabine, busulfan and rATG and none with alemtuzumab (BFA) in pediatric AlloSCT recipients. To determine the safety and percentage of mixed donor chimerism following a BFA RIC AlloSCT in C&A. We report results of a pilot study of BFA RIC AlloSCT in 12 recipients (<21 yrs) with malignant (n=7; 5 average-risk, 2 poor-risk: CML 4, APML 1, NHL 1, HTLV-LL 1), and non-malignant diseases (n=5: SAA 3, Scleroderma 1, Wolman's Disease 1). Median age 16 (2-20) yrs, 6F:6 M. Stem cell source: 2 unrelated cord blood (UCB) (2 5/6), 1 unrelated BM (10/10), 2 related (1 6/6, 1 5/6) and 7 unrelated PBSC (3 8/10, 3 9/10, 1 10/10). Positive CD34 selection was done in 5 unrelated PBSCT. RIC: fludarabine (180 mg/m2, 6 days), busulfan (16 mg/kg ≤4 yrs and 12.8 mg/kg for >4 yrs, 4 days, total 8 doses) + alemtuzumab (54 mg/m2, 5 escalating doses). GVHD prophylaxis: FK506/MMF. STR loci were used to measure donor chimerism. Median time to myeloid engraftment was 16d (16d vs. 16d for unselected PBSC/BM/CB vs. selected PBSC recipients, ns); median time to platelet engraftment: 31d (27d vs. 35d for unselected PBSC/BM/CB vs. selected PBSC recipients, ns). The probability of developing ≥grade II, ≥grade III AGVHD and CGVHD was 41.6%, 25%, and 9% respectively. There was 1 primary graft failure (GF), and no secondary GF. Median mixed donor chimerism day 100 and 1 yr: 99% and 96%, respectively; ≥90% of recipients achieved ≥80% donor chimerism. The 3 yr OS was 91.7±8% (100% for malignant vs 80% for non-malignant diseases, ns). The probability of 3 yr OS for patients receiving CD34-selected PBSC was 100% and receiving non-CD34-selected PBSC/BM/UCB was 85.7% (ns). 11 pts remain alive at median 2.8 (0.3-6.8) yrs. Only 1/12 developed ≥grade III toxicity (liver grade IV). Incidence of transplant-related mortality was 1/12 (9%). 1 patient died of IFI at day +40. Infectious complications included: CVL bacteremia (6/12), 2 IFI and 3 other fungal infections, 3 hematuria of viral etiology (BKV/ADV), and 1 each of ADV, CMV, RSV, Parainfluenza, HSV, or Mycobacterium infections. RI AlloSCT based on BFA conditioning is feasible and tolerable in C&A, and results in prompt achievement of durable mixed donor chimerism and excellent OS.
small molecules
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.
2023-08-02 | Evaluation of biochemical profile and oxidative damage to lipids and proteins in patients with lysosomal acid lipase deficiency.
Lysosomal acid lipase deficiency (LALD) is an inborn error of metabolism that lacks satisfactory treatment, which leads to the development of severe hepatic and cardiac complications and may even lead to death. In this sense, knowledge of the mechanisms involved in the pathophysiology of this disorder becomes essential to allow the search for new therapeutic strategies. There are no studies in the literature investigating the role of reactive species and inflammatory processes in the pathophysiology of this disorder. Therefore, the aim of this work was to investigate parameters of oxidative and inflammatory stress in LALD patients. In this work, we obtained results that demonstrate that LALD patients are susceptible to oxidative stress caused by an increase in the production of free radicals, observed by the increase of 2-7-dihydrodichlorofluorescein. The decrease in sulfhydryl content reflects oxidative damage to proteins, as well as a decrease in antioxidant defenses. Likewise, the increase in urinary levels of di-tyrosine observed also demonstrates oxidative damage to proteins. Furthermore, the determination of chitotriosidase activity in the plasma of patients with LALD was significantly higher, suggesting a pro-inflammatory state. An increase in plasma oxysterol levels was observed in patients with LALD, indicating an important relationship between this disease and cholesterol metabolism and oxidative stress. Also, we observed in LALD patients increased levels of nitrate production. The positive correlation found between oxysterol levels and activity of chitotriosidase in these patients indicates a possible link between the production of reactive species and inflammation. In addition, an increase in lipid profile biomarkers such as total and low-density lipoprotein cholesterol were demonstrated in the patients, which reinforces the involvement of cholesterol metabolism. Thus, we can assume that, in LALD, oxidative and nitrosative damage, in addition to inflammatory process, play an important role in its evolution and future clinical manifestations. In this way, we can suggest that the study of the potential benefit of the use of antioxidant and anti-inflammatory substances as an adjuvant tool in the treatment will be important, which should be associated with the already recommended therapy.
2023-03-16 | A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages.
Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves the transformation of infected phagolysosomes from a site of killing into a nutrient-rich replicative niche. Here, we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with terpenyl nucleoside-producing M. tuberculosis, caused intralysosomal and peribacillary lipid storage patterns that matched both the molecules and subcellular locations known in foamy macrophages. Lipidomics showed that 1-TbAd induced storage of triacylglycerides and cholesterylesters and that 1-TbAd increased M. tuberculosis growth under conditions of restricted lipid access in macrophages. Furthermore, lipidomics identified 1-TbAd-induced lipid substrates that define Gaucher's disease, Wolman's disease, and other inborn lysosomal storage diseases. These data identify genetic and molecular causes of M. tuberculosis-induced lysosomal failure, leading to successful testing of an agonist of TRPML1 calcium channels that reverses lipid storage in cells. These data establish the host-directed cellular functions of an orphan effector molecule that promotes survival in macrophages, providing both an upstream cause and detailed picture of lysosome failure in foamy macrophages.
2023-03-01 | LAL deficiency induced myeloid-derived suppressor cells as targets and biomarkers for lung cancer
Background Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells in tumor microenvironment, which suppress antitumor immunity. Expansion of various MDSC subpopulations is closely associated with poor clinical outcomes in cancer. Lysosomal acid lipase (LAL) is a key enzyme in the metabolic pathway of neutral lipids, whose deficiency (LAL-D) in mice induces the differentiation of myeloid lineage cells into MDSCs. These Lal -/- MDSCs not only suppress immune surveillance but also stimulate cancer cell proliferation and invasion. Understanding and elucidating the underlying mechanisms of MDSCs biogenesis will help to facilitate diagnosis/prognosis of cancer occurrence and prevent cancer growth and spreading. Methods Single-cell RNA sequencing (scRNA-seq) was performed to distinguish intrinsic molecular and cellular differences between normal versus Lal -/- bone marrow–derived Ly6G + myeloid populations in mice. In humans, LAL expression and metabolic pathways in various myeloid subsets of blood samples of patients with non-small cell lung cancer (NSCLC) were assessed by flow cytometry. The profiles of myeloid subsets were compared in patients with NSCLC before and after the treatment of programmed death-1 (PD-1) immunotherapy. Results scRNA-seq of Lal -/- CD11b + Ly6G + MDSCs identified two distinctive clusters with differential gene expression patterns and revealed a major metabolic shift towards glucose utilization and reactive oxygen species (ROS) overproduction. Blocking pyruvate dehydrogenase (PDH) in glycolysis reversed Lal -/- MDSCs’ capabilities of immunosuppression and tumor growth stimulation and reduced ROS overproduction. In the blood samples of human patients with NSCLC, LAL expression was significantly decreased in CD13 + /CD14 + /CD15 + /CD33 + myeloid cell subsets. Further analysis in the blood of patients with NSCLC revealed an expansion of CD13 + /CD14 + /CD15 + myeloid cell subsets, accompanied by upregulation of glucose-related and glutamine-related metabolic enzymes. Pharmacological inhibition of the LAL activity in the blood cells of healthy participants increased the numbers of CD13 + and CD14 + myeloid cell subsets. PD-1 checkpoint inhibitor treatment in patients with NSCLC reversed the increased number of CD13 + and CD14 + myeloid cell subsets and PDH levels in CD13 + myeloid cells. Conclusion These results demonstrate that LAL and the associated expansion of MDSCs could serve as targets and biomarkers for anticancer immunotherapy in humans.
2023-01-31 | Structure-based virtual screening to identify potential lipase inhibitors to reduce lipid storage in Wolman disorder.
Wolman disorder (WD) was first described in Iranian-Jewish (IJ) children, and it is caused by a deficiency of the lysosomal acid lipase (LAL). Newborns with WD are healthy and active at birth but soon develop severe malnutrition symptoms and often die before 1 year. In particular, spleens, livers, bone marrows, intestines, adrenal glands, and lymph nodes accumulate harmful amounts of lipids. G87V mutation in LIPA is responsible for Wolman disorder. Some reports suggest that δ-tocopherol can reduce lipid accumulation in cholesterol storage disorders. Hence, we used δ-tocopherol for the virtual screening process in this study. Initially, the lead compounds were docked with native and G87V mutant LIPA. Subsequently, the ADME and toxicity parameters for screened compounds were determined to ensure the safety profiles. Finally, the molecular dynamics simulations result indicated that dl-alpha-Tocopherol-13C3, a molecule obtained from the PubChem database, is identified as a potential and stable lead molecule that could be effective against the G87V mutant form of LIPA.
gene therapies
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.
2025-07-04 | Advanced Imaging and Cytometric Techniques to Characterize Lipid Accumulation in Wolman Disease.
Wolman disease (WD) is a severe lysosomal storage disorder characterized by fatal lipid accumulation caused by the deficiency of a lipid metabolic enzyme, Lysosomal Acid Lipase (LAL), involved in the lysosomal hydrolysis of cholesterols and triglycerides. Due to the imbalance of lipid homeostasis, WD patients suffer from severe hepatosplenomegaly, hepatic failure, and adrenal calcification resulting in a premature infant death within the first year of age. In this work, we explored multiple imaging analyses to fully characterize the phenotype of LAL-deficient cells. In particular, we stained WD patients' fibroblasts for intracellular lipid droplets (LD) and lysosomes, and we analyzed staining intensity and granularity, as well as an increased number of LD and lysosomes using fluorescence wide-field microscopy, confocal microscopy, conventional, and image flow cytometry. Noteworthy, we showed that lipid homeostasis was restored upon delivery of a functional LAL transgene. Finally, since fibroblasts cannot be used as routine clinical tests as they are difficult to collect from WD patients, we confirmed our observations in LAL deficient human blood cell lines and in peripheral blood mononuclear cells (PBMC) from the LAL deficient (LAL-D) mouse model, as a proxy for easily accessible WD PBMC. Overall, we expect that this novel imaging analysis pipeline will help to diagnose WD, follow its progression, and evaluate the success of enzyme replacement therapy or gene correction strategies for WD as well as other lysosomal storage disorders.
2025-03-18 | Novel cytometry-based characterization of lysosomal storage disease affected patient's cells
Wolman disease (WD) is a severe lysosomal storage disorder characterized by fatal lipid accumulation caused by the deficiency of a lipid metabolic enzyme, Lysosomal Acid Lipase (LAL), involved in the lysosomal hydrolysis of cholesterols and triglycerides. Due to the imbalance of lipids homeostasis, WD patients suffer from severe hepatosplenomegaly, hepatic failure and adrenal calcification resulting in a premature infant death within the first year of age. In this work, we explored multiple imaging analyses to fully characterize the phenotype of LAL deficient cells. In particular, we stained WD patients' fibroblasts for intracellular lipid droplets (LD) and lysosomes and we analysed staining intensity and granularity as well as an increased number of LD and lysosomes using fluorescence wide field microscopy, confocal microscopy, conventional and image flow cytometry. Noteworthy, we showed that lipid homeostasis was restored upon delivery of a functional LAL transgene. Finally, since fibroblasts cannot be used as routine clinical test as they are difficult to collect from WD patients, we confirmed our observations in LAL deficient human blood cell lines and in peripheral blood mononuclear cells (PBMC) from LAL deficient (LAL-D) mouse model, as a proxy for easily accessible WD PBMC. Overall, we expect that this novel imaging analysis pipeline will help to diagnose WD, follow its progression and evaluate the success of enzyme replacement therapy or gene correction strategies for WD as well as other lysosomal storage disorders.
2024-11-04 | Liver-directed AAV gene therapy normalizes disease symptoms and provides cross-correction in a model of lysosomal acid lipase deficiency.
Lysosomal acid lipase deficiency (LAL-D) is caused by mutations in the LIPA gene, which encodes the lysosomal enzyme that hydrolyzes triglycerides and cholesteryl esters to free fatty acids and free cholesterol. The objective of this study was to develop a curative single-treatment therapy for LAL-D using adeno-associated virus (AAV). Treatment at both early (1-2 days) and late (8-week) timepoints with rscAAVrh74.LP1.LIPA, a liver-directed AAV gene therapy, normalized many disease measures in Lipa-/- mice when measured at 24 weeks of age, including hepatosplenomegaly, serum transaminase activity, organ triglyceride and cholesterol levels, and biomarkers of liver inflammation and fibrosis. For most measures, liver-directed therapy was superior to therapy utilizing a constitutive tissue expression approach. rscAAVrh74.LP1.LIPA treatment elevated LAL enzyme activity above wild-type levels in all tissues tested, including liver, spleen, intestine, muscle, and brain, and treatment elicited minimal serum antibody responses to transgenic protein. AAV treatment at 8 weeks of age with 1 × 1013 vg/kg extended survival significantly, with all AAV-treated mice surviving beyond the maximal lifespan of untreated Lipa-/- mice. These results show that this liver-directed LIPA gene therapy has the potential to be a transformative treatment for LAL-D.
proteins
2026-01-28 | Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion.
Infantile-onset lysosomal acid lipase deficiency (LAL-D) (Wolman disease, historically) is a rare inherited, rapidly progressive disorder caused by pathogenic variants in the LIPA gene, which encodes the enzyme LAL. LAL is essential for the metabolism of cholesteryl esters and triglycerides. LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system. Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation. If untreated, rapidly progressive LAL-D typically leads to death within the first year of life. Treatment takes the two-pronged approach of sebelipase alfa, a human lysosomal acid lipase enzyme replacement therapy (ERT) that improves lipid metabolism, combined with nutritional management. Dietary substrate (lipid) reduction, known as substrate reduction therapy, is essential for optimal management in LAL-D. Following a nutritional plan and managing gastrointestinal disturbances together reduce systemic inflammation and improve growth, gut function, liver health, quality of life, and survival in patients with infantile-onset LAL-D. A multidisciplinary specialized team is necessary to manage the highly complex, multisystemic conditions in these patients. Nutritional management of LAL-D has evolved with increasing experience with the clinical management of ERT-treated infantile-onset LAL-D. A review of guidance for best practice nutritional management is needed. This narrative review aims to provide updated recommendations and guidance for the optimal nutritional management of infantile-onset LAL-D.
2024-12-30 | Results of Selective Biochemical Screening for Lysosomal Acid Lipase Deficiency and Sequencing of the LIPA Gene in the Risk Group Patients
Aim: to study the prevalence of lysosomal acid lipase deficiency (Wolman disease and cholesteryl ester storage disease) among high-risk patients using selective biochemical screening. Material and methods. Samples from 2805 patients are collected as dried blood spots on filter paper test forms. Biochemical study of the lysosomal acid lipase (LAL) enzyme activity was carried out according to Hamilton’s protocol of, using 4-methylumbelliferyl palmitate as a substrate and LAL inhibitor Lalistat-2. Changes in fluorescence in the wells were recorded on Wallac 1420 Multilabel Counter analyzer at absorption wavelength of 355 nm and emission wavelength of 460 nm. Sequencing of the LIPA gene (NM_001127605) was carried out on an Illumina MiSeq device (Illumina, USA) from dried blood spots from patients with reduced LAL enzyme activity to define genetic variations. Results. As a result of biochemical screening for LAL deficiency among patients from high-risk groups, 20 patients with reduced values of LAL enzyme activity were found. For 17 patients, search for mutations in the LIPA gene was carried out using NGS. In 9 patients, pathogenic genetic variants were found that led to decrease in LAL activity and the manifestation of clinical symptoms. In 100 % of detected cases, genetic mutations in the LIPA gene included single nucleotide substitution c.894G>A. Along with this mutation, two previously undescribed mutations (c.35dup and c.176A>G) were discovered in a compound heterozygous state. Conclusions. The variety of clinical symptoms and wide range of ages at which symptoms may begin (in the case of cholesteryl ester storage disease) can lead to errors in diagnosis. The c.894G>A variant is the most common variant worldwide among patients with a confirmed diagnosis of LAL deficiency and was present in all confirmed cases in this study, suggesting that this variant is the predominant mutation in the LIPA gene in Russian population. Pathogenicity status of previously undescribed discovered mutations (c.35dup and c.176A>G) needs to be determined.
cell therapies
2025-07-30 | Deletion of CH25H and LIPA Genes in Human Abolishes Biosynthesis of 25-Hydroxycholesterol but not of 7α,25-Dihydroxysterols and Enhances Non-enzymatic Cholesterol Oxidation: Metabolic Changes are Partially Reversed by Hematopoietic Stem Cell Transplant ‡
Abstract The CH25H ( cholesterol 25-hyroxylase ) and LIPA ( lipase A, lysosomal acid type ) genes are contiguous genes on chromosome 10. CH25H is translated to cholesterol 25-hydroxylase which generates 25- hydroxycholesterol (25-HC) from cholesterol, while LIPA codes for lysosomal acid lipase (LAL) which hydrolyses cholesteryl esters in the endosome – lysosome compartment. Here we report the effect on the oxysterol pattern in plasma of the homozygous deletion of these two genes and their restoration by allogeneic hematopoietic stem cell transplant (HSCT). In the absence of CH25H , 25-HC is not detected in plasma, but surprisingly, 7α,25-dihydroxysterols are present, indicating their formation by a second sterol 25-hydroxylase. As with the isolated deletion of LIPA seen in Wolman disease, patients with the homozygous contiguous deletion show high levels of cholesterol autoxidation products in plasma. HSCT of patients with the contiguous deletion restores both 25-HC and autoxidation products to normal levels following an initial burst in autoxidation soon after transplant.
2019-06-18 | A decade of excellent transplant survival in children with inherited metabolic diseases: A report from a single metabolic transplant centre in Europe
Hematopoietic cell transplantation (HCT) confers a long-term disease-modifying therapy for transplant-permissive inherited metabolic diseases (IMDs). We examined the overall survival (OS) and engrafted survival (ES) of children with IMDs, who received first HCT at Royal Manchester Children's hospital from 1985 to 2016. A total of 137 children with IMDs were included in this analysis (historical cohort [1985-2006], n＝65; current cohort [2007-2016], n＝72). Primary diagnoses included mucopolysaccharidoses (81%), X-linked adrenoleukodystrophy (6%), metachromatic leukodystrophy (4%), mannosidosis (3%), Wolman disease (2%), and other conditions (4%). The five-year OS has increased from 65% (95% confidence interval [CI], 52%-76%) in the historical cohort to 91% (95% CI, 81%-96%) in the current cohort (P<0.001). Moreover, the five-year ES, which was 64% (95 CI%, 56%-72%) for the entire cohort, has doubled from 41% (95% CI, 29%-53%) in the historical cohort to 85% (95% CI, 75%-92%) in the current cohort (P<0.001). The proportion of patients with graft failure has decreased from 37% in the historical cohort to 8% in the current cohort (P<0.001). In patients who received a second transplant, 13 out of 20 patients (65%) in the historical cohort and all four in the current cohort were alive and engrafted. Of 82 survivors followed-up at Manchester, 80% and 20% had full and mixed chimerism, respectively. Although this study was restricted to a single center, our findings show that HCT is an increasingly safe procedure and provides long-lasting endogenous enzyme replacement therapy for children with IMDs in the modern era of HCT.
2018-02-03 | A Decade of Low Transplant-Related Morbidity and Mortality in Children with Inherited Metabolic Diseases: A Report From a Single Metabolic Transplant Centre in the Europe
Hematopoietic cell transplantation (HCT) confers a long-term disease-modifying therapy for transplant-permissive inherited metabolic diseases (IMD). We examined the outcome of children with IMD received first HCT at Royal Manchester ChildrenÕs hospital from 1985 to 2016, a national metabolic transplant center in the United Kingdom. Cox proportional-hazard models were used to examine the predictors for overall survival. 137 children with IMD were included in this analysis (historical cohort (1985-2006), n = 65; current cohort (2007-2016), n = 72). Primary diagnoses were mucopolysaccharidoses (MPS, n = 112, 81%; MPS IH, n = 103, MPS II, n = 1, MPS III = 2, MPS VI = 6), X-linked adrenoleukodystrophy (XALD, n = 8, 6%), metachromatic leukodystrophy (n = 5, 4%), alpha mannosidosis (n = 4, 3%), Wolman disease (n = 3, 2%) and others (n = 5, 4%). The median age at transplant was 14.4 (range 1.6-220.7) months. Fifty-four children (40%) received relative donor HCT (marrow, n = 43 (78%), apheresis, n = 11 (20%) and cord blood (CB) = 2 (2%)) while 83 (60%) had unrelated donor HCT (marrow, n = 31 (37%), apheresis, n = 9 (11%) and CB, n = 43 (52%)). The estimated 5-year OS improved from 65% (95% CI, 53-76%) in the historical cohort to 91% (95%CI, 81-96%) in the current cohort (P < .001). Male (HR .35, 95%CI, .15-.81, P = .01) and grade III-IV GVHD (HR 5.10, 95%CI, 1.72-15.14, P = .003) were predictors for overall survival. In current cohort, none of the pre-transplant factors, transplant factors and transplant related complications were associated with OS. The estimated 5-year OS in children transplanted in the current cohort was 100% for XALD (n = 5), 98% (95% CI, 83%-98%) for MPS IH (n = 55) and 75% (95% CI, 42-92%) for other IMD. The estimated one-year TRM reduced from 23% (95% CI, 13-40%) in the historical cohort to 7% (95% CI, 3-18%) for current cohort (P = .006). The estimated 5-year engrafted survival (ES) has doubled from 41% (95% CI, 29-53%) in the historical cohort to 86% (95% CI, 75-92%) in the current cohort (P < .001). The proportion of patients with graft failure has decreased from 37% in the historical cohort to 8% in the current cohort (P < .001). Thirteen out of 18 patients (71%) in the historical cohort and all four patients (100%) in the current cohort receiving a second transplant were alive-and-engrafted. Of 82 survivors followed up at Manchester, 80% had full chimerism (_95% donor chimerism) while 20% had mixed chimerism (20-94% donor chimerism). Despite the limitation of a single centre, our findings reiterated the observation of HCT is a safe and life-long therapy for children with IMD. The outcome of a second transplant is good.
2013-03-20 | Unfavorable outcome of hematopoietic stem cell transplantation in two siblings with Wolman disease due to graft failure and hepatic complications
Wolman disease (WD) is a fatal storage disease caused by the deficiency of the lysosomal enzyme acid lipase. Only 3 cases of successful treatment by hematopoietic stem cell transplantation (HSCT), are reported. We report a case of two brothers with WD who were treated with HSCT, but both died from hepatic complications. Together they exemplify the obstacles to successful HSCT in WD. We suggest that different strategies should be investigated in order to offer treatment for this disease.
2010-02-01 | A Pilot Study Of Reduced Intensity Conditioning (RIC) With Busulfan, Fludarabine And Alemtuzumab (BFA) Prior To Allogeneic Stem Cell Transplantation (ALLOSCT) In Children And Adolescent (C&A) Recipients
AlloSCT following conditioning with fludarabine, busulfan, and alemtuzumab (BFA) in adult pts with AML/MDS was safe and permitted durable donor engraftment (Ho et al, Blood, 2004). There is a paucity of data of RIC with fludarabine, busulfan and rATG and none with alemtuzumab (BFA) in pediatric AlloSCT recipients. To determine the safety and percentage of mixed donor chimerism following a BFA RIC AlloSCT in C&A. We report results of a pilot study of BFA RIC AlloSCT in 12 recipients (<21 yrs) with malignant (n=7; 5 average-risk, 2 poor-risk: CML 4, APML 1, NHL 1, HTLV-LL 1), and non-malignant diseases (n=5: SAA 3, Scleroderma 1, Wolman's Disease 1). Median age 16 (2-20) yrs, 6F:6 M. Stem cell source: 2 unrelated cord blood (UCB) (2 5/6), 1 unrelated BM (10/10), 2 related (1 6/6, 1 5/6) and 7 unrelated PBSC (3 8/10, 3 9/10, 1 10/10). Positive CD34 selection was done in 5 unrelated PBSCT. RIC: fludarabine (180 mg/m2, 6 days), busulfan (16 mg/kg ≤4 yrs and 12.8 mg/kg for >4 yrs, 4 days, total 8 doses) + alemtuzumab (54 mg/m2, 5 escalating doses). GVHD prophylaxis: FK506/MMF. STR loci were used to measure donor chimerism. Median time to myeloid engraftment was 16d (16d vs. 16d for unselected PBSC/BM/CB vs. selected PBSC recipients, ns); median time to platelet engraftment: 31d (27d vs. 35d for unselected PBSC/BM/CB vs. selected PBSC recipients, ns). The probability of developing ≥grade II, ≥grade III AGVHD and CGVHD was 41.6%, 25%, and 9% respectively. There was 1 primary graft failure (GF), and no secondary GF. Median mixed donor chimerism day 100 and 1 yr: 99% and 96%, respectively; ≥90% of recipients achieved ≥80% donor chimerism. The 3 yr OS was 91.7±8% (100% for malignant vs 80% for non-malignant diseases, ns). The probability of 3 yr OS for patients receiving CD34-selected PBSC was 100% and receiving non-CD34-selected PBSC/BM/UCB was 85.7% (ns). 11 pts remain alive at median 2.8 (0.3-6.8) yrs. Only 1/12 developed ≥grade III toxicity (liver grade IV). Incidence of transplant-related mortality was 1/12 (9%). 1 patient died of IFI at day +40. Infectious complications included: CVL bacteremia (6/12), 2 IFI and 3 other fungal infections, 3 hematuria of viral etiology (BKV/ADV), and 1 each of ADV, CMV, RSV, Parainfluenza, HSV, or Mycobacterium infections. RI AlloSCT based on BFA conditioning is feasible and tolerable in C&A, and results in prompt achievement of durable mixed donor chimerism and excellent OS.
small molecules
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.
2023-08-02 | Evaluation of biochemical profile and oxidative damage to lipids and proteins in patients with lysosomal acid lipase deficiency.
Lysosomal acid lipase deficiency (LALD) is an inborn error of metabolism that lacks satisfactory treatment, which leads to the development of severe hepatic and cardiac complications and may even lead to death. In this sense, knowledge of the mechanisms involved in the pathophysiology of this disorder becomes essential to allow the search for new therapeutic strategies. There are no studies in the literature investigating the role of reactive species and inflammatory processes in the pathophysiology of this disorder. Therefore, the aim of this work was to investigate parameters of oxidative and inflammatory stress in LALD patients. In this work, we obtained results that demonstrate that LALD patients are susceptible to oxidative stress caused by an increase in the production of free radicals, observed by the increase of 2-7-dihydrodichlorofluorescein. The decrease in sulfhydryl content reflects oxidative damage to proteins, as well as a decrease in antioxidant defenses. Likewise, the increase in urinary levels of di-tyrosine observed also demonstrates oxidative damage to proteins. Furthermore, the determination of chitotriosidase activity in the plasma of patients with LALD was significantly higher, suggesting a pro-inflammatory state. An increase in plasma oxysterol levels was observed in patients with LALD, indicating an important relationship between this disease and cholesterol metabolism and oxidative stress. Also, we observed in LALD patients increased levels of nitrate production. The positive correlation found between oxysterol levels and activity of chitotriosidase in these patients indicates a possible link between the production of reactive species and inflammation. In addition, an increase in lipid profile biomarkers such as total and low-density lipoprotein cholesterol were demonstrated in the patients, which reinforces the involvement of cholesterol metabolism. Thus, we can assume that, in LALD, oxidative and nitrosative damage, in addition to inflammatory process, play an important role in its evolution and future clinical manifestations. In this way, we can suggest that the study of the potential benefit of the use of antioxidant and anti-inflammatory substances as an adjuvant tool in the treatment will be important, which should be associated with the already recommended therapy.
2023-03-16 | A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages.
Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves the transformation of infected phagolysosomes from a site of killing into a nutrient-rich replicative niche. Here, we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with terpenyl nucleoside-producing M. tuberculosis, caused intralysosomal and peribacillary lipid storage patterns that matched both the molecules and subcellular locations known in foamy macrophages. Lipidomics showed that 1-TbAd induced storage of triacylglycerides and cholesterylesters and that 1-TbAd increased M. tuberculosis growth under conditions of restricted lipid access in macrophages. Furthermore, lipidomics identified 1-TbAd-induced lipid substrates that define Gaucher's disease, Wolman's disease, and other inborn lysosomal storage diseases. These data identify genetic and molecular causes of M. tuberculosis-induced lysosomal failure, leading to successful testing of an agonist of TRPML1 calcium channels that reverses lipid storage in cells. These data establish the host-directed cellular functions of an orphan effector molecule that promotes survival in macrophages, providing both an upstream cause and detailed picture of lysosome failure in foamy macrophages.
2023-03-01 | LAL deficiency induced myeloid-derived suppressor cells as targets and biomarkers for lung cancer
Background Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells in tumor microenvironment, which suppress antitumor immunity. Expansion of various MDSC subpopulations is closely associated with poor clinical outcomes in cancer. Lysosomal acid lipase (LAL) is a key enzyme in the metabolic pathway of neutral lipids, whose deficiency (LAL-D) in mice induces the differentiation of myeloid lineage cells into MDSCs. These Lal -/- MDSCs not only suppress immune surveillance but also stimulate cancer cell proliferation and invasion. Understanding and elucidating the underlying mechanisms of MDSCs biogenesis will help to facilitate diagnosis/prognosis of cancer occurrence and prevent cancer growth and spreading. Methods Single-cell RNA sequencing (scRNA-seq) was performed to distinguish intrinsic molecular and cellular differences between normal versus Lal -/- bone marrow–derived Ly6G + myeloid populations in mice. In humans, LAL expression and metabolic pathways in various myeloid subsets of blood samples of patients with non-small cell lung cancer (NSCLC) were assessed by flow cytometry. The profiles of myeloid subsets were compared in patients with NSCLC before and after the treatment of programmed death-1 (PD-1) immunotherapy. Results scRNA-seq of Lal -/- CD11b + Ly6G + MDSCs identified two distinctive clusters with differential gene expression patterns and revealed a major metabolic shift towards glucose utilization and reactive oxygen species (ROS) overproduction. Blocking pyruvate dehydrogenase (PDH) in glycolysis reversed Lal -/- MDSCs’ capabilities of immunosuppression and tumor growth stimulation and reduced ROS overproduction. In the blood samples of human patients with NSCLC, LAL expression was significantly decreased in CD13 + /CD14 + /CD15 + /CD33 + myeloid cell subsets. Further analysis in the blood of patients with NSCLC revealed an expansion of CD13 + /CD14 + /CD15 + myeloid cell subsets, accompanied by upregulation of glucose-related and glutamine-related metabolic enzymes. Pharmacological inhibition of the LAL activity in the blood cells of healthy participants increased the numbers of CD13 + and CD14 + myeloid cell subsets. PD-1 checkpoint inhibitor treatment in patients with NSCLC reversed the increased number of CD13 + and CD14 + myeloid cell subsets and PDH levels in CD13 + myeloid cells. Conclusion These results demonstrate that LAL and the associated expansion of MDSCs could serve as targets and biomarkers for anticancer immunotherapy in humans.
2023-01-31 | Structure-based virtual screening to identify potential lipase inhibitors to reduce lipid storage in Wolman disorder.
Wolman disorder (WD) was first described in Iranian-Jewish (IJ) children, and it is caused by a deficiency of the lysosomal acid lipase (LAL). Newborns with WD are healthy and active at birth but soon develop severe malnutrition symptoms and often die before 1 year. In particular, spleens, livers, bone marrows, intestines, adrenal glands, and lymph nodes accumulate harmful amounts of lipids. G87V mutation in LIPA is responsible for Wolman disorder. Some reports suggest that δ-tocopherol can reduce lipid accumulation in cholesterol storage disorders. Hence, we used δ-tocopherol for the virtual screening process in this study. Initially, the lead compounds were docked with native and G87V mutant LIPA. Subsequently, the ADME and toxicity parameters for screened compounds were determined to ensure the safety profiles. Finally, the molecular dynamics simulations result indicated that dl-alpha-Tocopherol-13C3, a molecule obtained from the PubChem database, is identified as a potential and stable lead molecule that could be effective against the G87V mutant form of LIPA.
gene therapies
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.
2025-07-04 | Advanced Imaging and Cytometric Techniques to Characterize Lipid Accumulation in Wolman Disease.
Wolman disease (WD) is a severe lysosomal storage disorder characterized by fatal lipid accumulation caused by the deficiency of a lipid metabolic enzyme, Lysosomal Acid Lipase (LAL), involved in the lysosomal hydrolysis of cholesterols and triglycerides. Due to the imbalance of lipid homeostasis, WD patients suffer from severe hepatosplenomegaly, hepatic failure, and adrenal calcification resulting in a premature infant death within the first year of age. In this work, we explored multiple imaging analyses to fully characterize the phenotype of LAL-deficient cells. In particular, we stained WD patients' fibroblasts for intracellular lipid droplets (LD) and lysosomes, and we analyzed staining intensity and granularity, as well as an increased number of LD and lysosomes using fluorescence wide-field microscopy, confocal microscopy, conventional, and image flow cytometry. Noteworthy, we showed that lipid homeostasis was restored upon delivery of a functional LAL transgene. Finally, since fibroblasts cannot be used as routine clinical tests as they are difficult to collect from WD patients, we confirmed our observations in LAL deficient human blood cell lines and in peripheral blood mononuclear cells (PBMC) from the LAL deficient (LAL-D) mouse model, as a proxy for easily accessible WD PBMC. Overall, we expect that this novel imaging analysis pipeline will help to diagnose WD, follow its progression, and evaluate the success of enzyme replacement therapy or gene correction strategies for WD as well as other lysosomal storage disorders.
2025-03-18 | Novel cytometry-based characterization of lysosomal storage disease affected patient's cells
Wolman disease (WD) is a severe lysosomal storage disorder characterized by fatal lipid accumulation caused by the deficiency of a lipid metabolic enzyme, Lysosomal Acid Lipase (LAL), involved in the lysosomal hydrolysis of cholesterols and triglycerides. Due to the imbalance of lipids homeostasis, WD patients suffer from severe hepatosplenomegaly, hepatic failure and adrenal calcification resulting in a premature infant death within the first year of age. In this work, we explored multiple imaging analyses to fully characterize the phenotype of LAL deficient cells. In particular, we stained WD patients' fibroblasts for intracellular lipid droplets (LD) and lysosomes and we analysed staining intensity and granularity as well as an increased number of LD and lysosomes using fluorescence wide field microscopy, confocal microscopy, conventional and image flow cytometry. Noteworthy, we showed that lipid homeostasis was restored upon delivery of a functional LAL transgene. Finally, since fibroblasts cannot be used as routine clinical test as they are difficult to collect from WD patients, we confirmed our observations in LAL deficient human blood cell lines and in peripheral blood mononuclear cells (PBMC) from LAL deficient (LAL-D) mouse model, as a proxy for easily accessible WD PBMC. Overall, we expect that this novel imaging analysis pipeline will help to diagnose WD, follow its progression and evaluate the success of enzyme replacement therapy or gene correction strategies for WD as well as other lysosomal storage disorders.
2024-11-04 | Liver-directed AAV gene therapy normalizes disease symptoms and provides cross-correction in a model of lysosomal acid lipase deficiency.
Lysosomal acid lipase deficiency (LAL-D) is caused by mutations in the LIPA gene, which encodes the lysosomal enzyme that hydrolyzes triglycerides and cholesteryl esters to free fatty acids and free cholesterol. The objective of this study was to develop a curative single-treatment therapy for LAL-D using adeno-associated virus (AAV). Treatment at both early (1-2 days) and late (8-week) timepoints with rscAAVrh74.LP1.LIPA, a liver-directed AAV gene therapy, normalized many disease measures in Lipa-/- mice when measured at 24 weeks of age, including hepatosplenomegaly, serum transaminase activity, organ triglyceride and cholesterol levels, and biomarkers of liver inflammation and fibrosis. For most measures, liver-directed therapy was superior to therapy utilizing a constitutive tissue expression approach. rscAAVrh74.LP1.LIPA treatment elevated LAL enzyme activity above wild-type levels in all tissues tested, including liver, spleen, intestine, muscle, and brain, and treatment elicited minimal serum antibody responses to transgenic protein. AAV treatment at 8 weeks of age with 1 × 1013 vg/kg extended survival significantly, with all AAV-treated mice surviving beyond the maximal lifespan of untreated Lipa-/- mice. These results show that this liver-directed LIPA gene therapy has the potential to be a transformative treatment for LAL-D.
proteins
2026-01-28 | Best Practices for the Nutritional Management of Infantile-Onset Lysosomal Acid Lipase Deficiency: A Case-Based Discussion.
Infantile-onset lysosomal acid lipase deficiency (LAL-D) (Wolman disease, historically) is a rare inherited, rapidly progressive disorder caused by pathogenic variants in the LIPA gene, which encodes the enzyme LAL. LAL is essential for the metabolism of cholesteryl esters and triglycerides. LAL deficiency leads to the accumulation of cholesteryl esters and triglycerides within the lysosomes, macrophages, and parenchymal cells in most tissue types, including those in the liver, gastrointestinal tract, and lymph nodes but excluding the central nervous system. Infants with rapidly progressive LAL-D present with gastrointestinal disturbance, adrenomegaly with calcification, hepatosplenomegaly, growth failure due to malabsorption, and systemic inflammation. If untreated, rapidly progressive LAL-D typically leads to death within the first year of life. Treatment takes the two-pronged approach of sebelipase alfa, a human lysosomal acid lipase enzyme replacement therapy (ERT) that improves lipid metabolism, combined with nutritional management. Dietary substrate (lipid) reduction, known as substrate reduction therapy, is essential for optimal management in LAL-D. Following a nutritional plan and managing gastrointestinal disturbances together reduce systemic inflammation and improve growth, gut function, liver health, quality of life, and survival in patients with infantile-onset LAL-D. A multidisciplinary specialized team is necessary to manage the highly complex, multisystemic conditions in these patients. Nutritional management of LAL-D has evolved with increasing experience with the clinical management of ERT-treated infantile-onset LAL-D. A review of guidance for best practice nutritional management is needed. This narrative review aims to provide updated recommendations and guidance for the optimal nutritional management of infantile-onset LAL-D.
2024-12-30 | Results of Selective Biochemical Screening for Lysosomal Acid Lipase Deficiency and Sequencing of the LIPA Gene in the Risk Group Patients
Aim: to study the prevalence of lysosomal acid lipase deficiency (Wolman disease and cholesteryl ester storage disease) among high-risk patients using selective biochemical screening. Material and methods. Samples from 2805 patients are collected as dried blood spots on filter paper test forms. Biochemical study of the lysosomal acid lipase (LAL) enzyme activity was carried out according to Hamilton’s protocol of, using 4-methylumbelliferyl palmitate as a substrate and LAL inhibitor Lalistat-2. Changes in fluorescence in the wells were recorded on Wallac 1420 Multilabel Counter analyzer at absorption wavelength of 355 nm and emission wavelength of 460 nm. Sequencing of the LIPA gene (NM_001127605) was carried out on an Illumina MiSeq device (Illumina, USA) from dried blood spots from patients with reduced LAL enzyme activity to define genetic variations. Results. As a result of biochemical screening for LAL deficiency among patients from high-risk groups, 20 patients with reduced values of LAL enzyme activity were found. For 17 patients, search for mutations in the LIPA gene was carried out using NGS. In 9 patients, pathogenic genetic variants were found that led to decrease in LAL activity and the manifestation of clinical symptoms. In 100 % of detected cases, genetic mutations in the LIPA gene included single nucleotide substitution c.894G>A. Along with this mutation, two previously undescribed mutations (c.35dup and c.176A>G) were discovered in a compound heterozygous state. Conclusions. The variety of clinical symptoms and wide range of ages at which symptoms may begin (in the case of cholesteryl ester storage disease) can lead to errors in diagnosis. The c.894G>A variant is the most common variant worldwide among patients with a confirmed diagnosis of LAL deficiency and was present in all confirmed cases in this study, suggesting that this variant is the predominant mutation in the LIPA gene in Russian population. Pathogenicity status of previously undescribed discovered mutations (c.35dup and c.176A>G) needs to be determined.
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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 |
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