RARE DISEASE
Lysosomal acid lipase deficiency
Lysosomal acid lipase deficiency
Lysosomal acid lipase deficiency
Synonyms: LAL deficiency, LALD
Synonyms: LAL deficiency, LALD
Synonyms: LAL deficiency, LALD
Drug discovery
2
drugs
With orphan designations
Overview
Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive disorder caused by LIPA gene mutations, resulting in deficient enzyme activity and systemic accumulation of cholesteryl esters and triglycerides [1][2][4]. It manifests as a clinical spectrum: infantile-onset Wolman disease (rapid progression to liver failure) or later-onset cholesteryl ester storage disease (CESD), characterized by hepatosplenomegaly, dyslipidemia, and premature atherosclerosis [4][9][12]. Diagnosis involves LAL enzyme activity assays and molecular genetic testing [1][6]. Enzyme replacement therapy (sebelipase alfa) improves survival and metabolic parameters [6][8][18].
Burden
Infantile forms are fatal without ERT (median survival <1 year) [1][16]. Later-onset disease causes progressive liver fibrosis (67% of cases), cirrhosis, and accelerated atherosclerosis [4][9]. Despite ERT, lifelong treatment costs remain high, with residual risks of hepatic and cardiovascular complications [3][6].
Therapies
Enzyme replacement therapy (sebelipase alfa) as first-line, reducing hepatic lipid content and improving lipid profiles [3][8][18].
Supportive measures: statins, ezetimibe, and low-fat diets to manage dyslipidemia [3][6][8].
Liver transplantation for end-stage cirrhosis, though outcomes vary [3][6].
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism, rare transplant-related disorders
Research Papers
182 drug discovery papers about Lysosomal acid lipase deficiency, with 2 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
182 drug discovery papers about Lysosomal acid lipase deficiency, with 2 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-03-29 | Lysosomal cholesteryl ester hydrolysis drives white matter repair by reprogramming microglia into a novel reparative state.
White matter repair relies on microglial clearance of cholesterol-rich myelin debris. Microglia have been reported to predominantly depend on de novo sterol synthesis to support this repair process. Lysosomal acid lipase (LAL) is the only known lysosomal enzyme capable of hydrolyzing cholesterol esters. In stark contrast to previous studies, we demonstrate here that LAL-mediated lysosomal lipolysis—not de novo sterol synthesis—serves as a central determinant of the microglial capacity to drive white matter repair. Using single-cell RNA sequencing, we identified a novel reparative microglial state characterized by simultaneously high expression of glycoprotein nonmetastatic melanoma protein B (GPNMB) and LAL. Following white matter injury, GPNMB+ microglia expanded and constituted the major microglial subset responsible for myelin debris engulfment. However, GPNMB+ microglia displayed context-dependent capacity to digest internalized myelin debris and mediate remyelination, with marked differences between reparable white matter injury and nonregenerative injury induced by white matter stroke (WMS). Transcriptomic profiling identified LAL as a key regulator of the reparative phenotype in GPNMB+ microglia. Independent of cytosolic lipases—widely regarded as synergistic mediators of LAL in cholesteryl ester hydrolysis, microglial LAL was both indispensable for myelin debris clearance and spontaneous remyelination in the reparable injury model, and sufficient to restore these processes following WMS-induced irreparable white matter injury. Mechanistically, LAL-mediated lysosomal lipolysis constituted the primary pathway for cholesteryl ester hydrolysis in microglia after white matter injury. This pathway converted cholesteryl esters into free cholesterol and activates liver X receptors (LXRs), both of which were required to reprogram microglial into the reparative state. Consistently, LXR activation alone was insufficient to rescue defective white matter repair caused by LAL deficiency. Hydroxypropyl-β-cyclodextrin (HβCD), an FDA-approved drug carrier, effectively lowers intracellular cholesterol levels through incompletely defined mechanisms. HβCD specifically upregulated LAL expression within white matter lesions and promoted remyelination via a LAL-dependent manner following WMS, supporting its potential as a therapeutic agent for WMS. Collectively, this study identifies lysosomal cholesterol ester hydrolysis as a novel therapeutic target for the treatment of irreversible white matter injury.
2026-02-01 | Lysosomal acid lipase is essential in cholesterol-mediated mTORC1 signaling activation by maintaining a balance between cholesterol ester and free cholesterol in zebrafish
Cholesterol, as a signaling molecule, plays a critical role in regulating the mTORC1 signaling pathway within cells. Lysosomal acid lipase (LAL) is responsible for hydrolyzing cholesterol ester and triglyceride in lysosomes. However, the involvement of LAL in the regulation of the mTORC1 signaling pathway in animals remains controversial. Our study found that lal -deficient zebrafish exhibited retarded growth and reduced body protein content compared to wild type zebrafish. Correspondingly, the mTORC1 signaling pathway was significantly inhibited in the liver of lal −/− zebrafish. Additionally, both lal knockdown and lalistat (LAL inhibitor) treatments led to the accumulation of cholesterol ester (CE) and a decrease in free cholesterol (FC) within lysosomes of zebrafish liver (ZFL) cells. This imbalance inhibited the recruitment of mTORC1 to the lysosomal surface and suppressed the mTORC1 signaling pathway. Moreover, FC treatment promoted the recruitment of mTORC1 to the lysosomal surface and activated the mTORC1 signaling pathway regardless of LAL, whereas LDL-dependent mTORC1 activation required LAL. However, knockdown of slc38a9 (a cholesterol sensor) blocked the recruitment of mTORC1 in ZFL cells treated with FC or LDL. Furthermore, the interaction between P14 (a component of Ragulator complex) and RagA/C was weakened in ZFL cells following treatment with FC or LDL but was enhanced upon slc38a9 knockdown. In addition, both lal siRNA and lalistat treatments increased the interaction between P14 and RagA/C. Our findings indicated that LAL dysfunction hindered the recruitment and activation of mTORC1 through the Slc38a9-mediated lysosomal mTORC1-scaffolding complex in ZFL cells. This inhibition was associated with a decrease in lysosomal FC, which is detected by cholesterol sensor SLC38A9. Therefore, interventions targeting the role of LAL role in the hydrolysis of cholesterol esters within lysosomes could offer promising therapeutic strategies for diseases associated with dysregulated mTORC1 signaling in animals. • Lal -deficient zebrafish exhibited retarded growth and lower body protein content. • Lal -deficiency decreased lysosomal free cholesterol content in zebrafish liver cells. • Lysosomal cholesterol level regulated recruitment and activation of mTORC1 through Slc38a9.
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.
2024-11-28 | Supplementation of diet with Astaxanthin and DHA prevents gestational and lactational undernourishment-induced metabolic derangements in dams: a metabolomic approach.
Nutrition is the critical nongenetic factor that has a major influence on the health status of an organism. The nutritional status of the mother during gestation and lactation plays a vital role in defining the offspring's health. Undernutrition during these critical periods may induce chronic metabolic disorders like obesity and cardiovascular diseases in mothers as well as in offspring. The present study aims to evaluate the impact of undernutrition during gestational and lactational periods on the plasma metabolic profile of dams. Additionally, we investigated the potential synergistic mitigating effects of astaxanthin and docosahexaenoic acid (DHA) on dysregulated plasma metabolic profiles. Evaluation of plasma lipid profile revealed that undernourishment resulted in elevated levels of total cholesterol, triglycerides, low density and very low-density lipoproteins in dams. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based untargeted metabolomics illustrated that pathways related to lipid metabolism, such as cholesterol metabolism, steroid biosynthesis and metabolism of amine-derived hormones, were dysregulated by undernourishment. Additionally, pathway enrichment analysis predicted that there is a high incidence of development of desmosterolosis, hypercholesterolaemia, lysosomal acid lipase deficiency and Smith-Lemli-Opitz syndrome in the offspring, reflecting predisposition in mothers. However, synergistic supplementation of astaxanthin and DHA ameliorated these adverse effects by regulating a separate set of metabolic pathways associated with lipid metabolism. They included branched chain amino acid degradation such as valine, leucine and isoleucine, metabolism of alpha-linolenic acid, lipoic acid, lysine degradation, biosynthesis, elongation and degradation of fatty acids.
2024-04-01 | Characterization of lysosomal acid lipase in Ly6G+ and CD11c+ myeloid-derived suppressor cells.
Lysosomal acid lipase (LAL) is a key enzyme in the metabolic pathway of neutral lipids, whose deficiency (LAL-D) induces the differentiation of myeloid lineage cells into myeloid-derived suppressor cells (MDSCs), which promotes tumor growth and metastasis. This protocol provides detailed procedures for assessment of various LAL biochemical and physiological activities in Ly6G+ and CD11c+ MDSCs, including isolation of Ly6G+ and CD11c+ cells from the bone marrow and blood of mice, assays of LAL-D-induced cellular metabolic and mitochondrial activities, assessment of LAL-D-induced pathogenic immunosuppressive activity and tumor stimulatory activity. Pharmacological inhibition of the LAL activity was also described in both murine myeloid cells and human white blood cells.
gene therapies
2026-07-01 | Liver-specific gene therapy based on self-complementary adeno-associated virus for lysosomal acid lipase deficiency
Introduction Lysosomal acid lipase deficiency is a rare, autosomal-recessive disorder caused by inactivating mutations of the lysosomal acid lipase gene and accumulation of cholesteryl esters and triglycerides in lysosomes. Treatment with recombinant lysosomal acid lipase is effective, but involves safety risks and the production of neutralizing antibodies. In the current study, we examined gene therapy with a liver-specific, self-complementary adeno-associated virus 8 (P6-13/rscAAV8) that encodes the human lysosomal acid lipase. Methods Two age cohorts of C57BL/6J mice with homozygous lysosomal acid lipase deletion were included. A young cohort (9 weeks of age; n = 8 per dose group, four males and four females) received a single intravenous administration of P6-13/rscAAV8 at 0.6, 2, or 6 × 10 12 viral genomes per kg (vg/kg). An old cohort (28 weeks of age; n = 4 per dose group, all males) received P6-13/rscAAV8 at 1 or 6 × 10 12 vg/kg. Control mice received a non-coding vector encoding green fluorescent protein. Results In the young cohort, the treatment restored expression of enzyme activity, normalized lipid profiles and body weight, mitigated enlargement of the liver and spleen, and reduced steatosis, inflammation, and fibrosis in the liver. These effects were associated with rescue of autophagic flux and mitochondrial function, as well as reduction of endoplasmic reticulum stress. Notably, the observed effects were much weaker when gene therapy with the same dose was conducted in the old cohort. Conclusions These findings suggest that P6-13/rscAAV8, when delivered early enough, may mitigate or even prevent the pathology of lysosomal acid lipase deficiency.
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.
2025-08-02 | Clinical polymorphism of storage diseases: A diferential diagnostic algorithm
The article presents an overview of the current understanding of lysosomal storage diseases (LSD) – a group of rare genetic disorders characterized by abnormal accumulation of macromolecular degradation products within cell organelles. The clinical manifestations of LSD vary significantly depending on the type of disorder and may include liver damage, neurological symptoms, and involvement of other organs. To illustrate the unique features of clinical course and mechanisms of liver injury associated with different types of LSD, individual nosologies have been reviewed, including Gaucher’s disease, Niemann-Pick disease, lysosomal acid lipase deficiency, gangliosidoses, and mucopolysaccharidoses, all of which show substantial differences in their pathogenesis and clinical presentations. Diagnostic criteria were described, focusing on measurements of enzyme activities and identification of pathogenic genotypes, alongside specialized biomarkers utilized for confirming diagnoses. Diagnosis of LSDs relies on assessing enzyme activity or metabolite concentrations in biological samples, while molecular-genetic testing is employed to verify the diagnosis. In this review, various therapeutic strategies are discussed, encompassing enzyme replacement therapy (ERT), substrate reduction therapy, and liver transplantation when severe organ involvement occurs. Early detection and prompt initiation of treatment are emphasized as crucial steps to prevent irreversible organ damage. Additionally, the prospects of applying gene therapy, which has shown positive outcomes in experimental studies, are highlighted. This approach opens up new possibilities for innovative treatments aimed at restoring normal enzyme function and preventing disease progression. The presented data offer a comprehensive insight into the issues surrounding the diagnosis and management of LSDs, which is important for both clinicians and researchers engaged in the study of rare diseases.
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.
proteins
2026-07-21 | Lysosomal acid lipase deficiency in children: literature review and clinical observations
The enzyme lysosomal acid lipase, encoded by the LIPA gene, plays a key role in lipid metabolism in lysosomes. Mutations in the LIPA gene, of which about 120 have been registered, lead to a complete or partial absence of lysosomal acid lipase activity. This is accompanied by the accumulation of cholesterol esters and triglycerides in organs, primarily in the liver and spleen. There are two types of major phenotypic manifestations of lysosomal acid lipase deficiency: infantile lysosomal acid lipase deficiency (Wolman’s disease), and childhood/adult lysosomal acid lipase deficiency (cholesterol ester accumulation disease). The diagnosis of lysosomal acid lipase deficiency in children and adolescents should be established at an early stage of the disease, since the start of treatment affects the quality of life of patients in the long term. The article discusses both phenotypes of lysosomal acid lipase deficiency, etiology, pathogenesis, and approaches to the treatment of this disease. Clinical observations of patients with lysosomal acid lipase deficiency are also demonstrated.
2025-12-08 | Lysosomal acid lipase deficiency: The forgotten link between liver and cardiovascular disease.
Lysosomal acid lipase-deficiency (LAL-D) is a rare and systemic condition, secondary to lipase A gene mutations, responsible for lysosomal accumulation of cholesteryl esters and triglycerides in many tissues. It is a very heterogeneous disease in terms of the age of onset, severity, and the type of clinical and radiological manifestations. Dyslipidemia, hepatomegaly, and hepatosteatosis with increased levels of transaminases are the most common features. In association with liver dysfunction and evolution to cirrhosis, there is an increased risk of premature atherosclerosis and cardiovascular disorders, secondary to a generalized alteration of lipid profile and lipoprotein dysfunction associated with LAL-D. Therefore, we provide an update on the frequently under-recognized LAL-D, focusing on the late-onset form: Cholesteryl ester storage disease.
2025-09-01 | Beyond Cholesterol and Triglycerides in the Lipid Clinic: The Challenging Task of Identifying Lysosomal Acid Lipase Deficiency
Lysosomal acid lipase deficiency (LAL-D) is a rare, autosomal recessive genetic disorder. Biallelic pathogenic variants within the LIPA gene result in a deficiency of the lysosomal acid lipase (LAL) enzyme, which is crucial for the hydrolysis of cholesteryl esters (CE) via the endocytic pathway. This enzymatic defect consequently leads to the lysosomal accumulation of CE and triglycerides. The phenotype of LAL-D varies significantly depending on the specific genetic variation. Specifically, null allelic variants, characterized by the absence of residual enzymatic [...]
2025-08-30 | Cholesterol Ester Storage Disease in Two Field Spaniels With Lysosomal Acid Lipase Deficiency.
Cholesterol ester storage disease (CESD) is a rare genetic lysosomal storage disorder resulting from lower lysosomal acid lipase (LAL) activity. LAL is an essential enzyme required in intracellular lipid metabolism, and deficiency results in disability to properly break down and utilize lipids and in the accumulation of especially cholesterol esters in many organs such as the liver, spleen, and bone marrow. This case report describes clinical findings, LAL activity measurement, blood and liver tissue lipidomic changes, as well as pathological findings in two unrelated Field Spaniels with LAL deficiency and CESD.
2025-06-25 | The Hidden Burden: Gastrointestinal Involvement in Lysosomal Storage Disorders.
Lysosomal storage disorders (LSDs) are rare inherited metabolic diseases characterized by defects in lysosomal enzyme function or membrane transport. These defects lead to substrate accumulation and multisystemic manifestations. This review focuses on gastrointestinal (GI) involvement in LSDs, which is a significant but often overlooked aspect of these disorders. A comprehensive literature review was conducted to examine the pathophysiology, clinical presentation, diagnosis and management of GI manifestations in several LSDs, including Fabry disease, Gaucher disease, Pompe disease, Niemann-Pick disease type C, mucopolysaccharidoses and Wolman disease. The pathogenesis of GI involvement in LSDs varies and encompasses substrate accumulation in enterocytes, mesenteric lymphadenopathy, mass effects, smooth muscle dysfunction, vasculopathy, neuropathy, inflammation and alterations to the microbiota. Clinical presentations range from non-specific symptoms, such as abdominal pain, diarrhea and malabsorption, to more severe complications, such as protein-losing enteropathy and inflammatory bowel disease. Diagnosis often requires a high level of suspicion, as GI symptoms may precede the diagnosis of the underlying LSD or be misattributed to more common conditions. Management strategies include disease-specific treatments, such as enzyme replacement therapy or substrate reduction therapy, as well as supportive care and targeted interventions for specific GI complications. This review highlights the importance of recognizing and properly managing GI manifestations in LSDs to improve patient outcomes and quality of life. It also emphasizes the need for further research to develop more effective treatments for life-threatening GI complications associated with these rare genetic disorders.
small molecules
2026-03-29 | Lysosomal cholesteryl ester hydrolysis drives white matter repair by reprogramming microglia into a novel reparative state.
White matter repair relies on microglial clearance of cholesterol-rich myelin debris. Microglia have been reported to predominantly depend on de novo sterol synthesis to support this repair process. Lysosomal acid lipase (LAL) is the only known lysosomal enzyme capable of hydrolyzing cholesterol esters. In stark contrast to previous studies, we demonstrate here that LAL-mediated lysosomal lipolysis—not de novo sterol synthesis—serves as a central determinant of the microglial capacity to drive white matter repair. Using single-cell RNA sequencing, we identified a novel reparative microglial state characterized by simultaneously high expression of glycoprotein nonmetastatic melanoma protein B (GPNMB) and LAL. Following white matter injury, GPNMB+ microglia expanded and constituted the major microglial subset responsible for myelin debris engulfment. However, GPNMB+ microglia displayed context-dependent capacity to digest internalized myelin debris and mediate remyelination, with marked differences between reparable white matter injury and nonregenerative injury induced by white matter stroke (WMS). Transcriptomic profiling identified LAL as a key regulator of the reparative phenotype in GPNMB+ microglia. Independent of cytosolic lipases—widely regarded as synergistic mediators of LAL in cholesteryl ester hydrolysis, microglial LAL was both indispensable for myelin debris clearance and spontaneous remyelination in the reparable injury model, and sufficient to restore these processes following WMS-induced irreparable white matter injury. Mechanistically, LAL-mediated lysosomal lipolysis constituted the primary pathway for cholesteryl ester hydrolysis in microglia after white matter injury. This pathway converted cholesteryl esters into free cholesterol and activates liver X receptors (LXRs), both of which were required to reprogram microglial into the reparative state. Consistently, LXR activation alone was insufficient to rescue defective white matter repair caused by LAL deficiency. Hydroxypropyl-β-cyclodextrin (HβCD), an FDA-approved drug carrier, effectively lowers intracellular cholesterol levels through incompletely defined mechanisms. HβCD specifically upregulated LAL expression within white matter lesions and promoted remyelination via a LAL-dependent manner following WMS, supporting its potential as a therapeutic agent for WMS. Collectively, this study identifies lysosomal cholesterol ester hydrolysis as a novel therapeutic target for the treatment of irreversible white matter injury.
2026-02-01 | Lysosomal acid lipase is essential in cholesterol-mediated mTORC1 signaling activation by maintaining a balance between cholesterol ester and free cholesterol in zebrafish
Cholesterol, as a signaling molecule, plays a critical role in regulating the mTORC1 signaling pathway within cells. Lysosomal acid lipase (LAL) is responsible for hydrolyzing cholesterol ester and triglyceride in lysosomes. However, the involvement of LAL in the regulation of the mTORC1 signaling pathway in animals remains controversial. Our study found that lal -deficient zebrafish exhibited retarded growth and reduced body protein content compared to wild type zebrafish. Correspondingly, the mTORC1 signaling pathway was significantly inhibited in the liver of lal −/− zebrafish. Additionally, both lal knockdown and lalistat (LAL inhibitor) treatments led to the accumulation of cholesterol ester (CE) and a decrease in free cholesterol (FC) within lysosomes of zebrafish liver (ZFL) cells. This imbalance inhibited the recruitment of mTORC1 to the lysosomal surface and suppressed the mTORC1 signaling pathway. Moreover, FC treatment promoted the recruitment of mTORC1 to the lysosomal surface and activated the mTORC1 signaling pathway regardless of LAL, whereas LDL-dependent mTORC1 activation required LAL. However, knockdown of slc38a9 (a cholesterol sensor) blocked the recruitment of mTORC1 in ZFL cells treated with FC or LDL. Furthermore, the interaction between P14 (a component of Ragulator complex) and RagA/C was weakened in ZFL cells following treatment with FC or LDL but was enhanced upon slc38a9 knockdown. In addition, both lal siRNA and lalistat treatments increased the interaction between P14 and RagA/C. Our findings indicated that LAL dysfunction hindered the recruitment and activation of mTORC1 through the Slc38a9-mediated lysosomal mTORC1-scaffolding complex in ZFL cells. This inhibition was associated with a decrease in lysosomal FC, which is detected by cholesterol sensor SLC38A9. Therefore, interventions targeting the role of LAL role in the hydrolysis of cholesterol esters within lysosomes could offer promising therapeutic strategies for diseases associated with dysregulated mTORC1 signaling in animals. • Lal -deficient zebrafish exhibited retarded growth and lower body protein content. • Lal -deficiency decreased lysosomal free cholesterol content in zebrafish liver cells. • Lysosomal cholesterol level regulated recruitment and activation of mTORC1 through Slc38a9.
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.
2024-11-28 | Supplementation of diet with Astaxanthin and DHA prevents gestational and lactational undernourishment-induced metabolic derangements in dams: a metabolomic approach.
Nutrition is the critical nongenetic factor that has a major influence on the health status of an organism. The nutritional status of the mother during gestation and lactation plays a vital role in defining the offspring's health. Undernutrition during these critical periods may induce chronic metabolic disorders like obesity and cardiovascular diseases in mothers as well as in offspring. The present study aims to evaluate the impact of undernutrition during gestational and lactational periods on the plasma metabolic profile of dams. Additionally, we investigated the potential synergistic mitigating effects of astaxanthin and docosahexaenoic acid (DHA) on dysregulated plasma metabolic profiles. Evaluation of plasma lipid profile revealed that undernourishment resulted in elevated levels of total cholesterol, triglycerides, low density and very low-density lipoproteins in dams. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) based untargeted metabolomics illustrated that pathways related to lipid metabolism, such as cholesterol metabolism, steroid biosynthesis and metabolism of amine-derived hormones, were dysregulated by undernourishment. Additionally, pathway enrichment analysis predicted that there is a high incidence of development of desmosterolosis, hypercholesterolaemia, lysosomal acid lipase deficiency and Smith-Lemli-Opitz syndrome in the offspring, reflecting predisposition in mothers. However, synergistic supplementation of astaxanthin and DHA ameliorated these adverse effects by regulating a separate set of metabolic pathways associated with lipid metabolism. They included branched chain amino acid degradation such as valine, leucine and isoleucine, metabolism of alpha-linolenic acid, lipoic acid, lysine degradation, biosynthesis, elongation and degradation of fatty acids.
2024-04-01 | Characterization of lysosomal acid lipase in Ly6G+ and CD11c+ myeloid-derived suppressor cells.
Lysosomal acid lipase (LAL) is a key enzyme in the metabolic pathway of neutral lipids, whose deficiency (LAL-D) induces the differentiation of myeloid lineage cells into myeloid-derived suppressor cells (MDSCs), which promotes tumor growth and metastasis. This protocol provides detailed procedures for assessment of various LAL biochemical and physiological activities in Ly6G+ and CD11c+ MDSCs, including isolation of Ly6G+ and CD11c+ cells from the bone marrow and blood of mice, assays of LAL-D-induced cellular metabolic and mitochondrial activities, assessment of LAL-D-induced pathogenic immunosuppressive activity and tumor stimulatory activity. Pharmacological inhibition of the LAL activity was also described in both murine myeloid cells and human white blood cells.
gene therapies
2026-07-01 | Liver-specific gene therapy based on self-complementary adeno-associated virus for lysosomal acid lipase deficiency
Introduction Lysosomal acid lipase deficiency is a rare, autosomal-recessive disorder caused by inactivating mutations of the lysosomal acid lipase gene and accumulation of cholesteryl esters and triglycerides in lysosomes. Treatment with recombinant lysosomal acid lipase is effective, but involves safety risks and the production of neutralizing antibodies. In the current study, we examined gene therapy with a liver-specific, self-complementary adeno-associated virus 8 (P6-13/rscAAV8) that encodes the human lysosomal acid lipase. Methods Two age cohorts of C57BL/6J mice with homozygous lysosomal acid lipase deletion were included. A young cohort (9 weeks of age; n = 8 per dose group, four males and four females) received a single intravenous administration of P6-13/rscAAV8 at 0.6, 2, or 6 × 10 12 viral genomes per kg (vg/kg). An old cohort (28 weeks of age; n = 4 per dose group, all males) received P6-13/rscAAV8 at 1 or 6 × 10 12 vg/kg. Control mice received a non-coding vector encoding green fluorescent protein. Results In the young cohort, the treatment restored expression of enzyme activity, normalized lipid profiles and body weight, mitigated enlargement of the liver and spleen, and reduced steatosis, inflammation, and fibrosis in the liver. These effects were associated with rescue of autophagic flux and mitochondrial function, as well as reduction of endoplasmic reticulum stress. Notably, the observed effects were much weaker when gene therapy with the same dose was conducted in the old cohort. Conclusions These findings suggest that P6-13/rscAAV8, when delivered early enough, may mitigate or even prevent the pathology of lysosomal acid lipase deficiency.
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.
2025-08-02 | Clinical polymorphism of storage diseases: A diferential diagnostic algorithm
The article presents an overview of the current understanding of lysosomal storage diseases (LSD) – a group of rare genetic disorders characterized by abnormal accumulation of macromolecular degradation products within cell organelles. The clinical manifestations of LSD vary significantly depending on the type of disorder and may include liver damage, neurological symptoms, and involvement of other organs. To illustrate the unique features of clinical course and mechanisms of liver injury associated with different types of LSD, individual nosologies have been reviewed, including Gaucher’s disease, Niemann-Pick disease, lysosomal acid lipase deficiency, gangliosidoses, and mucopolysaccharidoses, all of which show substantial differences in their pathogenesis and clinical presentations. Diagnostic criteria were described, focusing on measurements of enzyme activities and identification of pathogenic genotypes, alongside specialized biomarkers utilized for confirming diagnoses. Diagnosis of LSDs relies on assessing enzyme activity or metabolite concentrations in biological samples, while molecular-genetic testing is employed to verify the diagnosis. In this review, various therapeutic strategies are discussed, encompassing enzyme replacement therapy (ERT), substrate reduction therapy, and liver transplantation when severe organ involvement occurs. Early detection and prompt initiation of treatment are emphasized as crucial steps to prevent irreversible organ damage. Additionally, the prospects of applying gene therapy, which has shown positive outcomes in experimental studies, are highlighted. This approach opens up new possibilities for innovative treatments aimed at restoring normal enzyme function and preventing disease progression. The presented data offer a comprehensive insight into the issues surrounding the diagnosis and management of LSDs, which is important for both clinicians and researchers engaged in the study of rare diseases.
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.
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2026-07-21 | Lysosomal acid lipase deficiency in children: literature review and clinical observations
The enzyme lysosomal acid lipase, encoded by the LIPA gene, plays a key role in lipid metabolism in lysosomes. Mutations in the LIPA gene, of which about 120 have been registered, lead to a complete or partial absence of lysosomal acid lipase activity. This is accompanied by the accumulation of cholesterol esters and triglycerides in organs, primarily in the liver and spleen. There are two types of major phenotypic manifestations of lysosomal acid lipase deficiency: infantile lysosomal acid lipase deficiency (Wolman’s disease), and childhood/adult lysosomal acid lipase deficiency (cholesterol ester accumulation disease). The diagnosis of lysosomal acid lipase deficiency in children and adolescents should be established at an early stage of the disease, since the start of treatment affects the quality of life of patients in the long term. The article discusses both phenotypes of lysosomal acid lipase deficiency, etiology, pathogenesis, and approaches to the treatment of this disease. Clinical observations of patients with lysosomal acid lipase deficiency are also demonstrated.
2025-12-08 | Lysosomal acid lipase deficiency: The forgotten link between liver and cardiovascular disease.
Lysosomal acid lipase-deficiency (LAL-D) is a rare and systemic condition, secondary to lipase A gene mutations, responsible for lysosomal accumulation of cholesteryl esters and triglycerides in many tissues. It is a very heterogeneous disease in terms of the age of onset, severity, and the type of clinical and radiological manifestations. Dyslipidemia, hepatomegaly, and hepatosteatosis with increased levels of transaminases are the most common features. In association with liver dysfunction and evolution to cirrhosis, there is an increased risk of premature atherosclerosis and cardiovascular disorders, secondary to a generalized alteration of lipid profile and lipoprotein dysfunction associated with LAL-D. Therefore, we provide an update on the frequently under-recognized LAL-D, focusing on the late-onset form: Cholesteryl ester storage disease.
2025-09-01 | Beyond Cholesterol and Triglycerides in the Lipid Clinic: The Challenging Task of Identifying Lysosomal Acid Lipase Deficiency
Lysosomal acid lipase deficiency (LAL-D) is a rare, autosomal recessive genetic disorder. Biallelic pathogenic variants within the LIPA gene result in a deficiency of the lysosomal acid lipase (LAL) enzyme, which is crucial for the hydrolysis of cholesteryl esters (CE) via the endocytic pathway. This enzymatic defect consequently leads to the lysosomal accumulation of CE and triglycerides. The phenotype of LAL-D varies significantly depending on the specific genetic variation. Specifically, null allelic variants, characterized by the absence of residual enzymatic [...]
2025-08-30 | Cholesterol Ester Storage Disease in Two Field Spaniels With Lysosomal Acid Lipase Deficiency.
Cholesterol ester storage disease (CESD) is a rare genetic lysosomal storage disorder resulting from lower lysosomal acid lipase (LAL) activity. LAL is an essential enzyme required in intracellular lipid metabolism, and deficiency results in disability to properly break down and utilize lipids and in the accumulation of especially cholesterol esters in many organs such as the liver, spleen, and bone marrow. This case report describes clinical findings, LAL activity measurement, blood and liver tissue lipidomic changes, as well as pathological findings in two unrelated Field Spaniels with LAL deficiency and CESD.
2025-06-25 | The Hidden Burden: Gastrointestinal Involvement in Lysosomal Storage Disorders.
Lysosomal storage disorders (LSDs) are rare inherited metabolic diseases characterized by defects in lysosomal enzyme function or membrane transport. These defects lead to substrate accumulation and multisystemic manifestations. This review focuses on gastrointestinal (GI) involvement in LSDs, which is a significant but often overlooked aspect of these disorders. A comprehensive literature review was conducted to examine the pathophysiology, clinical presentation, diagnosis and management of GI manifestations in several LSDs, including Fabry disease, Gaucher disease, Pompe disease, Niemann-Pick disease type C, mucopolysaccharidoses and Wolman disease. The pathogenesis of GI involvement in LSDs varies and encompasses substrate accumulation in enterocytes, mesenteric lymphadenopathy, mass effects, smooth muscle dysfunction, vasculopathy, neuropathy, inflammation and alterations to the microbiota. Clinical presentations range from non-specific symptoms, such as abdominal pain, diarrhea and malabsorption, to more severe complications, such as protein-losing enteropathy and inflammatory bowel disease. Diagnosis often requires a high level of suspicion, as GI symptoms may precede the diagnosis of the underlying LSD or be misattributed to more common conditions. Management strategies include disease-specific treatments, such as enzyme replacement therapy or substrate reduction therapy, as well as supportive care and targeted interventions for specific GI complications. This review highlights the importance of recognizing and properly managing GI manifestations in LSDs to improve patient outcomes and quality of life. It also emphasizes the need for further research to develop more effective treatments for life-threatening GI complications associated with these rare genetic disorders.
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Drug Discovery Landscape
2 orphan drug designations for Lysosomal acid lipase deficiency, including 2 approved therapies.
2 orphan drug designations for Lysosomal acid lipase deficiency, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Recombinant human lysosomal acid lipase [Kanuma] | proteins | EMA | 2010-12-17 | 2015-09-01 | Alexion Europe SAS |
sebelipase alfa [Kanuma] | proteins | FDA | 2010-07-01 | 2015-12-08 | Alexion Pharmaceuticals |
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