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
178 drug discovery papers about Lysosomal acid lipase deficiency, with 2 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
178 drug discovery papers about Lysosomal acid lipase deficiency, with 2 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
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.
2026-07-01 | 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.
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.
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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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