RARE DISEASE
LCAT deficiency
LCAT deficiency
LCAT deficiency
Synonyms: Lecithin-cholesterol acyltransferase deficiency
Synonyms: Lecithin-cholesterol acyltransferase deficiency
Synonyms: Lecithin-cholesterol acyltransferase deficiency
Drug discovery
3
drugs
With orphan designations
Overview
LCAT deficiency is a rare autosomal recessive disorder caused by mutations in the LCAT gene, impairing cholesterol esterification and HDL maturation. It manifests as two phenotypes: familial LCAT deficiency (FLD), characterized by corneal opacities, hemolytic anemia, progressive renal failure, and low HDL; and fish-eye disease (FED), marked by partial LCAT activity loss, corneal clouding, and increased cardiovascular risk. Diagnosis combines lipid panels (very low HDL), genetic testing, and clinical findings (e.g., corneal deposits, proteinuria) [1][6][11].
Therapies
Statins for LDL lowering; ACEi/ARBs to delay renal decline [1][6].
Dialysis/kidney transplantation for end-stage renal disease; corneal transplants for severe vision loss [1][16].
Emerging therapies: Recombinant LCAT (ACP-501) trials show HDL normalization; gene therapy (AAV-hLCAT) demonstrates efficacy in preclinical models [1][3][18].
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism, rare ophthalmic disorders, rare renal diseases, rare transplant-related disorders
Research Papers
244 drug discovery papers about LCAT deficiency, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
244 drug discovery papers about LCAT deficiency, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2025-10-01 | PS13.4: Autologous transplantation of LCAT gene-transduced adipocytes enabled long-term LCAT replacement in a patient with LCAT deficiency in first in human clinical trial.
Introduction: Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) syndrome is an autosomal recessive disease characterized by low plasma LCAT activity and severe dysfunction of HDL with subsequent impaired lipoprotein metabolisms. Patients often develop complications such as corneal opacity, hemolytic anemia, and renal dysfunction. In plasma protein deficiency such as LCAT deficiency, gene therapy-mediated continuous enzyme replacement is the most suitable therapeutic approach. We have postulated adipocyte-based ex vivo gene therapy-mediated enzyme replacement therapy (ERT), in which genetically-modified adipocytes (GMAC) reside at transplanted sites to continuously supply therapeutic proteins. We have applied our GMAC technology to treat FLD via transplantation of LCAT gene-transduced autologous preadipocytes (LCAT-GMAC). Methods: The ex vivo gene therapy protocol has been approved under the Act on Securement of Safety of Regenerative Medicine in Japan. A patient was enrolled in January of 2017, and LCAT-GMAC was administered subcutaneously with fibrin glue, which is a clinically applicable scaffold, and the clinical evaluation of the prescribed observation and subsequent follow-up period (total of 240 weeks after administration) was completed, then safety as well as efficacy of the LCAT-GMAC has been investigated in the patient.Results: Post administration pain was observed, however, no other treatment-related adverse effects were observed. In addition, no replication-competent retrovirus in patient’s blood sample or tumorigenicity of the LCAT-GMAC was observed. Increased serum LCAT activity has sustained for 240 weeks. Together with changes in laboratory values related to lipid metabolism, the long-term amelioration of abnormal lipoprotein metabolism was suggested in the patient. The hemoglobin-haptoglobin complex produced with hemolytic anemia was also reduced, which suggested improved vulnerability of erythrocytes. The patient is still undergoing follow-up and still has persistent LCAT activity in his blood eight years after the administration of LCAT-GMAC.Conclusion: These results suggest that LCAT-GMAC is a curative ex vivo gene/cell therapy product for FLD patients, and the following multicenter clinical trials are currently underway to obtain regulatory approval. In conclusion, the GMAC technology will provide a novel platform for ex vivo gene therapy mediated ERT for a variety of intractable diseases.
2024-04-01 | Emerging therapies for LCAT deficiency: a role for plasma exchange
Familial lecithin-cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare disorder of lipid metabolism causing decreased maturation of high-density lipoprotein (HDL) particles and impaired cholesterol esterification1. Patients with FLD develop corneal opacification, haemolytic anaemia, proteinuria, and lipid abnormalities including elevated triglycerides (TG), reduced HDL cholesterol and increased unesterified cholesterol-rich lipoprotein X (LpX)1. Renal failure is a major cause of mortalityS1.
2017-04-06 | [Gene-manipulated Adipocytes for the Treatment of Various Intractable Diseases].
Although protein replacement is an effective treatment for serum protein deficiencies such as diabetes and hemophilia, recombinant protein products are not available for all rare inherited diseases due to the instability of the recombinant proteins and/or to cost. Gene therapy is the most attractive option for treating patients with such rare diseases. To develop an effective ex vivo gene therapy-based protein replacement treatment requires recipient cells that differ from those used in standard gene therapy, which is performed to correct the function of the recipient cells. Adipose tissue is an expected source of proliferative cells for cell-based therapies, including regenerative medicine and gene transfer applications. Based on recent advances in cell biology and extensive clinical experience in transplantation therapy for adipose tissue, we focused on the mature adipocyte fraction, which is the floating fraction after collagenase digestion and centrifugation of adipose tissue. Proliferative adipocytes were propagated from the floating fraction by the ceiling culture technique. These cells are designated as ceiling culture-derived proliferative adipocytes (ccdPAs). We first focused on lecithin:cholesterol acyltransferase (LCAT) deficiency, an inherited metabolic disorder caused by lcat gene mutation, and ccdPAs as a therapeutic gene vehicle for LCAT replacement therapy. In our recent in vitro and animal model studies, we developed an adipose cell manipulation procedure using advanced gene transduction methods and transplantation scaffolds. We herein introduce the progress made in novel adipose tissue-based therapeutic strategies for the treatment of protein deficiencies and describe their future applications for other intractable diseases.
2016-09-24 | Sequential kidney–liver transplantation from the same living donor for lecithin cholesterol acyl transferase deficiency
Lecithin cholesterol acyl transferase (LCAT) deficiency is a rare autosomal recessive disorder of lipoprotein metabolism that results in end-stage renal disease (ESRD) necessitating transplantation. As LCAT is produced in the liver, combined kidney and liver transplantation was proposed to cure the clinical syndrome of LCAT deficiency.A 29-year-old male with ESRD secondary to LCAT deficiency underwent a sequential kidney-liver transplantation from the same living donor (LD). One year following the kidney transplant, auxiliary partial orthotopic liver transplant (APOLT) of a left lateral segment from the same donor was performed.At 5 years follow-up, there have been no major complications, readmissions, or rejection episodes. Serum lipid abnormalities recurred within the first year, but liver and kidney allograft function remains intact.Few cases of sequential transplantation from the same LD have been performed in adults. This is the first APOLT and multi-organ transplant performed for LCAT deficiency. Sequential organ transplant from the same LD for ESRD secondary to a metabolic disorder of the liver is feasible in adults and should be further investigated.
2011-03-25 | Fibrin glue increases the cell survival and the transduced gene product secretion of the ceiling culture-derived adipocytes transplanted in mice
The development of clinically applicable scaffolds is important for the application of cell transplantation in various human diseases. The aims of this study are to evaluate fibrin glue in a novel protein replacement therapy using proliferative adipocytes and to develop a mouse model system to monitor the delivery of the transgene product into the blood and the fate of the transduced cells after transplantation. Proliferative adipocytes from mouse adipose tissue were transduced by a retroviral vector harboring the human lecithin-cholesterol acyltransferase (lcat) gene, and were subcutaneously transplanted into mice combined with fibrin glue. The lcat gene transduction efficiency and the subsequent secretion of the product in mouse adipocytes were enhanced using a protamine concentration of 500 µg/ml. Adipogenesis induction did not significantly affect the lcat gene-transduced cell survival after transplantation. Immunohistochemistry showed the ectopic enzyme production to persist for 28 days in the subcutaneously transplanted gene-transduced adipocytes. The increased viability of transplanted cells with fibrin glue was accompanied with the decrease in apoptotic cell death. The immunodetectable serum LCAT levels in mice implanted with the fibrin glue were comparable with those observed in mice implanted with Matrigel, indicating that the transplanted lcat gene-transduced adipocytes survived and functioned in the transplanted spaces with fibrin glue as well as with Matrigel for 28 days. Thus, this in vivo system using fibrin is expected to serve as a good model to further improve the transplanted cell/scaffold conditions for the stable and durable cell-based replacement of defective proteins in patients with LCAT deficiency.
proteins
2020-08-13 | Plasma lipoprotein-X quantification on filipin-stained gels: monitoring recombinant LCAT treatment ex vivo.
Familial LCAT deficiency (FLD) patients accumulate lipoprotein-X (LP-X), an abnormal nephrotoxic lipoprotein enriched in free cholesterol (FC). The low neutral lipid content of LP-X limits the ability to detect it after separation by lipoprotein electrophoresis and staining with Sudan Black or other neutral lipid stains. A sensitive and accurate method for quantitating LP-X would be useful to examine the relationship between plasma LP-X and renal disease progression in FLD patients and could also serve as a biomarker for monitoring recombinant human LCAT (rhLCAT) therapy. Plasma lipoproteins were separated by agarose gel electrophoresis and cathodal migrating bands corresponding to LP-X were quantified after staining with filipin, which fluoresces with FC, but not with neutral lipids. rhLCAT was incubated with FLD plasma and lipoproteins and LP-X changes were analyzed by agarose gel electrophoresis. Filipin detects synthetic LP-X quantitatively (linearity 20-200 mg/dl FC; coefficient of variation <20%) and sensitively (lower limit of quantitation <1 mg/ml FC), enabling LP-X detection in FLD, cholestatic, and even fish-eye disease patients. rhLCAT incubation with FLD plasma ex vivo reduced LP-X dose dependently, generated HDL, and decreased lipoprotein FC content. Filipin staining after agarose gel electrophoresis sensitively detects LP-X in human plasma and accurately quantifies LP-X reduction after rhLCAT incubation ex vivo.
1988-07-01 | Transformation of large discoidal complexes of apolipoprotein A-I and phosphatidylcholine by lecithin-cholesterol acyltransferase
Using a cholate-dialysis recombination procedure, complexes of apolipoprotein A-I and synthetic phosphatidylcholine (1-palmitoyl-2-oleoylphosphatidylcholine (POPC) or dioleoylphosphatidylcholine (DOPC] were prepared in mixtures at a relatively high molar ratio of 150:1 phosphatidylcholine/apolipoprotein A-I. Particle size distribution analysis by gradient gel electrophoresis of the recombinant mixtures indicated the presence of a series of discrete complexes that included species migrating at RF values observed for discoidal particles in nascent high-density lipoproteins (HDL) in plasma of lecithin-cholesterol acyltransferase-deficient subjects. One of these complex species, designated complex class 6, formed with either phosphatidylcholine, was isolated by gel filtration and characterized at follows: discoidal shape (mean diameter 20.8 nm (POPC) and 19.0 nm (DOPC]; molar ratio, phosphatidylcholine/apolipoprotein A-I, 155:1 (POPC) and 130:1 (DOPC); and both containing 4 molecules of apolipoprotein A-I per particle. Incubation of class 6 complexes with lecithin-cholesterol acyltransferase (EC 2.3.1.43) and a source of unesterified cholesterol (low-density lipoprotein (LDL] was shown by electron microscopy to result in a progressive transformation of the discoidal particles (0 h) to deformable (2.5 h) and to spherical particles (24 h). The spherical particles (diameter 13.6 nm (POPC) and 12.5 nm (DOPC) exhibit sizes at the upper boundary of the interval defining the human plasma (HDL2b)gge (12.9-9.8 nm). The spherical particles contain a cholesteryl ester core that reaches a limiting molar ratio of approx. 50-55:1 cholesteryl ester/apolipoprotein A-I. The deformable particles assume a rectangular shape under negative staining and, relative to the 24-h spherical product, are enriched in phosphatidylcholine. Chemical crosslinking (by dimethyl suberimidate) of the isolated transformation products shows the 24-h spherical particle to contain predominantly 4 apolipoprotein A-I molecules; products produced after intermediate periods of time appear to contain species with 3 and 4 apolipoproteins per particle. Our in vitro studies indicate a potential pathway in the origins of large, apolipoprotein A-I-containing plasma HDL particles. The deformable species observed during transformation were similar in size and shape to particles observed in interstitial fluid.
1974-01-01 | The Ultrastructure of Plasma Lipoproteins in Lecithin: Cholesterol Acyltransferase Deficiency
The major plasma lipoprotein classes from patients with familial LCAT deficiency showed morphological abnormalities. Very low density lipoproteins (VLDL) contained particles with surface irregularities as well as sheet-like trilaminar structures which resembled phospholipid bilayers. Three types of particles were seen in the low density (LDL) region, large flattened structures approximately 1, 000A in size, intermediate particles 400–600A in diameter, and normal 200–250A particles. The high density lipoproteins (HDL) were characterized by discoidal particles 40A thick and 150–200A in diameter; these particles formed rouleaux. Abnormal HDL particles could be normalized by incubation of whole LCAT-deficient plasma (or HDL fraction) with LCAT; resulting structures resembled normal HDL (90–110A spheres). In severe liver disease with apparent biliary obstruction the structure of plasma lipoproteins often resembled those of familial LCAT deficiency. Rouleaux, consisting of disc-shaped particles, were in the HDL fraction, and these structures were also normalized by incubation with LCAT. Reassembly studies with apolipoproteins plus phospholipid suggested that the discs represent a bilayer structure stabilized by protein. Cholesteryl ester incorporated into the protein-lipid complex produced spherical particles.
small molecules
2025-11-03 | Abstract 4367648: Fish-Eye Disease: A Case Report
Description of Case: A 26-year-old female was referred to cardiology with bilateral corneal opacifications of four years’ duration, with no change in her visual acuity. Her workup revealed a high-density lipoprotein cholesterol (HDL-C) level of less than 10 mg/dL and a low-density lipoprotein cholesterol (LDL-C) level of 182 mg/dL, prompting genetic evaluation for disorders of lipid metabolism. She was found to have a heterozygous mutation, c.440C>T (p.Thr147Ile), and variant of uncertain significance, c.715G>A (p.Gly239Ser) in the lecithin-cholesterol acyltransferase ( LCAT ) gene. Additional studies showed low-normal serum cholesterol esters and no evidence of hematologic abnormalities or renal dysfunction. Based on these findings and her corneal opacifications, a clinical diagnosis of partial LCAT deficiency, or Fish-Eye Disease (FED), was made. Given her lipid abnormalities and the increased risk of atherosclerosis associated with FED, a high-potency statin was prescribed. Her LDL-C decreased from 182 mg/dL to 124 mg/dL. Discussion: FED is an autosomal recessive disorder of lipid metabolism caused by mutations in the LCAT gene, resulting in partial loss of enzymatic activity. LCAT catalyzes the esterification of free cholesterol, a key step in reverse cholesterol transport; esterification is lost in HDL-C (i.e., alpha activity) and conserved in lipoproteins containing apolipoprotein B (i.e., beta activity). Consequently, FED is biochemically characterized by reduced HDL-C and plasma cholesterol esters and elevated LDL-C, very-low-density lipoprotein cholesterol, triglycerides, and/or plasma unesterified cholesterol. Clinically, these patients typically present with worsening corneal opacities and decreased visual acuity and are at increased risk of atherosclerosis due to preserved beta activity. In contrast, patients may have complete loss of LCAT activity and present with more severe sequelae, a disease known as familial LCAT deficiency (FLD). Absent LCAT activity leads to unesterified cholesterol accumulation, which disrupts red blood cell membranes and deposits in the renal mesangium, leading to hemolytic anemia and renal dysfunction. It is therefore important to promptly determine the degree of LCAT activity loss and manage patients accordingly. Measuring LCAT activity, both alpha and beta, is the best diagnostic test. FED should be treated primarily with lipid-lowering medications, whereas FLD requires monitoring for anemia and renal dysfunction.
2025-08-25 | Short-Term Treatment for Immune-Mediated Acquired Lecithin-Cholesterol Acyltransferase Deficiency Restores the High-Density Lipoprotein Function: A Case Report.
Familial lecithin-cholesterol acyltransferase (LCAT) deficiency with a primary LCAT gene mutation results in various conditions, including corneal opacity, anemia, kidney disease, and low high-density lipoprotein (HDL) levels. In recent years, secondary LCAT deficiency with nearly identical symptoms has been identified as a rare case of immune-mediated acquired LCAT deficiency caused by LCAT autoantibodies. In limited cases, prednisolone treatment is required for severe conditions and has been shown to favorably modulate LCAT autoantibodies and restore LCAT activity, resulting in improved HDL-cholesterol (HDL-C) levels, renal dysfunction, and other complications. However, there is little detailed information regarding LCAT activity, lipid changes, and renal dysfunction after the initiation of prednisorone treatment. In the present study, in addition to the effects on LCAT activity, lipids, and proteinuria, we for the first time monitored the HDL cholesterol efflux capacity (CEC), an important anti-atherosclerotic HDL function, during the first month of treatment in a patient with this disease. We found that the LCAT activity, HDL-C concentration, and HDL CEC increased from undetectable or low values to normal ranges during this period, as did proteinuria. Specifically, the HDL CEC and LCAT activity recovered faster than the HDL-C levels. Based on these findings, the effects of prednisolone treatment on LCAT and HDL CEC activities prior to HDL-C levels suggest that normal HDL-C levels may not be essential as a treatment target in immune-mediated acquired LCAT deficiency patients who require treatment.
2024-09-17 | Rescue of Familial Lecithin:Cholesterol Acyltranferase Deficiency Mutations with an Allosteric Activator.
Lecithin:cholesterol acyltransferase (LCAT) deficiencies represent severe disorders characterized by aberrant cholesterol esterification in plasma, leading to life-threatening conditions. This study investigates the efficacy of Compound 2, a piperidinyl pyrazolopyridine allosteric activator that binds the membrane-binding domain of LCAT, in rescuing the activity of LCAT variants associated with disease. The variants K218N, N228K, and G230R, all located in the cap and lid domains of LCAT, demonstrated notable activity restoration in response to Compound 2. Molecular dynamics simulations and structural modeling indicate that these mutations disrupt the lid and membrane binding domain, with Compound 2 potentially dampening these structural alterations. Conversely, variants such as M252K and F382V in the cap and α/β-hydrolase domain, respectively, exhibited limited or no rescue by Compound 2. Future research should prioritize in vivo investigations that would validate the therapeutic potential of Compound 2 and related activators in familial LCAT deficiency patients with mutations in the cap and lid of the enzyme. SIGNIFICANCE STATEMENT: Lecithin:cholesterol acyltranferase (LCAT) catalyzes the first step of reverse cholesterol transport, namely the esterification of cholesterol in high density lipoprotein particles. Somatic mutations in LCAT lead to excess cholesterol in blood plasma and, in severe cases, kidney failure. In this study, we show that recently discovered small molecule activators can rescue function in LCAT-deficient variants when the mutations occur in the lid and cap domains of the enzyme.
2024-08-31 | Longitudinal analysis of clinical and laboratory biomarkers in a patient with familial lecithin: cholesterol acyltransferase deficiency (FLD) and accelerated eGFR decline: A case study.
Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is an ultra-rare autosomal recessive disease characterized by very low high-density lipoprotein cholesterol (HDL-C) levels, corneal opacity, anemia, and progressive renal disease. The rate and severity of renal disease are variable across FLD patients and the biomarkers and risk factors for disease progression are poorly understood. Here we report a 30 year-long comparative analysis of the clinical and laboratory biomarkers in an FLD patient with accelerated renal decline, who underwent two kidney and one liver transplantations. Results show that elevated triglyceride and non-HDL-C levels may promote the formation of LpX and accelerate renal function decline, whereas markers of anemia may be early predictors. Conversely, corneal opacity progresses at a steady rate and does not correlate with lipid, hematologic, or renal biomarkers. Our study suggests that monitoring of markers of anemia may aid the early detection and timely management of kidney disease with conservative therapies. Furthermore, it suggests that controlling hypercholesterolemia and hypertriglyceridemia may help improve renal disease prognosis.
2024-07-06 | Endogenous LXR signaling controls pulmonary surfactant homeostasis and prevents lung inflammation
Abstract Lung type 2 pneumocytes (T2Ps) and alveolar macrophages (AMs) play crucial roles in the synthesis, recycling and catabolism of surfactant material, a lipid/protein fluid essential for respiratory function. The liver X receptors (LXR), LXRα and LXRβ, are transcription factors important for lipid metabolism and inflammation. While LXR activation exerts anti-inflammatory actions in lung injury caused by lipopolysaccharide (LPS) and other inflammatory stimuli, the full extent of the endogenous LXR transcriptional activity in pulmonary homeostasis is incompletely understood. Here, using mice lacking LXRα and LXRβ as experimental models, we describe how the loss of LXRs causes pulmonary lipidosis, pulmonary congestion, fibrosis and chronic inflammation due to defective de novo synthesis and recycling of surfactant material by T2Ps and defective phagocytosis and degradation of excess surfactant by AMs. LXR-deficient T2Ps display aberrant lamellar bodies and decreased expression of genes encoding for surfactant proteins and enzymes involved in cholesterol, fatty acids, and phospholipid metabolism. Moreover, LXR-deficient lungs accumulate foamy AMs with aberrant expression of cholesterol and phospholipid metabolism genes. Using a house dust mite aeroallergen-induced mouse model of asthma, we show that LXR-deficient mice exhibit a more pronounced airway reactivity to a methacholine challenge and greater pulmonary infiltration, indicating an altered physiology of LXR-deficient lungs. Moreover, pretreatment with LXR agonists ameliorated the airway reactivity in WT mice sensitized to house dust mite extracts, confirming that LXR plays an important role in lung physiology and suggesting that agonist pharmacology could be used to treat inflammatory lung diseases. Graphical Abstract
gene therapies
2026-02-21 | Lecithin-cholesterol acyltransferase deficiency with the finding of "zebra bodies": A diagnostic challenge in the context of suspected Fabry disease.
Lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive disorder resulting from mutations in the LCAT gene, which leads to abnormal lipoprotein metabolism. This results in markedly reduced high-density lipoprotein cholesterol and the accumulation of lipoprotein X, leading to renal, corneal, and hemolytic damage. Two clinical variants have been described: familial LCAT deficiency (FLD) and fish-eye disease (FED). We report the case of a 41-year-old male with a history of hypertension, tinnitus, and progressive hearing loss, who presented with bilateral corneal opacity since childhood. Laboratory studies revealed significant proteinuria (2.56 g/24 h), preserved renal function (creatinine 0.85 mg/dL), mild anemia (Hb 10.2 g/dL), and extremely low HDL cholesterol (1.3 mg/dL). Renal biopsy showed focal segmental glomerulosclerosis and mesangial expansion. Electron microscopy demonstrated concentric lamellar inclusions known as "zebra bodies," a finding typically associated with Fabry disease. However, α-galactosidase A activity was normal, and genetic testing for Fabry disease was negative. Further genetic analysis identified the variant c.757 p.(Gln253Argfs*11) in the LCAT gene, confirming the diagnosis of familial LCAT deficiency. This case highlights the importance of differentiating LCAT deficiency from Fabry disease, given their overlapping clinical and histological features. Moreover, it represents the first description of "zebra bodies" in LCAT deficiency, emphasizing the diagnostic complexity and the need for a multidisciplinary approach to ensure accurate diagnosis and appropriate management.
2026-02-04 | A Novel Missense Mutation in a Compound Heterozygous Patient with Fish-Eye Disease: A Case Report.
Fish-eye disease (FED) is a rare autosomal recessive disorder caused by a partial deficiency of lecithin-cholesterol acyltransferase (LCAT) activity. It is characterized by progressive corneal opacification and dyslipidemia in the absence of systemic manifestations. We describe the clinical presentation, optical coherence tomography (OCT) imaging findings, and Scheimpflug-based corneal densitometry results in a patient with FED carrying both a pathogenic variant and a novel missense variant of the LCAT gene not reported in the current literature. We present a rare case of a 25-year-old female with bilateral corneal opacities, reduced plasma high-density lipoprotein cholesterol (<5 mg/dL), and elevated low-density lipoprotein cholesterol levels (>133 mg/dL). Visual acuity remained 20/20 in both eyes. Slit-lamp examination revealed diffuse subepithelial and anterior stromal deposits. The central corneal thickness was thinner than normal on Scheimpflug tomography, measuring 419 µm OD and 409 µm OS. OCT findings confirmed stromal thinning (479 µm OD and 470 µm OS), with preserved central epithelial thickness, and demonstrated corneal opacities throughout the cornea. Mean densitometry across the 12-mm corneal diameter was more than double that reported in healthy corneas. The cholesteryl ester-to-total cholesterol ratio remained within the normal range. Genetic analysis identified a previously reported pathogenic variant in exon 4 of LCAT (c.440C>T, p.Thr147Ile) and a novel missense mutation in exon 5 (c.715G>A, p.Gly239Ser), classified as a variant of uncertain significance. FED is a rare genetic disorder that is associated with corneal clouding and dyslipidemia. Genetic analysis confirmed the diagnosis with a compound heterozygous genotype, while OCT and corneal densitometry were effective modalities for quantifying and characterizing lipid deposits in FED.
2026-01-16 | Quantitative Assessment of Visual Function in Japanese Patients With Lecithin-Cholesterol Acyltransferase Gene Abnormalities: A Case-Control Study.
Introduction Fish-eye disease (FED) and familial lecithin-cholesterol acyltransferase (LCAT) deficiency (FLD) are rare. The aim of this study was to compare visual function between patients with LCAT abnormalities - namely, FED and FLD - and healthy controls. Methods This retrospective, comparative case-control study included four patients with FLD or FED (LCAT group) who presented with cloudy corneas at Miyata Eye Hospital between 2018 and 2024. Four age- and sex-matched individuals with normal results on ophthalmic examination were included as controls. We reviewed medical records for best-corrected visual acuity (BCVA), corneal astigmatism, forward light scattering, and contrast sensitivity. The parameters were compared between the groups. Results Sixteen eyes of eight women were included, including eight eyes of four patients with cloudy corneas in the LCAT group (two with FLD and six with FED) and eight eyes of four controls. The mean BCVA and corneal astigmatism revealed no significant intergroup differences. However, forward scattering was significantly higher in the LCAT group than in the control group (p = 0.007). The area under the log-contrast sensitivity function was significantly lower in the LCAT group than in the control group (p = 0.017). Conclusions Despite normal BCVA, patients with LCAT abnormalities (FLD and FED) showed considerably increased forward light scattering and decreased contrast sensitivity compared with the controls, indicating subtle but substantial visual functional impairment.
2024-11-14 | Novel pathogenic variant in the LCAT gene in a compound heterozygous patient with fish-eye disease and a mild phenotype.
Low high-density lipoprotein (HDL)-cholesterol and corneal opacity are associated with fish-eye disease (FED), familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD), apolipoprotein AI deficiency, and Tangier disease. The differential diagnosis is made by clinical and biochemical tests. Measuring the LCAT activity is the ideal way to distinguish conditions caused by LCAT gene variants (FED and FLD) from the other 2 diseases. However, this is not accessible from all clinics. The cholesteryl ester/total cholesterol (CE/TC) ratio, which is below the reference range in most cases with LCAT gene variants, has been proposed as an alternative. We report a case of compound heterozygous FED with a CE/TC ratio within the reference range. LCAT activity assays and genetic analyses were performed using patients' blood samples. Identified LCAT gene variants were examined by an in vitro expression assay. The proband showed approximately 20% LCAT α-activity relative to the normolipidemic controls, whereas a patient with a typical FED-causing variant (p.Thr147Ile) showed only 3% activity. We identified compound heterozygous variants (c.101C > T/c.460A > G) resulting in a p.Pro34Leu/p.Asn154Asp amino acid residue substitution in the LCAT gene of the proband. The former variant has been reported previously, but the latter was newly identified. An in vitro expression assay demonstrated that the LCAT α-activity of the p.Asn154Asp variant significantly decreased regarding the wild type, but it was relatively well preserved compared to the typical FED-causing variants (p.Pro34Leu and p.Thr147Ile). These results suggest that the residual 20% LCAT α-activity is sufficient to normalize CE/TC, but not sufficient to prevent the development of corneal opacity in FED.
2021-08-30 | Correction of Familial LCAT Deficiency by AAV-hLCAT Prevents Renal Injury and Atherosclerosis in Hamsters-Brief Report.
[Figure: see text].
other
2025-09-21 | IgG3κ Monoclonal Membranous Nephropathy Associated With Acquired Lecithin Cholesterol Acyltransferase Deficiency.
Lecithin cholesterol acyltransferase (LCAT) deficiency, inherited or acquired, is characterized by markedly low plasma high-density lipoprotein (HDL) cholesterol levels and increased unesterified cholesterol. We report a case of an elderly patient with persistently very low HDL and proteinuria. Serum cholesteryl esters were markedly low, and kidney biopsy revealed diffuse global glomerular lipid deposition, classic for LCAT deficiency, whereas genetic testing for variants associated with LCAT deficiency was negative. Kidney biopsy also showed concomitant monoclonal (IgG3κ) membranous nephropathy (MN). Proteomic analysis of glomeruli detected spectra for LCAT and serum amyloid P (SAP), suggesting that LCAT could be a target antigen in monoclonal MN with SAP enrichment and associated LCAT deficiency. Furthermore, lipidomic analysis revealed an accumulation of phosphatidylcholines and sphingomyelin and a decrease in ceramides. The patient was treated with daratumumab, and at 22 months follow-up his proteinuria was decreased while HDL level remained low.
2015-12-09 | Agonistic Human Antibodies Binding to Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism
Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouseTM platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 Å LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease. Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouseTM platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 Å LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease.
cell therapies
2025-10-01 | PS13.4: Autologous transplantation of LCAT gene-transduced adipocytes enabled long-term LCAT replacement in a patient with LCAT deficiency in first in human clinical trial.
Introduction: Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) syndrome is an autosomal recessive disease characterized by low plasma LCAT activity and severe dysfunction of HDL with subsequent impaired lipoprotein metabolisms. Patients often develop complications such as corneal opacity, hemolytic anemia, and renal dysfunction. In plasma protein deficiency such as LCAT deficiency, gene therapy-mediated continuous enzyme replacement is the most suitable therapeutic approach. We have postulated adipocyte-based ex vivo gene therapy-mediated enzyme replacement therapy (ERT), in which genetically-modified adipocytes (GMAC) reside at transplanted sites to continuously supply therapeutic proteins. We have applied our GMAC technology to treat FLD via transplantation of LCAT gene-transduced autologous preadipocytes (LCAT-GMAC). Methods: The ex vivo gene therapy protocol has been approved under the Act on Securement of Safety of Regenerative Medicine in Japan. A patient was enrolled in January of 2017, and LCAT-GMAC was administered subcutaneously with fibrin glue, which is a clinically applicable scaffold, and the clinical evaluation of the prescribed observation and subsequent follow-up period (total of 240 weeks after administration) was completed, then safety as well as efficacy of the LCAT-GMAC has been investigated in the patient.Results: Post administration pain was observed, however, no other treatment-related adverse effects were observed. In addition, no replication-competent retrovirus in patient’s blood sample or tumorigenicity of the LCAT-GMAC was observed. Increased serum LCAT activity has sustained for 240 weeks. Together with changes in laboratory values related to lipid metabolism, the long-term amelioration of abnormal lipoprotein metabolism was suggested in the patient. The hemoglobin-haptoglobin complex produced with hemolytic anemia was also reduced, which suggested improved vulnerability of erythrocytes. The patient is still undergoing follow-up and still has persistent LCAT activity in his blood eight years after the administration of LCAT-GMAC.Conclusion: These results suggest that LCAT-GMAC is a curative ex vivo gene/cell therapy product for FLD patients, and the following multicenter clinical trials are currently underway to obtain regulatory approval. In conclusion, the GMAC technology will provide a novel platform for ex vivo gene therapy mediated ERT for a variety of intractable diseases.
2024-04-01 | Emerging therapies for LCAT deficiency: a role for plasma exchange
Familial lecithin-cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare disorder of lipid metabolism causing decreased maturation of high-density lipoprotein (HDL) particles and impaired cholesterol esterification1. Patients with FLD develop corneal opacification, haemolytic anaemia, proteinuria, and lipid abnormalities including elevated triglycerides (TG), reduced HDL cholesterol and increased unesterified cholesterol-rich lipoprotein X (LpX)1. Renal failure is a major cause of mortalityS1.
2017-04-06 | [Gene-manipulated Adipocytes for the Treatment of Various Intractable Diseases].
Although protein replacement is an effective treatment for serum protein deficiencies such as diabetes and hemophilia, recombinant protein products are not available for all rare inherited diseases due to the instability of the recombinant proteins and/or to cost. Gene therapy is the most attractive option for treating patients with such rare diseases. To develop an effective ex vivo gene therapy-based protein replacement treatment requires recipient cells that differ from those used in standard gene therapy, which is performed to correct the function of the recipient cells. Adipose tissue is an expected source of proliferative cells for cell-based therapies, including regenerative medicine and gene transfer applications. Based on recent advances in cell biology and extensive clinical experience in transplantation therapy for adipose tissue, we focused on the mature adipocyte fraction, which is the floating fraction after collagenase digestion and centrifugation of adipose tissue. Proliferative adipocytes were propagated from the floating fraction by the ceiling culture technique. These cells are designated as ceiling culture-derived proliferative adipocytes (ccdPAs). We first focused on lecithin:cholesterol acyltransferase (LCAT) deficiency, an inherited metabolic disorder caused by lcat gene mutation, and ccdPAs as a therapeutic gene vehicle for LCAT replacement therapy. In our recent in vitro and animal model studies, we developed an adipose cell manipulation procedure using advanced gene transduction methods and transplantation scaffolds. We herein introduce the progress made in novel adipose tissue-based therapeutic strategies for the treatment of protein deficiencies and describe their future applications for other intractable diseases.
2016-09-24 | Sequential kidney–liver transplantation from the same living donor for lecithin cholesterol acyl transferase deficiency
Lecithin cholesterol acyl transferase (LCAT) deficiency is a rare autosomal recessive disorder of lipoprotein metabolism that results in end-stage renal disease (ESRD) necessitating transplantation. As LCAT is produced in the liver, combined kidney and liver transplantation was proposed to cure the clinical syndrome of LCAT deficiency.A 29-year-old male with ESRD secondary to LCAT deficiency underwent a sequential kidney-liver transplantation from the same living donor (LD). One year following the kidney transplant, auxiliary partial orthotopic liver transplant (APOLT) of a left lateral segment from the same donor was performed.At 5 years follow-up, there have been no major complications, readmissions, or rejection episodes. Serum lipid abnormalities recurred within the first year, but liver and kidney allograft function remains intact.Few cases of sequential transplantation from the same LD have been performed in adults. This is the first APOLT and multi-organ transplant performed for LCAT deficiency. Sequential organ transplant from the same LD for ESRD secondary to a metabolic disorder of the liver is feasible in adults and should be further investigated.
2011-03-25 | Fibrin glue increases the cell survival and the transduced gene product secretion of the ceiling culture-derived adipocytes transplanted in mice
The development of clinically applicable scaffolds is important for the application of cell transplantation in various human diseases. The aims of this study are to evaluate fibrin glue in a novel protein replacement therapy using proliferative adipocytes and to develop a mouse model system to monitor the delivery of the transgene product into the blood and the fate of the transduced cells after transplantation. Proliferative adipocytes from mouse adipose tissue were transduced by a retroviral vector harboring the human lecithin-cholesterol acyltransferase (lcat) gene, and were subcutaneously transplanted into mice combined with fibrin glue. The lcat gene transduction efficiency and the subsequent secretion of the product in mouse adipocytes were enhanced using a protamine concentration of 500 µg/ml. Adipogenesis induction did not significantly affect the lcat gene-transduced cell survival after transplantation. Immunohistochemistry showed the ectopic enzyme production to persist for 28 days in the subcutaneously transplanted gene-transduced adipocytes. The increased viability of transplanted cells with fibrin glue was accompanied with the decrease in apoptotic cell death. The immunodetectable serum LCAT levels in mice implanted with the fibrin glue were comparable with those observed in mice implanted with Matrigel, indicating that the transplanted lcat gene-transduced adipocytes survived and functioned in the transplanted spaces with fibrin glue as well as with Matrigel for 28 days. Thus, this in vivo system using fibrin is expected to serve as a good model to further improve the transplanted cell/scaffold conditions for the stable and durable cell-based replacement of defective proteins in patients with LCAT deficiency.
proteins
2020-08-13 | Plasma lipoprotein-X quantification on filipin-stained gels: monitoring recombinant LCAT treatment ex vivo.
Familial LCAT deficiency (FLD) patients accumulate lipoprotein-X (LP-X), an abnormal nephrotoxic lipoprotein enriched in free cholesterol (FC). The low neutral lipid content of LP-X limits the ability to detect it after separation by lipoprotein electrophoresis and staining with Sudan Black or other neutral lipid stains. A sensitive and accurate method for quantitating LP-X would be useful to examine the relationship between plasma LP-X and renal disease progression in FLD patients and could also serve as a biomarker for monitoring recombinant human LCAT (rhLCAT) therapy. Plasma lipoproteins were separated by agarose gel electrophoresis and cathodal migrating bands corresponding to LP-X were quantified after staining with filipin, which fluoresces with FC, but not with neutral lipids. rhLCAT was incubated with FLD plasma and lipoproteins and LP-X changes were analyzed by agarose gel electrophoresis. Filipin detects synthetic LP-X quantitatively (linearity 20-200 mg/dl FC; coefficient of variation <20%) and sensitively (lower limit of quantitation <1 mg/ml FC), enabling LP-X detection in FLD, cholestatic, and even fish-eye disease patients. rhLCAT incubation with FLD plasma ex vivo reduced LP-X dose dependently, generated HDL, and decreased lipoprotein FC content. Filipin staining after agarose gel electrophoresis sensitively detects LP-X in human plasma and accurately quantifies LP-X reduction after rhLCAT incubation ex vivo.
1988-07-01 | Transformation of large discoidal complexes of apolipoprotein A-I and phosphatidylcholine by lecithin-cholesterol acyltransferase
Using a cholate-dialysis recombination procedure, complexes of apolipoprotein A-I and synthetic phosphatidylcholine (1-palmitoyl-2-oleoylphosphatidylcholine (POPC) or dioleoylphosphatidylcholine (DOPC] were prepared in mixtures at a relatively high molar ratio of 150:1 phosphatidylcholine/apolipoprotein A-I. Particle size distribution analysis by gradient gel electrophoresis of the recombinant mixtures indicated the presence of a series of discrete complexes that included species migrating at RF values observed for discoidal particles in nascent high-density lipoproteins (HDL) in plasma of lecithin-cholesterol acyltransferase-deficient subjects. One of these complex species, designated complex class 6, formed with either phosphatidylcholine, was isolated by gel filtration and characterized at follows: discoidal shape (mean diameter 20.8 nm (POPC) and 19.0 nm (DOPC]; molar ratio, phosphatidylcholine/apolipoprotein A-I, 155:1 (POPC) and 130:1 (DOPC); and both containing 4 molecules of apolipoprotein A-I per particle. Incubation of class 6 complexes with lecithin-cholesterol acyltransferase (EC 2.3.1.43) and a source of unesterified cholesterol (low-density lipoprotein (LDL] was shown by electron microscopy to result in a progressive transformation of the discoidal particles (0 h) to deformable (2.5 h) and to spherical particles (24 h). The spherical particles (diameter 13.6 nm (POPC) and 12.5 nm (DOPC) exhibit sizes at the upper boundary of the interval defining the human plasma (HDL2b)gge (12.9-9.8 nm). The spherical particles contain a cholesteryl ester core that reaches a limiting molar ratio of approx. 50-55:1 cholesteryl ester/apolipoprotein A-I. The deformable particles assume a rectangular shape under negative staining and, relative to the 24-h spherical product, are enriched in phosphatidylcholine. Chemical crosslinking (by dimethyl suberimidate) of the isolated transformation products shows the 24-h spherical particle to contain predominantly 4 apolipoprotein A-I molecules; products produced after intermediate periods of time appear to contain species with 3 and 4 apolipoproteins per particle. Our in vitro studies indicate a potential pathway in the origins of large, apolipoprotein A-I-containing plasma HDL particles. The deformable species observed during transformation were similar in size and shape to particles observed in interstitial fluid.
1974-01-01 | The Ultrastructure of Plasma Lipoproteins in Lecithin: Cholesterol Acyltransferase Deficiency
The major plasma lipoprotein classes from patients with familial LCAT deficiency showed morphological abnormalities. Very low density lipoproteins (VLDL) contained particles with surface irregularities as well as sheet-like trilaminar structures which resembled phospholipid bilayers. Three types of particles were seen in the low density (LDL) region, large flattened structures approximately 1, 000A in size, intermediate particles 400–600A in diameter, and normal 200–250A particles. The high density lipoproteins (HDL) were characterized by discoidal particles 40A thick and 150–200A in diameter; these particles formed rouleaux. Abnormal HDL particles could be normalized by incubation of whole LCAT-deficient plasma (or HDL fraction) with LCAT; resulting structures resembled normal HDL (90–110A spheres). In severe liver disease with apparent biliary obstruction the structure of plasma lipoproteins often resembled those of familial LCAT deficiency. Rouleaux, consisting of disc-shaped particles, were in the HDL fraction, and these structures were also normalized by incubation with LCAT. Reassembly studies with apolipoproteins plus phospholipid suggested that the discs represent a bilayer structure stabilized by protein. Cholesteryl ester incorporated into the protein-lipid complex produced spherical particles.
small molecules
2025-11-03 | Abstract 4367648: Fish-Eye Disease: A Case Report
Description of Case: A 26-year-old female was referred to cardiology with bilateral corneal opacifications of four years’ duration, with no change in her visual acuity. Her workup revealed a high-density lipoprotein cholesterol (HDL-C) level of less than 10 mg/dL and a low-density lipoprotein cholesterol (LDL-C) level of 182 mg/dL, prompting genetic evaluation for disorders of lipid metabolism. She was found to have a heterozygous mutation, c.440C>T (p.Thr147Ile), and variant of uncertain significance, c.715G>A (p.Gly239Ser) in the lecithin-cholesterol acyltransferase ( LCAT ) gene. Additional studies showed low-normal serum cholesterol esters and no evidence of hematologic abnormalities or renal dysfunction. Based on these findings and her corneal opacifications, a clinical diagnosis of partial LCAT deficiency, or Fish-Eye Disease (FED), was made. Given her lipid abnormalities and the increased risk of atherosclerosis associated with FED, a high-potency statin was prescribed. Her LDL-C decreased from 182 mg/dL to 124 mg/dL. Discussion: FED is an autosomal recessive disorder of lipid metabolism caused by mutations in the LCAT gene, resulting in partial loss of enzymatic activity. LCAT catalyzes the esterification of free cholesterol, a key step in reverse cholesterol transport; esterification is lost in HDL-C (i.e., alpha activity) and conserved in lipoproteins containing apolipoprotein B (i.e., beta activity). Consequently, FED is biochemically characterized by reduced HDL-C and plasma cholesterol esters and elevated LDL-C, very-low-density lipoprotein cholesterol, triglycerides, and/or plasma unesterified cholesterol. Clinically, these patients typically present with worsening corneal opacities and decreased visual acuity and are at increased risk of atherosclerosis due to preserved beta activity. In contrast, patients may have complete loss of LCAT activity and present with more severe sequelae, a disease known as familial LCAT deficiency (FLD). Absent LCAT activity leads to unesterified cholesterol accumulation, which disrupts red blood cell membranes and deposits in the renal mesangium, leading to hemolytic anemia and renal dysfunction. It is therefore important to promptly determine the degree of LCAT activity loss and manage patients accordingly. Measuring LCAT activity, both alpha and beta, is the best diagnostic test. FED should be treated primarily with lipid-lowering medications, whereas FLD requires monitoring for anemia and renal dysfunction.
2025-08-25 | Short-Term Treatment for Immune-Mediated Acquired Lecithin-Cholesterol Acyltransferase Deficiency Restores the High-Density Lipoprotein Function: A Case Report.
Familial lecithin-cholesterol acyltransferase (LCAT) deficiency with a primary LCAT gene mutation results in various conditions, including corneal opacity, anemia, kidney disease, and low high-density lipoprotein (HDL) levels. In recent years, secondary LCAT deficiency with nearly identical symptoms has been identified as a rare case of immune-mediated acquired LCAT deficiency caused by LCAT autoantibodies. In limited cases, prednisolone treatment is required for severe conditions and has been shown to favorably modulate LCAT autoantibodies and restore LCAT activity, resulting in improved HDL-cholesterol (HDL-C) levels, renal dysfunction, and other complications. However, there is little detailed information regarding LCAT activity, lipid changes, and renal dysfunction after the initiation of prednisorone treatment. In the present study, in addition to the effects on LCAT activity, lipids, and proteinuria, we for the first time monitored the HDL cholesterol efflux capacity (CEC), an important anti-atherosclerotic HDL function, during the first month of treatment in a patient with this disease. We found that the LCAT activity, HDL-C concentration, and HDL CEC increased from undetectable or low values to normal ranges during this period, as did proteinuria. Specifically, the HDL CEC and LCAT activity recovered faster than the HDL-C levels. Based on these findings, the effects of prednisolone treatment on LCAT and HDL CEC activities prior to HDL-C levels suggest that normal HDL-C levels may not be essential as a treatment target in immune-mediated acquired LCAT deficiency patients who require treatment.
2024-09-17 | Rescue of Familial Lecithin:Cholesterol Acyltranferase Deficiency Mutations with an Allosteric Activator.
Lecithin:cholesterol acyltransferase (LCAT) deficiencies represent severe disorders characterized by aberrant cholesterol esterification in plasma, leading to life-threatening conditions. This study investigates the efficacy of Compound 2, a piperidinyl pyrazolopyridine allosteric activator that binds the membrane-binding domain of LCAT, in rescuing the activity of LCAT variants associated with disease. The variants K218N, N228K, and G230R, all located in the cap and lid domains of LCAT, demonstrated notable activity restoration in response to Compound 2. Molecular dynamics simulations and structural modeling indicate that these mutations disrupt the lid and membrane binding domain, with Compound 2 potentially dampening these structural alterations. Conversely, variants such as M252K and F382V in the cap and α/β-hydrolase domain, respectively, exhibited limited or no rescue by Compound 2. Future research should prioritize in vivo investigations that would validate the therapeutic potential of Compound 2 and related activators in familial LCAT deficiency patients with mutations in the cap and lid of the enzyme. SIGNIFICANCE STATEMENT: Lecithin:cholesterol acyltranferase (LCAT) catalyzes the first step of reverse cholesterol transport, namely the esterification of cholesterol in high density lipoprotein particles. Somatic mutations in LCAT lead to excess cholesterol in blood plasma and, in severe cases, kidney failure. In this study, we show that recently discovered small molecule activators can rescue function in LCAT-deficient variants when the mutations occur in the lid and cap domains of the enzyme.
2024-08-31 | Longitudinal analysis of clinical and laboratory biomarkers in a patient with familial lecithin: cholesterol acyltransferase deficiency (FLD) and accelerated eGFR decline: A case study.
Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is an ultra-rare autosomal recessive disease characterized by very low high-density lipoprotein cholesterol (HDL-C) levels, corneal opacity, anemia, and progressive renal disease. The rate and severity of renal disease are variable across FLD patients and the biomarkers and risk factors for disease progression are poorly understood. Here we report a 30 year-long comparative analysis of the clinical and laboratory biomarkers in an FLD patient with accelerated renal decline, who underwent two kidney and one liver transplantations. Results show that elevated triglyceride and non-HDL-C levels may promote the formation of LpX and accelerate renal function decline, whereas markers of anemia may be early predictors. Conversely, corneal opacity progresses at a steady rate and does not correlate with lipid, hematologic, or renal biomarkers. Our study suggests that monitoring of markers of anemia may aid the early detection and timely management of kidney disease with conservative therapies. Furthermore, it suggests that controlling hypercholesterolemia and hypertriglyceridemia may help improve renal disease prognosis.
2024-07-06 | Endogenous LXR signaling controls pulmonary surfactant homeostasis and prevents lung inflammation
Abstract Lung type 2 pneumocytes (T2Ps) and alveolar macrophages (AMs) play crucial roles in the synthesis, recycling and catabolism of surfactant material, a lipid/protein fluid essential for respiratory function. The liver X receptors (LXR), LXRα and LXRβ, are transcription factors important for lipid metabolism and inflammation. While LXR activation exerts anti-inflammatory actions in lung injury caused by lipopolysaccharide (LPS) and other inflammatory stimuli, the full extent of the endogenous LXR transcriptional activity in pulmonary homeostasis is incompletely understood. Here, using mice lacking LXRα and LXRβ as experimental models, we describe how the loss of LXRs causes pulmonary lipidosis, pulmonary congestion, fibrosis and chronic inflammation due to defective de novo synthesis and recycling of surfactant material by T2Ps and defective phagocytosis and degradation of excess surfactant by AMs. LXR-deficient T2Ps display aberrant lamellar bodies and decreased expression of genes encoding for surfactant proteins and enzymes involved in cholesterol, fatty acids, and phospholipid metabolism. Moreover, LXR-deficient lungs accumulate foamy AMs with aberrant expression of cholesterol and phospholipid metabolism genes. Using a house dust mite aeroallergen-induced mouse model of asthma, we show that LXR-deficient mice exhibit a more pronounced airway reactivity to a methacholine challenge and greater pulmonary infiltration, indicating an altered physiology of LXR-deficient lungs. Moreover, pretreatment with LXR agonists ameliorated the airway reactivity in WT mice sensitized to house dust mite extracts, confirming that LXR plays an important role in lung physiology and suggesting that agonist pharmacology could be used to treat inflammatory lung diseases. Graphical Abstract
gene therapies
2026-02-21 | Lecithin-cholesterol acyltransferase deficiency with the finding of "zebra bodies": A diagnostic challenge in the context of suspected Fabry disease.
Lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive disorder resulting from mutations in the LCAT gene, which leads to abnormal lipoprotein metabolism. This results in markedly reduced high-density lipoprotein cholesterol and the accumulation of lipoprotein X, leading to renal, corneal, and hemolytic damage. Two clinical variants have been described: familial LCAT deficiency (FLD) and fish-eye disease (FED). We report the case of a 41-year-old male with a history of hypertension, tinnitus, and progressive hearing loss, who presented with bilateral corneal opacity since childhood. Laboratory studies revealed significant proteinuria (2.56 g/24 h), preserved renal function (creatinine 0.85 mg/dL), mild anemia (Hb 10.2 g/dL), and extremely low HDL cholesterol (1.3 mg/dL). Renal biopsy showed focal segmental glomerulosclerosis and mesangial expansion. Electron microscopy demonstrated concentric lamellar inclusions known as "zebra bodies," a finding typically associated with Fabry disease. However, α-galactosidase A activity was normal, and genetic testing for Fabry disease was negative. Further genetic analysis identified the variant c.757 p.(Gln253Argfs*11) in the LCAT gene, confirming the diagnosis of familial LCAT deficiency. This case highlights the importance of differentiating LCAT deficiency from Fabry disease, given their overlapping clinical and histological features. Moreover, it represents the first description of "zebra bodies" in LCAT deficiency, emphasizing the diagnostic complexity and the need for a multidisciplinary approach to ensure accurate diagnosis and appropriate management.
2026-02-04 | A Novel Missense Mutation in a Compound Heterozygous Patient with Fish-Eye Disease: A Case Report.
Fish-eye disease (FED) is a rare autosomal recessive disorder caused by a partial deficiency of lecithin-cholesterol acyltransferase (LCAT) activity. It is characterized by progressive corneal opacification and dyslipidemia in the absence of systemic manifestations. We describe the clinical presentation, optical coherence tomography (OCT) imaging findings, and Scheimpflug-based corneal densitometry results in a patient with FED carrying both a pathogenic variant and a novel missense variant of the LCAT gene not reported in the current literature. We present a rare case of a 25-year-old female with bilateral corneal opacities, reduced plasma high-density lipoprotein cholesterol (<5 mg/dL), and elevated low-density lipoprotein cholesterol levels (>133 mg/dL). Visual acuity remained 20/20 in both eyes. Slit-lamp examination revealed diffuse subepithelial and anterior stromal deposits. The central corneal thickness was thinner than normal on Scheimpflug tomography, measuring 419 µm OD and 409 µm OS. OCT findings confirmed stromal thinning (479 µm OD and 470 µm OS), with preserved central epithelial thickness, and demonstrated corneal opacities throughout the cornea. Mean densitometry across the 12-mm corneal diameter was more than double that reported in healthy corneas. The cholesteryl ester-to-total cholesterol ratio remained within the normal range. Genetic analysis identified a previously reported pathogenic variant in exon 4 of LCAT (c.440C>T, p.Thr147Ile) and a novel missense mutation in exon 5 (c.715G>A, p.Gly239Ser), classified as a variant of uncertain significance. FED is a rare genetic disorder that is associated with corneal clouding and dyslipidemia. Genetic analysis confirmed the diagnosis with a compound heterozygous genotype, while OCT and corneal densitometry were effective modalities for quantifying and characterizing lipid deposits in FED.
2026-01-16 | Quantitative Assessment of Visual Function in Japanese Patients With Lecithin-Cholesterol Acyltransferase Gene Abnormalities: A Case-Control Study.
Introduction Fish-eye disease (FED) and familial lecithin-cholesterol acyltransferase (LCAT) deficiency (FLD) are rare. The aim of this study was to compare visual function between patients with LCAT abnormalities - namely, FED and FLD - and healthy controls. Methods This retrospective, comparative case-control study included four patients with FLD or FED (LCAT group) who presented with cloudy corneas at Miyata Eye Hospital between 2018 and 2024. Four age- and sex-matched individuals with normal results on ophthalmic examination were included as controls. We reviewed medical records for best-corrected visual acuity (BCVA), corneal astigmatism, forward light scattering, and contrast sensitivity. The parameters were compared between the groups. Results Sixteen eyes of eight women were included, including eight eyes of four patients with cloudy corneas in the LCAT group (two with FLD and six with FED) and eight eyes of four controls. The mean BCVA and corneal astigmatism revealed no significant intergroup differences. However, forward scattering was significantly higher in the LCAT group than in the control group (p = 0.007). The area under the log-contrast sensitivity function was significantly lower in the LCAT group than in the control group (p = 0.017). Conclusions Despite normal BCVA, patients with LCAT abnormalities (FLD and FED) showed considerably increased forward light scattering and decreased contrast sensitivity compared with the controls, indicating subtle but substantial visual functional impairment.
2024-11-14 | Novel pathogenic variant in the LCAT gene in a compound heterozygous patient with fish-eye disease and a mild phenotype.
Low high-density lipoprotein (HDL)-cholesterol and corneal opacity are associated with fish-eye disease (FED), familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD), apolipoprotein AI deficiency, and Tangier disease. The differential diagnosis is made by clinical and biochemical tests. Measuring the LCAT activity is the ideal way to distinguish conditions caused by LCAT gene variants (FED and FLD) from the other 2 diseases. However, this is not accessible from all clinics. The cholesteryl ester/total cholesterol (CE/TC) ratio, which is below the reference range in most cases with LCAT gene variants, has been proposed as an alternative. We report a case of compound heterozygous FED with a CE/TC ratio within the reference range. LCAT activity assays and genetic analyses were performed using patients' blood samples. Identified LCAT gene variants were examined by an in vitro expression assay. The proband showed approximately 20% LCAT α-activity relative to the normolipidemic controls, whereas a patient with a typical FED-causing variant (p.Thr147Ile) showed only 3% activity. We identified compound heterozygous variants (c.101C > T/c.460A > G) resulting in a p.Pro34Leu/p.Asn154Asp amino acid residue substitution in the LCAT gene of the proband. The former variant has been reported previously, but the latter was newly identified. An in vitro expression assay demonstrated that the LCAT α-activity of the p.Asn154Asp variant significantly decreased regarding the wild type, but it was relatively well preserved compared to the typical FED-causing variants (p.Pro34Leu and p.Thr147Ile). These results suggest that the residual 20% LCAT α-activity is sufficient to normalize CE/TC, but not sufficient to prevent the development of corneal opacity in FED.
2021-08-30 | Correction of Familial LCAT Deficiency by AAV-hLCAT Prevents Renal Injury and Atherosclerosis in Hamsters-Brief Report.
[Figure: see text].
other
2025-09-21 | IgG3κ Monoclonal Membranous Nephropathy Associated With Acquired Lecithin Cholesterol Acyltransferase Deficiency.
Lecithin cholesterol acyltransferase (LCAT) deficiency, inherited or acquired, is characterized by markedly low plasma high-density lipoprotein (HDL) cholesterol levels and increased unesterified cholesterol. We report a case of an elderly patient with persistently very low HDL and proteinuria. Serum cholesteryl esters were markedly low, and kidney biopsy revealed diffuse global glomerular lipid deposition, classic for LCAT deficiency, whereas genetic testing for variants associated with LCAT deficiency was negative. Kidney biopsy also showed concomitant monoclonal (IgG3κ) membranous nephropathy (MN). Proteomic analysis of glomeruli detected spectra for LCAT and serum amyloid P (SAP), suggesting that LCAT could be a target antigen in monoclonal MN with SAP enrichment and associated LCAT deficiency. Furthermore, lipidomic analysis revealed an accumulation of phosphatidylcholines and sphingomyelin and a decrease in ceramides. The patient was treated with daratumumab, and at 22 months follow-up his proteinuria was decreased while HDL level remained low.
2015-12-09 | Agonistic Human Antibodies Binding to Lecithin-Cholesterol Acyltransferase Modulate High Density Lipoprotein Metabolism
Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouseTM platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 Å LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease. Drug discovery opportunities where loss-of-function alleles of a target gene link to a disease-relevant phenotype often require an agonism approach to up-regulate or re-establish the activity of the target gene. Antibody therapy is increasingly recognized as a favored drug modality due to multiple desirable pharmacological properties. However, agonistic antibodies that enhance the activities of the target enzymes are rarely developed because the discovery of agonistic antibodies remains elusive. Here we report an innovative scheme of discovery and characterization of human antibodies capable of binding to and agonizing a circulating enzyme lecithin cholesterol acyltransferase (LCAT). Utilizing a modified human LCAT protein with enhanced enzymatic activity as an immunogen, we generated fully human monoclonal antibodies using the XenoMouseTM platform. One of the resultant agonistic antibodies, 27C3, binds to and substantially enhances the activity of LCAT from humans and cynomolgus macaques. X-ray crystallographic analysis of the 2.45 Å LCAT-27C3 complex shows that 27C3 binding does not induce notable structural changes in LCAT. A single administration of 27C3 to cynomolgus monkeys led to a rapid increase of plasma LCAT enzymatic activity and a 35% increase of the high density lipoprotein cholesterol that was observed up to 32 days after 27C3 administration. Thus, this novel scheme of immunization in conjunction with high throughput screening may represent an effective strategy for discovering agonistic antibodies against other enzyme targets. 27C3 and other agonistic human anti-human LCAT monoclonal antibodies described herein hold potential for therapeutic development for the treatment of dyslipidemia and cardiovascular disease.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
3 orphan drug designations for LCAT deficiency.
3 orphan drug designations for LCAT deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Recombinant human apolipoprotein A-I/phospholipid complexes | proteins | FDA | 2022-01-10 | — | Abionyx Pharma |
Recombinant human apolipoprotein A-I | proteins | EMA | 2021-08-20 | — | Abionyx Pharma |
RECOMBINANT HUMAN LECITHIN:CHOLESTEROL ACYLTRANSFERASE | proteins | EMA | 2012-10-10 | — | AstraZeneca AB |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.