RARE DISEASE
Familial LCAT deficiency
Familial LCAT deficiency
Familial LCAT deficiency
Synonyms: Complete LCAT deficiency, FLD, Norum disease
Synonyms: Complete LCAT deficiency, FLD, Norum disease
Synonyms: Complete LCAT deficiency, FLD, Norum disease
Drug discovery
1
drug
With orphan designation
Overview
Familial LCAT deficiency (FLD) is a rare autosomal recessive disorder caused by mutations in the LCAT gene (16q22.1), resulting in complete loss of lecithin-cholesterol acyltransferase activity [1][5]. This disrupts cholesterol esterification, causing extremely low HDL levels, corneal opacities (onset in childhood), hemolytic anemia, and progressive renal dysfunction, often leading to end-stage renal failure by the fourth decade [1][13][17]. Extrarenal manifestations include hepatosplenomegaly and atherosclerosis in some cases [10][19]. Diagnosis involves lipid profiling, genetic testing, and renal biopsy showing glomerular lipid deposits [5][13].
Therapies
Symptomatic care: ACE inhibitors/ARBs for proteinuria, statins for dyslipidemia, and erythropoietin for anemia [7][9].
Renal replacement: Hemodialysis or kidney transplantation for ESRD; disease recurrence post-transplant reported [7][13].
Emerging therapies: Gene therapy (AAV-hLCAT) and recombinant LCAT replacement show promise in preclinical studies [3][17].
Categories: rare endocrine diseases, rare genetic diseases, rare hematological diseases, rare inborn errors of metabolism, rare ophthalmic disorders, rare renal diseases, rare transplant-related disorders
Research Papers
144 drug discovery papers about Familial LCAT deficiency, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
144 drug discovery papers about Familial LCAT deficiency, with 2 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2023-12-20 | Systematic Evaluation of Lecithin:Cholesterol Acyltransferase Binding Sites in Apolipoproteins via Peptide Based Nanodiscs: Regulatory Role of Charged Residues at Positions 4 and 7
ABSTRACT Lecithin:cholesterol acyltransferase (LCAT) exhibits α-activity on high-density and β-activity on low-density lipoproteins. However, the molecular determinants governing LCAT activation by different apolipoproteins remain elusive. Uncovering these determinants would offer the opportunity to design and explore advanced therapies against dyslipidemias. Here, we have conducted coarse-grained and all-atom molecular dynamics simulations of LCAT with nanodiscs made with α-helical amphiphilic peptides either derived from apolipoproteins A1 and E (apoA1 and apoE) or apoA1 mimetic peptide 22A that was optimized to activate LCAT. This study aims to explore what drives the binding of peptides to our previously identified interaction site in LCAT. We hypothesized that this approach could be used to screen for binding sites of LCAT in different apolipoproteins and would provide insights to differently localized LCAT activities. Our screening approach was able to discriminate apoA1 helixes 4, 6, and 7 as key contributors to the interaction with LCAT supporting the previous research data. The simulations provided detailed molecular determinants driving the interaction with LCAT: the formation of hydrogen bonds or salt bridges between peptides E4 or D4 and LCAT S236 or K238 residues. Additionally, salt bridging between R7 and D73 was observed, depending on the availability of R7. Expanding our investigation to diverse plasma proteins, we detected novel LCAT binding helixes in apoL1, apoB100, and serum amyloid A. Our findings suggest that the same binding determinants, involving E4 or D4 -S236 and R7-D73 interactions, influence LCAT β-activity on low-density lipoproteins, where apoE and or apoB100 are hypothesized to interact with LCAT.
2023-11-29 | Flipped C-Terminal Ends of apoA1 Promote ABCA1-Dependent Cholesterol Efflux by Small HDLs
BACKGROUND: Cholesterol efflux capacity (CEC) predicts cardiovascular disease independently of high-density lipoprotein (HDL) cholesterol levels. Isolated small HDL particles are potent promoters of macrophage CEC by the ABCA1 (ATP-binding cassette transporter A1) pathway, but the underlying mechanisms are unclear. METHODS: We used model system studies of reconstituted HDL and plasma from control and lecithin-cholesterol acyltransferase (LCAT)–deficient subjects to investigate the relationships among the sizes of HDL particles, the structure of apoA1 (apolipoprotein A1) in the different particles, and the CECs of plasma and isolated HDLs. RESULTS: We quantified macrophage and ABCA1 CEC of 4 distinct sizes of reconstituted HDL. CEC increased as particle size decreased. Tandem mass spectrometry analysis of chemically cross-linked peptides and molecular dynamics simulations of apoA1, the major protein of HDL, indicated that the mobility of C-terminus of that protein was markedly higher and flipped off the surface in the smallest particles. To explore the physiological relevance of the model system studies, we isolated HDL from LCAT-deficient subjects, the small HDLs (eg, reconstituted HDLs) of which are discoidal and composed of apoA1, cholesterol, and phospholipid. Despite their very low plasma levels of HDL particles, these subjects had normal CEC. In both the LCAT-deficient subjects and control subjects, the CEC of isolated extra-small HDL (a mixture of extra-small and small HDL by calibrated ion mobility analysis) was 3- to 5-fold greater than that of the larger sizes of isolated HDL. Incubating LCAT-deficient plasma and control plasma with human LCAT converted extra-small and small HDL particles into larger particles, and it markedly inhibited CEC. CONCLUSIONS: We present a mechanism for the enhanced CEC of small HDLs. In smaller particles, the C-termini of the 2 antiparallel molecules of apoA1 are “flipped” off the lipid surface of HDL. This extended conformation allows them to engage with ABCA1. In contrast, the C-termini of larger HDLs are unable to interact productively with ABCA1 because they form a helical bundle that strongly adheres to the lipid on the particle. Enhanced CEC, as seen with the smaller particles, predicts decreased cardiovascular disease risk. Thus, extra-small and small HDLs may be key mediators and indicators of the cardioprotective effects of HDL.
2023-06-20 | Effects of Administration of Recombinant Human Lecithin-Cholesterol Acyltransferase on Lipoprotein Metabolism in Humans
Abstract Lecithin cholesterol acyl transferase (LCAT) catalyzes the conversion of unesterified, or free cholesterol (FC), to cholesteryl ester (CE), which moves from the surface of HDL into the neutral lipid core. As this iterative process continues, nascent lipid-poor HDL is converted to a series of larger, spherical cholesterol ester enriched HDL particles that can be cleared by the liver in a process that has been termed reverse cholesterol transport (RCT). We conducted a randomized, placebo controlled, cross-over study in 5 volunteers with ASCVD, to examine the effects of an acute increase of recombinant human (rh) LCAT via intravenous administration on the in vivo metabolism of HDL apolipoprotein (APO)A1 and APOA2, and the APOB100-lipoproteins, very low density (VLDL), intermediate density (IDL), and low density (LDL) lipoproteins. As expected, rhLCAT treatment significantly increased HDL CE content. This change did not affect the fractional clearance or production rates of HDL-APOA1 and HDL-APOA2. The metabolism of APOB100-lipoproteins was likewise unaffected. Our results suggest that an acute increase in LCAT activity drives greater flux of CE through the RCT pathway without altering the clearance and production of the main HDL proteins and without affecting the metabolism of APOB100-lipoproteins. Long-term elevations of LCAT might, therefore, have beneficial effects on total body cholesterol balance and atherogenesis.
2021-08-13 | Lecithin:cholesterol acyltransferase: symposium on 50 years of biomedical research from its discovery to latest findings.
LCAT converts free cholesterol to cholesteryl esters in the process of reverse cholesterol transport. Familial LCAT deficiency (FLD) is a genetic disease that was first described by Kaare R. Norum and Egil Gjone in 1967. This report is a summary from a 2017 symposium where Dr. Norum recounted the history of FLD and leading experts on LCAT shared their results. The Tesmer laboratory shared structural findings on LCAT and the close homolog, lysosomal phospholipase A2. Results from studies of FLD patients in Finland, Brazil, Norway, and Italy were presented, as well as the status of a patient registry. Drs. Kuivenhoven and Calabresi presented data from carriers of genetic mutations suggesting that FLD does not necessarily accelerate atherosclerosis. Dr. Ng shared that LCAT-null mice were protected from diet-induced obesity, insulin resistance, and nonalcoholic fatty liver disease. Dr. Zhou presented multiple innovations for increasing LCAT activity for therapeutic purposes, whereas Dr. Remaley showed results from treatment of an FLD patient with recombinant human LCAT (rhLCAT). Dr. Karathanasis showed that rhLCAT infusion in mice stimulates cholesterol efflux and suggested that it could also enhance cholesterol efflux from macrophages. While the role of LCAT in atherosclerosis remains elusive, the consensus is that a continued study of both the enzyme and disease will lead toward better treatments for patients with heart disease and FLD.
2018-08-22 | Agent-Based Modeling Predicts HDL-independent Pathway of Removal of Excess Surface Lipids from Very Low Density Lipoprotein
Abstract A hallmark of the metabolic syndrome is low HDL-cholesterol coupled with high plasma triglycerides (TG), but it is unclear what drives this close association. Plasma triglycerides and HDL cholesterol are thought to communicate through two distinct mechanisms. Firstly, excess surface lipids from VLDL released during lipolysis are transferred to HDL, thereby contributing to HDL directly but also indirectly through providing substrate for LCAT. Secondly, high plasma TG increases clearance of HDL through core-lipid exchange between VLDL and HDL via CETP and subsequent hydrolysis of the TG in HDL, resulting in smaller HDL and thus increased clearance rates. To test our understanding of how high plasma TG induces low HDL-cholesterol, making use of established knowledge, we developed a comprehensive agent-based model of lipoprotein metabolism which was validated using monogenic disorders of lipoprotein metabolism. By perturbing plasma TG in the model, we tested whether the current theoretical framework reproduces experimental findings. Interestingly, while increasing plasma TG through simulating decreased lipolysis of VLDL resulted in the expected decrease in HDL cholesterol, perturbing plasma TG through simulating increased VLDL production rates did not result in the expected HDL-TG relation at physiological lipid fluxes. However, model perturbations and experimental findings can be reconciled if we assume a pathway removing excess surface-lipid from VLDL that does not contribute to HDL cholesterol ester production through LCAT. In conclusion, our model simulations suggest that excess surface lipid from VLDL is cleared in part independently from HDL. Author summary While it has long been known that high plasma triglycerides are associated with low HDL cholesterol, the reason for this association has remained unclear. One of the proposed mechanisms is that during catabolism of VLDL, lipoproteins rich in triglyceride, the excess surface of these particles become a source for the production of HDL cholesterol, and that therefore decreased catabolism of VLDL will lead to both higher plasma triglyceride and low HDL cholesterol. Another proposed mechanism is that during increased production of VLDL, there will be increased exchange of core lipids between VLDL and HDL, with subsequent hydrolysis of the triglyceride in HDL, leading to smaller HDL that is cleared more rapidly. To investigate these mechanisms further we developed a computational model based on established knowledge concerning lipoprotein metabolism and validated the model with known findings in monogenetic disorders. Upon perturbing the plasma triglycerides within the model by increasing the VLDL production rate, we unexpectedly found an increase in both triglyceride and HDL cholesterol. However, upon assuming that less excess surface lipid is available to HDL, HDL decreases in response to increased VLDL production. We therefore propose that there must be a pathway removing excess surface lipids that is independent from HDL. Abbreviations PR (production rate) FCR (fractional catabolic rate) ppd (pool per day) SRB1 (scavenger receptor B1) EL (endothelial lipase) HL (hepatic lipase) PLTP (phospholipid transfer protein) CETP (cholesteryl ester transfer protein) FC (free cholesterol) CE (cholesterol ester) PL (phospholipid) LpX (lipoprotein X).
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.
2024-10-31 | Gliflozins, sucrose and flavonoids are allosteric activators of lecithin-cholesterol acyltransferase.
Lecithin-cholesterol acyltransferase (LCAT) serves as a pivotal enzyme in preserving cholesterol homeostasis via reverse cholesterol transport, a process closely associated with the onset of atherosclerosis. Impaired LCAT function can lead to severe LCAT deficiency disorders for which no pharmacological treatment exists. LCAT-based therapies, such as small molecule positive allosteric modulators (PAMs), against LCAT deficiencies and atherosclerosis hold promise, although their efficacy against atherosclerosis remains challenging. Herein we utilized a quantitative in silico metric to predict the activity of novel PAMs and tested their potencies with in vitro enzymatic assays. As predicted, sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins), sucrose and flavonoids activate LCAT. This has intriguing implications for the mechanism of action of gliflozins, which are commonly used in the treatment of type 2 diabetes, and for the endogenous activation of LCAT. Our results underscore the potential of molecular dynamics simulations in rational drug design.
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.
2021-11-11 | The HDL mimetic CER‐001 remodels plasma lipoproteins and reduces kidney lipid deposits in inherited lecithin:cholesterol acyltransferase deficiency
Kidney failure is the major cause of morbidity and mortality in familial lecithin:cholesterol acyltransferase deficiency (FLD), a rare inherited lipid disorder with no cure. Lipoprotein X (LpX), an abnormal lipoprotein, is primarily accountable for nephrotoxicity.CER-001 was tested in an FLD patient with dramatic kidney disease for 12 weeks.Infusions of CER-001 normalized the lipoprotein profile, with a disappearance of the abnormal LpX in favour of normal-sized LDL. The worsening of kidney function was slowed by the treatment, and kidney biopsy showed a slight reduction of lipid deposits and a stabilization of the disease. In vitro experiments demonstrate that CER-001 progressively reverts lipid accumulation in podocytes by a dual effect: remodelling plasma lipoproteins and removing LpX-induced lipid deposit.This study demonstrates that CER-001 may represent a therapeutic option in FLD patients. It also has the potential to be beneficial in other renal diseases characterized by kidney lipid deposits.
2021-02-24 | CER-001 ameliorates lipid profile and kidney disease in a mouse model of familial LCAT deficiency.
CER-001 is an HDL mimetic that has been tested in different pathological conditions, but never with LCAT deficiency. This study was designed to investigate whether the absence of LCAT affects the catabolic fate of CER-001, and to evaluate the effects of CER-001 on kidney disease associated with LCAT deficiency. Lcat-/- and wild-type mice received CER-001 (2.5, 5, 10 mg/kg) intravenously for 2 weeks. The plasma lipid/ lipoprotein profile and HDL subclasses were analyzed. In a second set of experiments, Lcat-/- mice were injected with LpX to induce renal disease and treated with CER-001 and then the plasma lipid profile, lipid accumulation in the kidney, albuminuria and glomerular podocyte markers were evaluated. In Lcat-/- mice a decrease in total cholesterol and triglycerides, and an increase in HDL-c was observed after CER-001 treatment. While in wild-type mice CER-001 entered the classical HDL remodeling pathway, in the absence of LCAT it disappeared from the plasma shortly after injection and ended up in the kidney. In a mouse model of renal disease in LCAT deficiency, treatment with CER-001 at 10 mg/kg for one month had beneficial effects not only on the lipid profile, but also on renal disease, by limiting albuminuria and podocyte dysfunction. Treatment with CER-001 ameliorates the dyslipidemia typically associated with LCAT deficiency and more importantly limits renal damage in a mouse model of renal disease in LCAT deficiency. The present results provide a rationale for using CER-001 in FLD patients.
cell therapies
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.
2016-08-04 | 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.
2011-07-19 | 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.
1995-09-07 | Lecithin-cholesterol acyltransferase deficiency presenting with acute pancreatitis: effect of infusion of normal plasma on triglyceride-rich lipoproteins.
A 38-year-old Asian man presented with acute pancreatitis, marked hypertriglyceridaemia and macroproteinuria, 20 years after the diagnosis of lecithin-cholesterol acyltransferase (LCAT) deficiency. After recovery, he exhibited macroproteinuria and chylomicronaemia despite treatment with a very-low-fat diet. Infusion of normal plasma significantly increased the proportion of cholesterol esters in the patient's plasma and significantly lowered chylomicron-triglyceride levels, but not proteinuria. We conclude that renal dysfunction may be a late manifestation of LCAT deficiency and that it may lead to severe chylomicronaemia and acute pancreatitis. Infusion of normal plasma corrects the dyslipidaemia in LCAT deficiency, but in the short term does not improve renal function.
1979-01-01 | Familial LCAT deficiency in view of hyperlipidemia
Since the first report of familial LCAT deficiency in 1967, the patients with the disease have been increasing all over the world. Originally, hypercholesterolemia or hyperlipidemia was regarded as one of the essential features of the disease, but later, non-hypercholesterolemic patients were reported. Because plasma lipids and lipoproteins may vary greatly by the living circumstances, observations on similarity and dissimilarity of lipid and lipoprotein patterns among patients within the same family may have a value to find a role of LCAT in plasma lipid metabolism. There were marked differences in terms of serum cholesterol concentration among three Japanese siblings with familial LCAT deficiency, who have been living in the same circumstances. On examining them, the following conclusions have been drawn. (1) Hypercholesterolemia may not be the essential feature in LCAT deficiency. We observed marked to moderate hypocholesterolemia in two out of three patients. (2) Triglyceride concentration in relation to cholesterol concentration is usually high in LCAT deficiency and this is especially marked in HDL and LDL fractions. (3) Lipoprotein lipase activity, in general, appeared to decrease in familial LCAT deficiency. (4) Fresh frozen plasma transfusion increased total cholesterol as well as esterified one. (5) Linoleic acid content in cholesterol ester is significantly low in all patients, and it may be directly related to LCAT deficiency. (6) Lysolecithin concentration in relation to lecithin is higher in VLDL than in HDL, and increases in VHDL in all patients. (7) On our examination of the patients, it was hardly thought that esterified cholesterol in VLDL was exclusively derived from HDL. (8) It was suggested that LCAT might directly act on nascent VLDL.
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.
2026-01-19 | Lecithin-Cholesterol Acyltransferase Deficiency as a Rare Cause of Bilateral Corneal Opacities: A Case Report of a Novel Frameshift Mutation.
Lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive disorder of lipid metabolism characterized by corneal opacification, hemolytic anemia, and chronic kidney disease. We describe the ophthalmic, systemic, and genetic findings of a patient with LCAT deficiency and report a novel frameshift mutation in the LCAT gene. Ophthalmic findings may represent the first clinical sign and guide the diagnosis. A 50-year-old white male with end-stage renal disease on hemodialysis and a history of recurrent hemolytic anemia was referred for bilateral corneal opacities. Despite diffuse opacification involving all corneal layers, his best corrected visual acuity remained 20/20 in both eyes with normal color vision, although contrast sensitivity was reduced. Laboratory testing revealed normocytic, normochromic anemia, low HDL cholesterol, and reduced apolipoprotein A levels. Genetic analysis identified compound heterozygosity in the LCAT gene: a novel frameshift variant c.580_598del p.(Ala194Serfs*64), classified as likely pathogenic, and the previously described missense variant c.619G>A p.(Gly207Ser), also classified as likely pathogenic. This case highlights the importance of considering metabolic disorders in the differential diagnosis of bilateral corneal opacities and expands the genetic spectrum of LCAT deficiency by reporting a novel frameshift mutation.
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.
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.
2023-06-08 | High-Density Lipoprotein in Metabolic Disorders and Beyond: An Exciting New World Full of Challenges and Opportunities
High-density lipoprotein (HDL) is an enigmatic member of the plasma lipid and lipoprotein transport system, best known for its ability to promote the reverse cholesterol efflux and the unloading of excess cholesterol from peripheral tissues. More recently, data in experimental mice and humans suggest that HDL may play important novel roles in other physiological processes associated with various metabolic disorders. Important parameters in the HDL functions are its apolipoprotein and lipid content, further reinforcing the principle that HDL structure defines its functionality. Thus, based on current evidence, low levels of HDL-cholesterol (HDL-C) or dysfunctional HDL particles contribute to the development of metabolic diseases such as morbid obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. Interestingly, low levels of HDL-C and dysfunctional HDL particles are observed in patients with multiple myeloma and other types of cancer. Therefore, adjusting HDL-C levels within the optimal range and improving HDL particle functionality is expected to benefit such pathological conditions. The failure of previous clinical trials testing various HDL-C-raising pharmaceuticals does not preclude a significant role for HDL in the treatment of atherosclerosis and related metabolic disorders. Those trials were designed on the principle of "the more the better", ignoring the U-shape relationship between HDL-C levels and morbidity and mortality. Thus, many of these pharmaceuticals should be retested in appropriately designed clinical trials. Novel gene-editing-based pharmaceuticals aiming at altering the apolipoprotein composition of HDL are expected to revolutionize the treatment strategies, improving the functionality of dysfunctional HDL.
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.
2016-02-01 | 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.
proteins
2023-12-20 | Systematic Evaluation of Lecithin:Cholesterol Acyltransferase Binding Sites in Apolipoproteins via Peptide Based Nanodiscs: Regulatory Role of Charged Residues at Positions 4 and 7
ABSTRACT Lecithin:cholesterol acyltransferase (LCAT) exhibits α-activity on high-density and β-activity on low-density lipoproteins. However, the molecular determinants governing LCAT activation by different apolipoproteins remain elusive. Uncovering these determinants would offer the opportunity to design and explore advanced therapies against dyslipidemias. Here, we have conducted coarse-grained and all-atom molecular dynamics simulations of LCAT with nanodiscs made with α-helical amphiphilic peptides either derived from apolipoproteins A1 and E (apoA1 and apoE) or apoA1 mimetic peptide 22A that was optimized to activate LCAT. This study aims to explore what drives the binding of peptides to our previously identified interaction site in LCAT. We hypothesized that this approach could be used to screen for binding sites of LCAT in different apolipoproteins and would provide insights to differently localized LCAT activities. Our screening approach was able to discriminate apoA1 helixes 4, 6, and 7 as key contributors to the interaction with LCAT supporting the previous research data. The simulations provided detailed molecular determinants driving the interaction with LCAT: the formation of hydrogen bonds or salt bridges between peptides E4 or D4 and LCAT S236 or K238 residues. Additionally, salt bridging between R7 and D73 was observed, depending on the availability of R7. Expanding our investigation to diverse plasma proteins, we detected novel LCAT binding helixes in apoL1, apoB100, and serum amyloid A. Our findings suggest that the same binding determinants, involving E4 or D4 -S236 and R7-D73 interactions, influence LCAT β-activity on low-density lipoproteins, where apoE and or apoB100 are hypothesized to interact with LCAT.
2023-11-29 | Flipped C-Terminal Ends of apoA1 Promote ABCA1-Dependent Cholesterol Efflux by Small HDLs
BACKGROUND: Cholesterol efflux capacity (CEC) predicts cardiovascular disease independently of high-density lipoprotein (HDL) cholesterol levels. Isolated small HDL particles are potent promoters of macrophage CEC by the ABCA1 (ATP-binding cassette transporter A1) pathway, but the underlying mechanisms are unclear. METHODS: We used model system studies of reconstituted HDL and plasma from control and lecithin-cholesterol acyltransferase (LCAT)–deficient subjects to investigate the relationships among the sizes of HDL particles, the structure of apoA1 (apolipoprotein A1) in the different particles, and the CECs of plasma and isolated HDLs. RESULTS: We quantified macrophage and ABCA1 CEC of 4 distinct sizes of reconstituted HDL. CEC increased as particle size decreased. Tandem mass spectrometry analysis of chemically cross-linked peptides and molecular dynamics simulations of apoA1, the major protein of HDL, indicated that the mobility of C-terminus of that protein was markedly higher and flipped off the surface in the smallest particles. To explore the physiological relevance of the model system studies, we isolated HDL from LCAT-deficient subjects, the small HDLs (eg, reconstituted HDLs) of which are discoidal and composed of apoA1, cholesterol, and phospholipid. Despite their very low plasma levels of HDL particles, these subjects had normal CEC. In both the LCAT-deficient subjects and control subjects, the CEC of isolated extra-small HDL (a mixture of extra-small and small HDL by calibrated ion mobility analysis) was 3- to 5-fold greater than that of the larger sizes of isolated HDL. Incubating LCAT-deficient plasma and control plasma with human LCAT converted extra-small and small HDL particles into larger particles, and it markedly inhibited CEC. CONCLUSIONS: We present a mechanism for the enhanced CEC of small HDLs. In smaller particles, the C-termini of the 2 antiparallel molecules of apoA1 are “flipped” off the lipid surface of HDL. This extended conformation allows them to engage with ABCA1. In contrast, the C-termini of larger HDLs are unable to interact productively with ABCA1 because they form a helical bundle that strongly adheres to the lipid on the particle. Enhanced CEC, as seen with the smaller particles, predicts decreased cardiovascular disease risk. Thus, extra-small and small HDLs may be key mediators and indicators of the cardioprotective effects of HDL.
2023-06-20 | Effects of Administration of Recombinant Human Lecithin-Cholesterol Acyltransferase on Lipoprotein Metabolism in Humans
Abstract Lecithin cholesterol acyl transferase (LCAT) catalyzes the conversion of unesterified, or free cholesterol (FC), to cholesteryl ester (CE), which moves from the surface of HDL into the neutral lipid core. As this iterative process continues, nascent lipid-poor HDL is converted to a series of larger, spherical cholesterol ester enriched HDL particles that can be cleared by the liver in a process that has been termed reverse cholesterol transport (RCT). We conducted a randomized, placebo controlled, cross-over study in 5 volunteers with ASCVD, to examine the effects of an acute increase of recombinant human (rh) LCAT via intravenous administration on the in vivo metabolism of HDL apolipoprotein (APO)A1 and APOA2, and the APOB100-lipoproteins, very low density (VLDL), intermediate density (IDL), and low density (LDL) lipoproteins. As expected, rhLCAT treatment significantly increased HDL CE content. This change did not affect the fractional clearance or production rates of HDL-APOA1 and HDL-APOA2. The metabolism of APOB100-lipoproteins was likewise unaffected. Our results suggest that an acute increase in LCAT activity drives greater flux of CE through the RCT pathway without altering the clearance and production of the main HDL proteins and without affecting the metabolism of APOB100-lipoproteins. Long-term elevations of LCAT might, therefore, have beneficial effects on total body cholesterol balance and atherogenesis.
2021-08-13 | Lecithin:cholesterol acyltransferase: symposium on 50 years of biomedical research from its discovery to latest findings.
LCAT converts free cholesterol to cholesteryl esters in the process of reverse cholesterol transport. Familial LCAT deficiency (FLD) is a genetic disease that was first described by Kaare R. Norum and Egil Gjone in 1967. This report is a summary from a 2017 symposium where Dr. Norum recounted the history of FLD and leading experts on LCAT shared their results. The Tesmer laboratory shared structural findings on LCAT and the close homolog, lysosomal phospholipase A2. Results from studies of FLD patients in Finland, Brazil, Norway, and Italy were presented, as well as the status of a patient registry. Drs. Kuivenhoven and Calabresi presented data from carriers of genetic mutations suggesting that FLD does not necessarily accelerate atherosclerosis. Dr. Ng shared that LCAT-null mice were protected from diet-induced obesity, insulin resistance, and nonalcoholic fatty liver disease. Dr. Zhou presented multiple innovations for increasing LCAT activity for therapeutic purposes, whereas Dr. Remaley showed results from treatment of an FLD patient with recombinant human LCAT (rhLCAT). Dr. Karathanasis showed that rhLCAT infusion in mice stimulates cholesterol efflux and suggested that it could also enhance cholesterol efflux from macrophages. While the role of LCAT in atherosclerosis remains elusive, the consensus is that a continued study of both the enzyme and disease will lead toward better treatments for patients with heart disease and FLD.
2018-08-22 | Agent-Based Modeling Predicts HDL-independent Pathway of Removal of Excess Surface Lipids from Very Low Density Lipoprotein
Abstract A hallmark of the metabolic syndrome is low HDL-cholesterol coupled with high plasma triglycerides (TG), but it is unclear what drives this close association. Plasma triglycerides and HDL cholesterol are thought to communicate through two distinct mechanisms. Firstly, excess surface lipids from VLDL released during lipolysis are transferred to HDL, thereby contributing to HDL directly but also indirectly through providing substrate for LCAT. Secondly, high plasma TG increases clearance of HDL through core-lipid exchange between VLDL and HDL via CETP and subsequent hydrolysis of the TG in HDL, resulting in smaller HDL and thus increased clearance rates. To test our understanding of how high plasma TG induces low HDL-cholesterol, making use of established knowledge, we developed a comprehensive agent-based model of lipoprotein metabolism which was validated using monogenic disorders of lipoprotein metabolism. By perturbing plasma TG in the model, we tested whether the current theoretical framework reproduces experimental findings. Interestingly, while increasing plasma TG through simulating decreased lipolysis of VLDL resulted in the expected decrease in HDL cholesterol, perturbing plasma TG through simulating increased VLDL production rates did not result in the expected HDL-TG relation at physiological lipid fluxes. However, model perturbations and experimental findings can be reconciled if we assume a pathway removing excess surface-lipid from VLDL that does not contribute to HDL cholesterol ester production through LCAT. In conclusion, our model simulations suggest that excess surface lipid from VLDL is cleared in part independently from HDL. Author summary While it has long been known that high plasma triglycerides are associated with low HDL cholesterol, the reason for this association has remained unclear. One of the proposed mechanisms is that during catabolism of VLDL, lipoproteins rich in triglyceride, the excess surface of these particles become a source for the production of HDL cholesterol, and that therefore decreased catabolism of VLDL will lead to both higher plasma triglyceride and low HDL cholesterol. Another proposed mechanism is that during increased production of VLDL, there will be increased exchange of core lipids between VLDL and HDL, with subsequent hydrolysis of the triglyceride in HDL, leading to smaller HDL that is cleared more rapidly. To investigate these mechanisms further we developed a computational model based on established knowledge concerning lipoprotein metabolism and validated the model with known findings in monogenetic disorders. Upon perturbing the plasma triglycerides within the model by increasing the VLDL production rate, we unexpectedly found an increase in both triglyceride and HDL cholesterol. However, upon assuming that less excess surface lipid is available to HDL, HDL decreases in response to increased VLDL production. We therefore propose that there must be a pathway removing excess surface lipids that is independent from HDL. Abbreviations PR (production rate) FCR (fractional catabolic rate) ppd (pool per day) SRB1 (scavenger receptor B1) EL (endothelial lipase) HL (hepatic lipase) PLTP (phospholipid transfer protein) CETP (cholesteryl ester transfer protein) FC (free cholesterol) CE (cholesterol ester) PL (phospholipid) LpX (lipoprotein X).
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.
2024-10-31 | Gliflozins, sucrose and flavonoids are allosteric activators of lecithin-cholesterol acyltransferase.
Lecithin-cholesterol acyltransferase (LCAT) serves as a pivotal enzyme in preserving cholesterol homeostasis via reverse cholesterol transport, a process closely associated with the onset of atherosclerosis. Impaired LCAT function can lead to severe LCAT deficiency disorders for which no pharmacological treatment exists. LCAT-based therapies, such as small molecule positive allosteric modulators (PAMs), against LCAT deficiencies and atherosclerosis hold promise, although their efficacy against atherosclerosis remains challenging. Herein we utilized a quantitative in silico metric to predict the activity of novel PAMs and tested their potencies with in vitro enzymatic assays. As predicted, sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins), sucrose and flavonoids activate LCAT. This has intriguing implications for the mechanism of action of gliflozins, which are commonly used in the treatment of type 2 diabetes, and for the endogenous activation of LCAT. Our results underscore the potential of molecular dynamics simulations in rational drug design.
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.
2021-11-11 | The HDL mimetic CER‐001 remodels plasma lipoproteins and reduces kidney lipid deposits in inherited lecithin:cholesterol acyltransferase deficiency
Kidney failure is the major cause of morbidity and mortality in familial lecithin:cholesterol acyltransferase deficiency (FLD), a rare inherited lipid disorder with no cure. Lipoprotein X (LpX), an abnormal lipoprotein, is primarily accountable for nephrotoxicity.CER-001 was tested in an FLD patient with dramatic kidney disease for 12 weeks.Infusions of CER-001 normalized the lipoprotein profile, with a disappearance of the abnormal LpX in favour of normal-sized LDL. The worsening of kidney function was slowed by the treatment, and kidney biopsy showed a slight reduction of lipid deposits and a stabilization of the disease. In vitro experiments demonstrate that CER-001 progressively reverts lipid accumulation in podocytes by a dual effect: remodelling plasma lipoproteins and removing LpX-induced lipid deposit.This study demonstrates that CER-001 may represent a therapeutic option in FLD patients. It also has the potential to be beneficial in other renal diseases characterized by kidney lipid deposits.
2021-02-24 | CER-001 ameliorates lipid profile and kidney disease in a mouse model of familial LCAT deficiency.
CER-001 is an HDL mimetic that has been tested in different pathological conditions, but never with LCAT deficiency. This study was designed to investigate whether the absence of LCAT affects the catabolic fate of CER-001, and to evaluate the effects of CER-001 on kidney disease associated with LCAT deficiency. Lcat-/- and wild-type mice received CER-001 (2.5, 5, 10 mg/kg) intravenously for 2 weeks. The plasma lipid/ lipoprotein profile and HDL subclasses were analyzed. In a second set of experiments, Lcat-/- mice were injected with LpX to induce renal disease and treated with CER-001 and then the plasma lipid profile, lipid accumulation in the kidney, albuminuria and glomerular podocyte markers were evaluated. In Lcat-/- mice a decrease in total cholesterol and triglycerides, and an increase in HDL-c was observed after CER-001 treatment. While in wild-type mice CER-001 entered the classical HDL remodeling pathway, in the absence of LCAT it disappeared from the plasma shortly after injection and ended up in the kidney. In a mouse model of renal disease in LCAT deficiency, treatment with CER-001 at 10 mg/kg for one month had beneficial effects not only on the lipid profile, but also on renal disease, by limiting albuminuria and podocyte dysfunction. Treatment with CER-001 ameliorates the dyslipidemia typically associated with LCAT deficiency and more importantly limits renal damage in a mouse model of renal disease in LCAT deficiency. The present results provide a rationale for using CER-001 in FLD patients.
cell therapies
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.
2016-08-04 | 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.
2011-07-19 | 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.
1995-09-07 | Lecithin-cholesterol acyltransferase deficiency presenting with acute pancreatitis: effect of infusion of normal plasma on triglyceride-rich lipoproteins.
A 38-year-old Asian man presented with acute pancreatitis, marked hypertriglyceridaemia and macroproteinuria, 20 years after the diagnosis of lecithin-cholesterol acyltransferase (LCAT) deficiency. After recovery, he exhibited macroproteinuria and chylomicronaemia despite treatment with a very-low-fat diet. Infusion of normal plasma significantly increased the proportion of cholesterol esters in the patient's plasma and significantly lowered chylomicron-triglyceride levels, but not proteinuria. We conclude that renal dysfunction may be a late manifestation of LCAT deficiency and that it may lead to severe chylomicronaemia and acute pancreatitis. Infusion of normal plasma corrects the dyslipidaemia in LCAT deficiency, but in the short term does not improve renal function.
1979-01-01 | Familial LCAT deficiency in view of hyperlipidemia
Since the first report of familial LCAT deficiency in 1967, the patients with the disease have been increasing all over the world. Originally, hypercholesterolemia or hyperlipidemia was regarded as one of the essential features of the disease, but later, non-hypercholesterolemic patients were reported. Because plasma lipids and lipoproteins may vary greatly by the living circumstances, observations on similarity and dissimilarity of lipid and lipoprotein patterns among patients within the same family may have a value to find a role of LCAT in plasma lipid metabolism. There were marked differences in terms of serum cholesterol concentration among three Japanese siblings with familial LCAT deficiency, who have been living in the same circumstances. On examining them, the following conclusions have been drawn. (1) Hypercholesterolemia may not be the essential feature in LCAT deficiency. We observed marked to moderate hypocholesterolemia in two out of three patients. (2) Triglyceride concentration in relation to cholesterol concentration is usually high in LCAT deficiency and this is especially marked in HDL and LDL fractions. (3) Lipoprotein lipase activity, in general, appeared to decrease in familial LCAT deficiency. (4) Fresh frozen plasma transfusion increased total cholesterol as well as esterified one. (5) Linoleic acid content in cholesterol ester is significantly low in all patients, and it may be directly related to LCAT deficiency. (6) Lysolecithin concentration in relation to lecithin is higher in VLDL than in HDL, and increases in VHDL in all patients. (7) On our examination of the patients, it was hardly thought that esterified cholesterol in VLDL was exclusively derived from HDL. (8) It was suggested that LCAT might directly act on nascent VLDL.
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.
2026-01-19 | Lecithin-Cholesterol Acyltransferase Deficiency as a Rare Cause of Bilateral Corneal Opacities: A Case Report of a Novel Frameshift Mutation.
Lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare autosomal recessive disorder of lipid metabolism characterized by corneal opacification, hemolytic anemia, and chronic kidney disease. We describe the ophthalmic, systemic, and genetic findings of a patient with LCAT deficiency and report a novel frameshift mutation in the LCAT gene. Ophthalmic findings may represent the first clinical sign and guide the diagnosis. A 50-year-old white male with end-stage renal disease on hemodialysis and a history of recurrent hemolytic anemia was referred for bilateral corneal opacities. Despite diffuse opacification involving all corneal layers, his best corrected visual acuity remained 20/20 in both eyes with normal color vision, although contrast sensitivity was reduced. Laboratory testing revealed normocytic, normochromic anemia, low HDL cholesterol, and reduced apolipoprotein A levels. Genetic analysis identified compound heterozygosity in the LCAT gene: a novel frameshift variant c.580_598del p.(Ala194Serfs*64), classified as likely pathogenic, and the previously described missense variant c.619G>A p.(Gly207Ser), also classified as likely pathogenic. This case highlights the importance of considering metabolic disorders in the differential diagnosis of bilateral corneal opacities and expands the genetic spectrum of LCAT deficiency by reporting a novel frameshift mutation.
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.
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.
2023-06-08 | High-Density Lipoprotein in Metabolic Disorders and Beyond: An Exciting New World Full of Challenges and Opportunities
High-density lipoprotein (HDL) is an enigmatic member of the plasma lipid and lipoprotein transport system, best known for its ability to promote the reverse cholesterol efflux and the unloading of excess cholesterol from peripheral tissues. More recently, data in experimental mice and humans suggest that HDL may play important novel roles in other physiological processes associated with various metabolic disorders. Important parameters in the HDL functions are its apolipoprotein and lipid content, further reinforcing the principle that HDL structure defines its functionality. Thus, based on current evidence, low levels of HDL-cholesterol (HDL-C) or dysfunctional HDL particles contribute to the development of metabolic diseases such as morbid obesity, type 2 diabetes mellitus, and nonalcoholic fatty liver disease. Interestingly, low levels of HDL-C and dysfunctional HDL particles are observed in patients with multiple myeloma and other types of cancer. Therefore, adjusting HDL-C levels within the optimal range and improving HDL particle functionality is expected to benefit such pathological conditions. The failure of previous clinical trials testing various HDL-C-raising pharmaceuticals does not preclude a significant role for HDL in the treatment of atherosclerosis and related metabolic disorders. Those trials were designed on the principle of "the more the better", ignoring the U-shape relationship between HDL-C levels and morbidity and mortality. Thus, many of these pharmaceuticals should be retested in appropriately designed clinical trials. Novel gene-editing-based pharmaceuticals aiming at altering the apolipoprotein composition of HDL are expected to revolutionize the treatment strategies, improving the functionality of dysfunctional HDL.
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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.
2016-02-01 | 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.
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Drug Discovery Landscape
1 orphan drug designation for Familial LCAT deficiency.
1 orphan drug designation for Familial LCAT deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
recombinant human lecithin:cholesterol acyltransferase (rhLCAT) | proteins | FDA | 2010-09-02 | — | MedImmune |
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