RARE DISEASE
Familial chylomicronemia syndrome
Familial chylomicronemia syndrome
Familial chylomicronemia syndrome
Drug discovery
10
drugs
With orphan designations
Overview
Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by severe hypertriglyceridemia (>10 mmol/L or >885 mg/dL) due to impaired chylomicron clearance. Caused primarily by bi-allelic loss-of-function variants in LPL (60-80% of cases) or genes regulating lipoprotein lipase activity (APOA5, APOC2, GPIHBP1, LMF1), FCS manifests with recurrent pancreatitis, abdominal pain, eruptive xanthomas, and lipemia retinalis [1][3][7]. Management centers on lifelong strict fat restriction (<20 g/day), though standard lipid-lowering therapies are largely ineffective [1][11]. Emerging RNA-targeted therapies (e.g., ApoC-III inhibitors) show promise in reducing triglycerides and pancreatitis risk [8][13].
Population
Burden
Clinical: Median 34 lifetime pancreatitis episodes; 40% require annual hospitalization [4][9][16]
Psychosocial: 58–82% report impaired mental health, employment limitations (94%), and restricted social functioning [4][14]
Economic: Mean 6.5-day hospital stays per pancreatitis episode; frequent specialist consultations and dietary management costs [4][9][14]
Therapies
Diet: First-line very low-fat diet (<10% of calories from fat) [1][3][16]
Pharmacotherapy: Volanesorsen (EU-approved ApoC-III inhibitor), olezarsen (FDA-approved RNA-targeted therapy), and investigational plozasiran (siRNA) [8][11][13]
Adjuncts: Medium-chain triglyceride (MCT) supplementation; avoidance of alcohol, refined carbohydrates, and estrogen [1][6]
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism
Research Papers
279 drug discovery papers about Familial chylomicronemia syndrome, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
279 drug discovery papers about Familial chylomicronemia syndrome, with 5 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2026-04-04 | Lipoprotein lipase DNA methylation in the adipose tissue of patients with persistent chylomicronemia.
Persistent chylomicronemia (PC) is a rare condition characterized by plasma triglyceride concentration persistently >10 mmol/L despite treatment, reflecting a lack of lipoprotein lipase (LPL) bioavailability. PC encompasses patients with the familial chylomicronemia syndrome (FCS) and patients with multifactorial PC. Life habits and environmental factors are known modulators of DNA methylation (DNAme), which can influence access to the LPL gene and possibly contribute to the expression of PC. To compare LPL DNAme in blood and adipose tissue of patients with PC or other causes of hypertriglyceridemia (HTG) and normotriglyceridemic controls. DNA was extracted from blood and adipose tissue in 186 participants: 31 with PC (21 FCS, 10 multifactorial PC), 125 with HTG, and 30 controls. DNAme was measured using pyrosequencing at 22 cytosine-phosphate-guanine sites (CpGs) located in the promoter and between the first exons of the LPL gene. Differences in LPL DNAme were assessed according to the genotype and severity of HTG. No difference in LPL DNAme was observed in blood samples. In adipose tissues, patients with FCS were significantly less methylated at 2 CpGs located in the LPL gene body compared with other genotypes (Δϐ = 2.85% and 3.78%, P = .011). When DNAme was analyzed according to HTG severity, the same CpGs were less methylated in patients with PC of any cause compared with other groups (Δϐ = 4.55%, P = .002; Δϐ = 7.70%, P < .001). In this study, the LPL DNAme signature in adipose tissue differed in patients with PC compared with others, highlighting that different factors might contribute to PC and its associated risks.
2026-03-30 | Milky blood in a middle-aged man with Diabetes mellitus: Familial chylomicronemia syndrome due to GPIHBP1 mutation
Milky blood in a middle-aged man with Diabetes mellitus: Familial chylomicronemia syndrome due to GPIHBP1 mutation1Mukti Nath Sankhi, 2Naresh Bansal,3Samir Samadarshi, 4Santosh Kumar Singh2Rohit Vashisht1Nepalese Army Institute of Health Sciences College of MedicineKathmandu, Bagmati, Nepal2Army Hospital, Research and ReferralNew Delhi, Delhi, India3Command Hospital Air ForceBangalore, India4Armed Forces Medical CollegePune, IndiaCorresponding author: Mukti Nath Sankhi, Lecturer, Nepalese Army Institute of Health Sciences College of Medicine Kathmandu, Bagmati, Nepal. Email: muktinath.sankhi@naihs.edu.np
2026-02-09 | Case Report: Clinical and genetic analysis of a family with hereditary spherocytosis combined with familial chylomicronemia syndrome.
This study was conducted to investigate the clinical and genetic characteristics of a family affected by hereditary spherocytosis (HS) combined with familial chylomicronemia syndrome (FCS), identify the pathogenic cause, and provide a basis for the clinical diagnosis, treatment, and genetic counseling of affected children. Clinical data were collected from family members. High-throughput sequencing was performed to identify pathogenic variants in genes associated with HS and FCS in the proband. Suspected pathogenic mutations were confirmed in family members via PCR-Sanger sequencing. Bioinformatics analysis and three-dimensional protein structure prediction were also conducted. The proband presented with severe anemia, splenomegaly, and jaundice. Genetic testing revealed a heterozygous mutation, c.6005G>A (p.Trp2002*), in the spectrin beta chain (SPTB)gene (NM_001355436.2) and a missense mutation, c.292G>A (p.Ala98Thr), in the lipoprotein lipase (LPL) gene (NM_000237.3). The SPTB c.6005G>A (p.Trp2002*) mutation was inherited from the mother, who exhibited mild anemia, jaundice, and splenomegaly. The LPL c.292G>A (p.Ala98Thr) mutation was inherited from the father, who had hypertriglyceridemia. The SPTB c.6005G>A (p.Trp2002*) mutation is extremely rare in the general population. The heterozygous mutations SPTB c.6005G>A (p.Trp2002*) and LPL c.292G>A (p.Ala98Thr) are the pathogenic causes in this family and provide a basis for clinical management and genetic counseling. Based on the HGMD, 1000G, and ExAC databases, the SPTB c.6005G>A (p.Trp2002*) mutation is reported here for the first time, enriching the mutation spectrum of the SPTB gene.
2025-11-03 | Abstract 4370295: Single dose of a novel CRISPR-CasX editor potently reduces triglycerides in preclinical models and efficiently edits APOC3 in non-human primates
Background: Severe hypertriglyceridemia (SHTG) and familial chylomicronemia syndrome (FCS) are marked by extreme triglyceride (TG) elevations, raising the risk for acute pancreatitis and cardiovascular complications. Apolipoprotein C-III (APOC3) impairs TG catabolism and clearance. Loss-of-function APOC3 mutations are linked to lower TGs and reduced atherosclerotic risk, highlighting APOC3 as a promising therapeutic target. CRISPR-CasXE (XE) is an engineered gene editing platform with improved potency and specificity over natural systems. Here, we report the development of STX-1400, the first liver-targeted XE gene editing therapy designed to disrupt APOC3 expression and reduce circulating TGs. Approach: STX-1400 consists of an mRNA encoding an engineered XE editor and a single APOC3-targeting gRNA delivered via lipid nanoparticles. We evaluated the efficacy of a STX-1400 prototype in multiple in vitro and in vivo models. Specificity was assessed using a comprehensive off-target strategy to nominate potential off-target sites, followed by deep sequencing evaluation in primary human hepatocytes (PHHs) treated at 10xEC90. A non-human primate (NHP) surrogate was also tested in cynomolgus monkeys at escalating doses, with APOC3 editing measured in liver biopsies 18 days post-dose. Results: In PHHs, a STX-1400 prototype showed dose-dependent APOC3 editing (up to 90%) with >70% decrease in secreted APOC3 protein. In human APOC3 transgenic mice, hepatic editing at the APOC3 locus exceeded >70%, reducing circulating APOC3 by 80%. In hypertriglyceridemic mice, the STX-1400 prototype reduced APOC3 mRNA by >90% and protein by >95%, which corresponded with decreasing plasma TGs by >95% and total cholesterol by >80%. No off-target editing was observed in PHHs treated at 10xEC90. Notably, a single administration of the NHP analog of the STX-1400 prototype in cynomolgus monkeys achieved saturated editing levels (>70%) in the liver at 1mg/kg, with liver enzyme profiles comparable to controls. Conclusions: Our findings demonstrate that the STX-1400 prototype potently and specifically edits APOC3 across human cells, mouse models, and non-human primates. This study is the first demonstration that a CRISPR-based therapy has achieved saturated in vivo editing of the APOC3 locus in NHP liver. These results provide strong preclinical evidence supporting the potential of STX-1400 as a first-in class genome editing therapy for hypertriglyceridemia in patients with SHTG and FCS.
2025-07-05 | Heterozygous pathogenic PPARG variants in patients with severe hypertriglyceridemia.
Heterozygous pathogenic variants in PPARG cause familial partial lipodystrophy type 3 (FPLD3, Mendelian Inheritance in Man [MIM] #604367), a heritable form of insulin resistance with multiple metabolic disturbances including hypertriglyceridemia. We investigated the prevalence of FPLD3 individuals in our cohort of patients with multifactorial chylomicronemia syndrome (MCS). We used our targeted DNA sequencing panel to screen the PPARG gene in 182 clinically diagnosed MCS patients. We found that 3.3% of MCS patients (6/182) had a heterozygous pathogenic PPARG variant, consistent with a diagnosis of FPLD3. The variants were PPARG p.Lys186fs (ClinVar identifier 8132), p.Glu217Lys, p.Pro454fs (ClinVar identifier 436405), p.Met284Ile, p.Ser383Arg, and p.Arg181Trp. None of these patients had previously been diagnosed with FPLD3 and their clinical and biochemical features were otherwise comparable to those of the entire MCS cohort. A small but clinically relevant subgroup of individuals with MCS has FPLD3. Clinical features in FPLD3 are subtle but the phenotype can be metabolically severe. Genetic screening of patients with severe hypertriglyceridemia should include assessment of lipodystrophy genes, since management of lipodystrophy patients is distinct from that of typical MCS patients.
cell therapies
2026-01-01 | Sequential Continuous Renal Replacement Therapy and Therapeutic Plasma Exchange in Pediatric Necrotizing Hypertriglyceridemia-Induced Pancreatitis with Suspected Familial Chylomicronemia Syndrome: A Case Report
Background: Hypertriglyceridemia-induced acute pancreatitis (HTG-AP) is a severe and underrecognized etiology of pancreatitis, accounting for 1% - 4% of all cases in adults, with extreme triglyceridemia raising the risk of fulminant multi-organ failure. When underlying lipoprotein lipase (LPL) deficiency is suspected—as in familial chylomicronemia syndrome (FCS)—conventional pharmacologic strategies are inherently limited, and therapeutic plasma exchange (TPE) represents the most effective currently available approach for the rapid removal of chylomicrons and triglyceride-rich lipoproteins from the circulation. Case Summary: We report a 14-year-old girl presenting with triglycerides > 14,000 mg/dL, severe necrotizing pancreatitis, acute kidney injury (AKI), mild acute respiratory distress syndrome (ARDS), and metabolic encephalopathy. No prior medical history was identified. Despite aggressive pharmacologic therapy with intravenous insulin, heparin, and fibrates, triglyceride levels remained critically elevated. Continuous renal replacement therapy (CRRT) was initiated for AKI, metabolic acidosis, and hemodynamic instability, achieving significant physiologic stabilization. However, because CRRT does not effectively clear chylomicrons, lipid levels remained dangerously high. Two urgent sessions of TPE reduced triglycerides from >14,000 mg/dL to approximately 300 mg/dL, with subsequent normalization of pancreatic enzymes and full recovery of renal, respiratory, and neurological function. The patient was discharged in good clinical condition. Conclusion: This case illustrates that CRRT and TPE fulfill distinct, non-overlapping roles in severe HTG-AP. CRRT provides essential metabolic bridge support, and TPE achieves definitive lipid clearance. When LPL deficiency is suspected, early escalation to TPE is potentially lifesaving. A high index of clinical suspicion and timely decision-making are the key determinants of outcome in this rare but catastrophic condition.
2025-07-01 | Experience with apheretic treatment in the chronic management of severe hypertriglyceridemia: case series.
Chylomicronemia Syndrome (CS) refers to a group of lipid disorders characterized by the accumulation of chylomicrons in the plasma due to impaired lipolytic clearance. It encompasses various clinical features, including Familial Chylomicronemia Syndrome (FCS) and Multifactorial Chylomicronemia Syndrome (MCS). Diagnosing CS is a significant clinical challenge, as it is essential for identifying patients at highest risk of acute pancreatitis, preventing recurrence, and improving cardiovascular outcomes. Methods and Case Descriptions. Since 2008, we have identified eight patients residing in the same geographical area of Central Italy (Tuscany Region), all referred to us for severe and treatment-resistant hypertriglyceridemia. During this time, new therapeutic agents such as volanesorsen and lomitapide became available. However, none of these patients met the reimbursement criteria set by the Italian Medicines Agency (AIFA). We describe the clinical management and follow-up of these patients, in whom plasma and lipoprotein apheresis remain an effective therapy for reducing the risk of pancreatitis.
2024-03-27 | Exchange Transfusion: A Good Option for the Acute Treatment of Familial Chylomicronemia Syndrome in the Neonatal Period
Familial chylomicronemia syndrome (FCS) is one of the rare causes of hypertriglyceridemia. Plasmapheresis is recommended in patients with triglyceride levels greater than 2000 mg/dL. However, plasmapheresis is difficult to perform in most centers due to technical inadequacies in the neonatal period. There are some reports in the literature on the efficacy of exchange transfusion. The index case involves a 20-day-old male patient who was admitted to the emergency department for restlessness and poor feeding. He was born at term with a birth weight of 4000 g. He was exclusively breastfed. The patient was taken to the neonatal intensive care unit due to his plasma being in the form of excessive lipemia. The first measurable triglyceride level was 5100 mg/dL (57.6 mmol/L). Breast milk was restricted, and intravenous hydration was started. However, his triglyceride level did not decrease despite this treatment. Other laboratory values could not be read due to excessive lipemic serum. On the third day of hospitalization, an exchange transfusion was decided upon in this case due to the development of respiratory distress (oxygen support, tachypnea). After exchange transfusion, the patient's triglyceride level reduced dramatically to 592 mg/dL (6.6 mmol/L), and his respiratory symptoms resolved. The aim of this case report is to demonstrate that exchange transfusion therapy is a safe and effective treatment modality in the neonatal period for the acute management of FCS. Furthermore, dietary therapy restricted to long-chain fatty acids combined with medium-chain fatty acid supplementation is highly effective in the chronic management of these patients.
2023-11-13 | Acute pancreatitis in pregnancy and familial chylomicronemia syndrome: case report and literature review
Acute pancreatitis rarely occurs in pregnancy, with hypertriglyceridemia being the fourth leading cause during pregnancy. Hypertriglyceridemia, of which Familial Chylomicronemia Syndrome is the most severe form, ranks among the four principal causes of pancreatitis in pregnancy. Total Plasma exchange (TPE) has been found to be an effective and safe intervention both as a therapeutic and a prophylactic act. A 22-year-old female with FCS presented at the 21st week of gestation with acute hypertriglyceridemia pancreatitis. Despite medical management, she was then started on TPE at the two-week follow-up after serum triglyceride level was out of control. The triglyceride dropped from 55.0 % to 77.5 % during these sessions. Despite these interventions, pancreatitis recurred in week 34. An emergency C-section was carried out after a drop in the fetal heart rate. Postpartum triglycerides dropped by 57 % but remained above 1,000 mg/dl. FCS is difficult to manage during pregnancy, and it frequently fails to respond to various pharmacologic lines. TPE can help prolong a pregnancy, but it is not a definite treatment. Novel therapies for hypertriglyceridemia in pregnancy await additional safety testing.
2022-08-16 | Plasma exchange therapy for familial chylomicronemia syndrome in infant: A case report.
Familial chylomicronemia syndrome (FCS) is a rare genetic disease. FCS usually manifests by the age of 10 years, and 25% of cases of FCS occur during infancy. Here we present a case of FCS in a male infant and summarize our experiences on the diagnosis and therapy of this case. A male infant aged 1 month and 8 days had recurrent hematochezia and hyperchylomicronemia. FCS based on symptoms and genetic test. Plasma exchange therapy. His development was normal with a good spirit and satisfactory weight gain, and no hematochezia occurred again. Genetic test is important for accurate diagnosis of FCS, and we identified a new mutation of lipoprotein lipase gene c.88C>A which conformed to autosomal recessive inheritance. Plasma exchange therapy can be applied to infants with FCS with low risk and good outcomes.
small molecules
2026-08-05 | Monogenic Familial Chylomicronemia Syndrome in Children: Clinical Divergences and Management Paradigms
Monogenic familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder caused by disrupted intravascular lipoprotein lipase (LPL) pathways. Phenotypic variation often leads to diagnostic delays. We contrast two unique pediatric presentations of FCS, highlighting distinct pathophysiology. Case 1 describes a 21-month-old girl with eruptive xanthomas, which was initially misdiagnosed as an infectious rash, later revealed to be secondary to severe hypertriglyceridemia of 100.6 mmol/L (reference range < 0.8 mmol/L). Molecular testing confirmed a genetic mutation in the GPIHBP1 gene. Case 2 describes a 2-day-old neonate with incidental finding of lipemia during jaundice evaluation, subsequently revealing a fasting triglyceride level of 8.5 mmol/L. Genetic analysis identified compound heterozygous mutations in the LPL gene. Case 1 required intensive insulin therapy, strict dietary fat restriction and adjunctive gemfibrozil. Case 2 was managed via dietary restriction and medium-chain triglyceride formula supplementation. This two-case series illustrates the diagnostic challenges of FCS in pediatric practice and the contribution of molecular confirmation to establishing the underlying aetiology and informing counselling and long-term management.
2026-08-01 | EP1843 - LBA_ECE_1388 - Resistant hypertriglyceridaemia associated with low-molecular-weight heparin in heterozygous LPL variant carriers
Abstract Introduction and Objective Biallelic pathogenic variants in the apolipoprotein (APO) C2, APOA5l, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation factor 1 (LMF1), and lipoprotein lipase (LPL) genes cause familial chylomicronemia syndrome (FCS). Although heterozygous carriers typically exhibit a milder phenotype, severe hypertriglyceridemia (HTG) may develop in the presence of secondary triggers. Low-molecular-weight heparin (LMWH) can increase the release of LPL from the endothelium, potentially leading to an initial transient reduction in triglyceride (TG) levels; however, with continued use, rapid clearance of circulating LPL and limited resynthesis capacity may result in depletion of the functional LPL pool. In this report, we present a possible association between enoxaparin use and resistant HTG in a patient carrying a heterozygous pathogenic LPL variant. Case Presentation A 49-year-old man presented with a TG level of 5502 mg/dL (63.3 mmol/L), without a history of alcohol consumption. His medical history was notable for myocardial infarction 14 years earlier, 11 episodes of pancreatitis, and portal and splenic vein thrombosis following a severe pancreatitis episode six months prior, as well as pancreatitis-related secondary diabetes mellitus. Glycemic control was stable, with a hemoglobin A1c level of 6.4% at presentation. Genetic analysis identified a heterozygous pathogenic variant in the LPL gene, c.347G>C (p.Arg116Pro). Although the patient's sister carried the same heterozygous variant, her TG levels had been reported to be no higher than 500 mg/dL (5.6 mmol/L). Despite treatment with fenofibrate, rosuvastatin, nicotinic acid, orlistat, and intravenous insulin infusion, the TG level remained elevated at 4770 mg/dL (53.9 mmol/L), without a meaningful reduction. After treatment reassessment, LMWH was discontinued due to its potential contributory role, and rivaroxaban was initiated. Following this modification, the TG level decreased to 1516 mg/dL (17.1 mmol/L). Discussion and Conclusion The marked interindividual variability in phenotypic severity among heterozygous LPL variant carriers suggests a substantial contribution of secondary modifiers. In our patient, persistently elevated TG levels despite intensive lipid-lowering therapy and adequate glycemic control suggested an ongoing precipitating factor. The substantial decline in TG levels following discontinuation of LMWH suggests that anticoagulant therapy may have had a clinically relevant impact in the setting of genetically limited LPL activity. This observation underscores the importance of carefully reviewing not only metabolic determinants but also concomitant pharmacologic treatments in patients with severe and refractory HTG. In individuals with an underlying genetic predisposition, LMWH use should be assessed on an individual basis for its potential contributory role.
2026-06-18 | A Case of Familial Chylomicronemia Syndrome Caused by a Novel Homozygous GPIHBP1 Mutation Successfully Treated with the Selective PPARα Modulator Pemafibrate.
Familial chylomicronemia syndrome (FCS) is a rare disorder characterized by the accumulation of chylomicrons in the circulation due to genetic defects or autoantibodies affecting lipoprotein lipase (LPL), the key enzyme responsible for the metabolism of chylomicrons and very-low-density lipoproteins (VLDL), or its associated proteins, including apolipoprotein (apo) C-II, apoA-V, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), and lipase maturation factor 1 (LMF1). This condition is associated with markedly elevated serum triglyceride (TG) levels and, in severe cases, recurrent episodes of pancreatitis and eruptive xanthomas. Among these etiologies, genetic deficiency of GPIHBP1 is exceedingly rare. We aimed to clarify the clinical and genetic basis and treatment strategies of a patient with GPIHBP1 deficiency. A 47-year-old woman with a childhood diagnosis of FCS presented with severe epigastric pain and was admitted to Rinku General Medical Center for emergency management of acute pancreatitis secondary to severe chylomicronemia. She had a history of severe hypertriglyceridemia complicated by pancreatitis during her first pregnancy and extreme hypertriglyceridemia exceeding 6,000 mg/dL during her second pregnancy without the development of pancreatitis. DNA sequence analysis was performed as a clinical diagnostic test and outsourced to KUBIX Inc. (Hakusan, Ishikawa, Japan). Laboratory evaluation revealed marked hypertriglyceridemia (1,262 mg/dL) with a type V hyperlipoproteinemia pattern. Serum preheparin LPL mass was markedly reduced, and circulating GPIHBP1 was undetectable. Genetic analysis identified a novel homozygous frameshift mutation in the GPIHBP1 gene (NM_178172.4:c.20del [p.Val7AlafsTer73]), which has not been previously reported in public databases. No pathogenic variants were detected in other LPL-related genes. Acute pancreatitis improved rapidly with fasting and intravenous fluid therapy. Strict dietary fat restriction, followed by the addition of the selective PPARα modulator pemafibrate, successfully maintained TG levels below 500 mg/dL during follow-up. We report an extremely rare case of FCS caused by a novel homozygous mutation in the GPIHBP1 gene, in which pregnancy served as a major trigger for severe hypertriglyceridemia. Early diagnosis and strict lipid control are essential to prevent recurrent pancreatitis in patients with GPIHBP1 deficiency.
2026-06-17 | Heterozygosity for pathogenic variants in familial chylomicronemia syndrome genes: from carrier state to complex trait.
Biallelic loss-of-function (LOF) variants in any of five canonical genes - LPL, GPIHBP1, APOA5, APOC2 , and LMF1 - cause familial chylomicronemia syndrome (FCS), a rare and severe Mendelian disorder. Heterozygosity for these same variants is far more common but its clinical implications have only recently come into focus. Here, the past 18months of evidence on the monoallelic carrier state across the FCS genes is synthesized. Longitudinal studies of LPL and APOA5 heterozygotes have demonstrated that triglyceride phenotypes vary widely both between individuals and within the same individual over time, ranging from completely normal levels to severe hypertriglyceridemia. Heterozygosity contributes to 15-25% of multifactorial chylomicronemia syndrome (MCS) cases. Mechanistic data implicate dominant-negative effects for some truncating variants and saturation of compromised lipolytic reserve as unifying explanations, rather than simple haploinsufficiency. Common intermediate-effect risk alleles such as LPL p.D36N and p.N318S, and APOA5 p.S19W and p.G185C, behave differently and should not be conflated with rare LOF variants. The phenotype of FCS-gene heterozygotes is best understood as a complex trait modulated by polygenic background and secondary factors. This understanding has practical implications for cascade screening, counseling, and selection of patients who may benefit from emerging apolipoprotein C-III-targeted therapies, particularly those in the refractory MCS subgroup.
2026-06-15 | Multifactorial Chylomicronemia Syndrome With a Rare APOA5 Variant and Recurrent Acute Pancreatitis: A Case Report From Rural Colombia
Severe hypertriglyceridemia (triglycerides ≥ 500 mg/dL) carries a high risk of recurrent acute pancreatitis and cardiovascular disease. Pathogenic variants in the APOA5 gene are associated with hyperlipoproteinemia type V and familial hypertriglyceridemia; however, detailed case reports involving variants of uncertain significance (VUS) with a severe clinical phenotype and documented therapeutic response are rarely published. A 46-year-old woman from rural Supía, Caldas, Colombia, presented with persistent very severe hypertriglyceridemia (peak: 2,170 mg/dL), three hospitalizations for acute pancreatitis, and inadequate response to statins and fibrates. Targeted exome sequencing identified a heterozygous APOA5 VUS: c.694T>C, p.Ser232Pro (NM_052968.5), classified as PM2/PP3 per ACMG criteria (ClinVar: VCV002617654.3). An off-label PCSK9 inhibitor regimen achieved a greater than 90% triglyceride reduction (nadir: 118 mg/dL), though adherence has been intermittent due to economic and healthcare access barriers. This case highlights the diagnostic value of targeted genetic testing in severe familial hypertriglyceridemia and illustrates how an APOA5 VUS may underlie a severe multifactorial chylomicronemia phenotype. Segregation analysis and functional studies in first-degree relatives are warranted to support variant reclassification. This report also underscores the impact of healthcare access barriers on rare metabolic disease outcomes in rural Latin America.
oligonucleotides
2026-09-30 | Gapmers: Invention and Early History.
Gapmers are antisense oligonucleotides composed of a central DNA segment flanked by nucleotides of modified chemistry. Hybridizing with transcripts by sequence complementarity, gapmers recruit ribonuclease H and induce target RNA degradation. Since its concept first emerged in the 1980s, much work has gone into developing gapmers for use in basic research and therapy. These include improvements in gapmer chemistry, delivery, and therapeutic safety. Gapmers have also successfully entered clinical trials for various genetic disorders, with two approved by the US Food and Drug Administration for the treatment of familial hypercholesterolemia and transthyretin amyloidosis-associated polyneuropathy, and one approved by the European Commission for the treatment of familial chylomicronemia syndrome. Here, we review the events surrounding the early development of gapmers, from conception to their maturity, and briefly conclude with perspectives on their use in therapy.
2026-09-30 | Olezarsen for the Treatment of Hypertriglyceridemia.
Hypertriglyceridemia (HTG) is a common dyslipidemic disorder characterized by fasting serum triglyceride (TG) concentrations exceeding 150 mg/dL. Elevated TG levels contribute substantially to cardiovascular risk, as remnant lipoprotein particles derived from triglyceride-rich lipoproteins (TRL) exhibit marked atherogenicity. Conventional therapies, such as statins and fibrates, often fail to adequately lower TG levels or improve clinical outcomes. Advances in antisense technology have enabled the development of precise oligonucleotide-based therapies that reduce TG levels by targeting key regulators of lipid metabolism. Apolipoprotein C-III (ApoC-III) is a key regulator of TLR clearance, positioning it as a critical therapeutic target. Olezarsen, a next-generation N-acetylgalactosamine-conjugated antisense oligonucleotide (ASO) designed to induce RNase H-mediated degradation of APOC3 mRNA, received FDA approval in December 2024 as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). In this chapter, we review the pharmacological mechanism, clinical development, and safety profile of olezarsen for FCS and broader hypertriglyceridemia-related indications.
2026-07-31 | Olezarsen for hypertriglyceridemia and familial chylomicronemia syndrome: A Next-generation APOC3-targeted RNA therapy
Abstract: Olezarsen is a next-generation N acetylgalactosamine-conjugated antisense oligonucleotide (ASO) designed to selectively suppress the synthesis of apolipoprotein C-III (ApoC-III), hence reducing triglyceride (TG)-rich lipoproteins and reducing the metabolic burden of familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (HTG). Olezarsen achieves highly efficient ApoC-III inhibition and substantial, sustained TG lowering, simultaneously minimizing systemic exposure and related adverse eventsas observed with earlier ASO therapies. Evidence accumulated from Phase 2 and pivotal Phase 3 clinical trials, namely ESSENCE–TIMI 73b, CORE–TIMI 72a/72b, and BALANCE which established consistent ~ 50%–70% reductions in plasma TGs and 60%–80% decline in ApoC-III levels among patients with severe HTG. These lipid level improvements extend to remnant cholesterol and nonhigh-density lipoprotein cholesterol, and importantly, resulted in meaningful reductions in acute pancreatitis risk in population groups who are predisposed to recurrent episodes. Compared with conventional therapy, Olezarsen exhibits enhanced hepatoselectivity and a distinctly favorable platelet safety profile, allowing its suitability for long-term management. The once-monthly subcutaneous dosing regimen further enhances adherence potential and real-world feasibility experience. With the United States Food and Drug Administration approval granted in 2024 for the treatment of FCS, Olezarsen stands as a major evolution in precision lipid therapeutics. Regulatory review is ongoing globally for broader HTG indications. Although cardiovascular outcome data and extended postmarketing surveillance results are still awaited, present clinical evidence establishes Olezarsen as a transformative therapy for patients with FCS, severe HTG, and treatment-refractory TG elevation, efficiently addressing an unmet clinical need in reducing both metabolic risk and pancreatitis-related morbidity.
2026-07-06 | Olezarsen and Plozasiran: Novel apoC-III targeting medications for the treatment of hypertriglyceridemia.
Hypertriglyceridemia is a prevalent lipid disorder associated with residual atherosclerotic cardiovascular disease (ASCVD) risk and increased risk of acute pancreatitis at triglyceride (TG) levels above 1000 mg/dL. Causes of hypertriglyceridemia are multifactorial and may be a result of secondary causes (Western diet, alcohol, medications, uncontrolled diseases/disorders), genetic disorders, or a combination of both. Two novel medications (olezarsen, plozasiran), which inhibit hepatic production of apoC-III mRNA and increase TG clearance, have recently been approved to reduce TG levels in adults with familial chylomicronemia syndrome (FCS). Both olezarsen and plozasiran have been evaluated in randomized, placebo-controlled, clinical trials in patients with varying degrees of hypertriglyceridemia. In this review, we report the lipid-lowering effects and safety of both olezarsen and plozasiran from clinical trials in patients with hypertriglyceridemia. Based on available data, both agents are associated with significant TG-lowering effects via reductions in apoC-III, as well as favorable effects on other lipid parameters. Overall, both agents appear generally well tolerated, although monitoring of liver enzymes and glycemic control is warranted for both agents, and additional monitoring of platelet counts for olezarsen. Future clinical trials are needed to assess whether the TG-lowering effects of each agent are associated with reduced risk of pancreatitis and ASCVD events.
2026-06-19 | Comparative efficacy and safety of olezarsen versus volanesorsen for familial chylomicronemia syndrome: a matching-adjusted indirect comparison.
Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by severe hypertriglyceridemia causing recurrent acute pancreatitis (AP). Since FCS is a genetic deficiency in functional lipoprotein lipase, conventional triglyceride-lowering therapies are ineffective in this metabolic disorder. Apolipoprotein C-III (apoC-III) inhibitors, including volanesorsen and olezarsen, have emerged as targeted treatments for FCS. Aim: To compare the efficacy and safety of olezarsen 80 mg every four weeks (Q4W) versus volanesorsen 300 mg weekly (QW) in patients with FCS using an anchored matching-adjusted indirect comparison. Materials & methods: Individual patient data from the Balance trial of olezarsen (n = 45) were weighted to match baseline characteristics reported in the APPROACH trial of volanesorsen (n = 66). Outcomes included percent change in fasting triglycerides (TG) and apoC-III at 26 and 52 weeks, and risks of AP events and adverse events at 52 weeks. Results: At 52 weeks, mean differences in fasting TG and apoC-III were -27.4% (95% CI: -69.4, 14.5) and -21.3% (95% CI: -61.9, 19.3). Relative risks of AP, treatment-emergent adverse events, and serious adverse events were 0.23 (95% CI: 0.01, 5.02), 0.87 (95% CI: 0.66, 1.13) and 0.50 (95% CI: 0.08, 3.26) at week 52. The rate ratio for AP events per patient-year was 0.06 (95% CI: 0.003, 1.41). No comparisons were statistically significant. Conclusion: In this matching-adjusted indirect comparison, no statistically significant differences in outcomes were observed between olezarsen and volanesorsen in patients with FCS. These findings provide important comparative context in a setting where head-to-head evidence is unavailable.
other
2026-09-10 | Clinical and functional evidence supporting pathogenicity of a novel APOA5 variant in familial chylomicronemia syndrome.
This study aimed to evaluate the clinical and functional impact of a novel apolipoprotein A5 (ApoA5) variant by assessing lipoprotein lipase (LPL) activity. Demographic and clinical data, including blood lipid levels and body mass index, were retrospectively collected from an endocrinology clinic registry. Ten individuals with familial chylomicronemia syndrome (FCS) carrying a novel APOA5 variant were included. Whole-exome sequencing was performed using the latest generation DNB-SEQ400 platform. LPL activity was measured in post-heparin plasma using a radiometric assay. Statistical analysis: Categorical variables were summarized as frequencies and percentages, and continuous variables as mean ± standard deviation or median (range), as appropriate. Group comparisons were performed using the Mann-Whitney U test or chi-square test. Analyses were conducted using the Statistical Package for the Social Sciences software (v. 25.0). A p-value < 0.05 was considered statistically significant. We report ten cases of FCS with a homozygous missense variant of uncertain significance in APOA5: c.694T>C; p.(Ser232Pro), located in exon 3. In six patients assessed for LPL activity, levels remained consistently below 20% compared to normotriglyceridemic controls. The addition of exogenous serum containing APOA5 restored LPL activity to above 20% in all cases, indicating functional rescue. Measurement of LPL activity demonstrated the functional impact of the APOA5 c.694T>C; p.(Ser232Pro) variant. These findings support reclassification of the variant as likely pathogenic and enable differentiation from multifactorial chylomicronemia syndrome.
2026-03-15 | Post-heparin plasma lipase activities in patients with severe hypertriglyceridemia treated with evinacumab.
Patients with severe hypertriglyceridemia (sHTG) have variable lipoprotein lipase (LPL) activity levels that may influence therapeutic response. This exploratory analysis investigated post-heparin triglyceride lipase and phospholipase activities in three cohorts of patients with sHTG who received evinacumab (angiopoietin-like 3 inhibitor) for 12 or 24 weeks during a phase 2 trial: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function (LOF) LPL pathway mutations; cohort 2, multifactorial chylomicronemia syndrome (MCS) with heterozygous LOF LPL pathway mutations; and cohort 3, MCS without LPL pathway mutations. Post-heparin plasma samples were obtained at baseline and at week 24 (end of the treatment period). Triglyceride lipase activities (LPL and hepatic lipase [HL]) were measured using both a colorimetric and a scintillation assays. Phospholipase activities (HL and endothelial lipase [EL]) were measured using a colorimetric assay. Baseline post-heparin LPL triglyceride lipase activity was lowest in cohort 1; treatment with evinacumab for 12 or 24 weeks did not alter activity at week 24 versus baseline across cohorts using the colorimetric assay. Non-HL triglyceride lipase activity (mostly LPL) assessed using the scintillation assay showed a significant increase in cohort 1 at 24 weeks versus baseline (P = 0.04). Neither HL nor EL phospholipase activities differed among cohorts or changed with evinacumab treatment. High intra- and inter-patient variability in lipase activity was observed with all methods. Post-heparin LPL triglyceride lipase activity was lower in patients with sHTG with bi-allelic LPL pathway mutations and increased in that group with evinacumab. The high variability in lipase activities observed via differing methods supports the need for more robust assays.
2025-03-06 | Treatment With Evinacumab Links a New Pathogenic Variant in the LPL Gene to Persistent Chylomicronemia.
Persistent chylomicronemia is caused by lipoprotein lipase deficiency (LPLD) or lack of lipoprotein lipase (LPL) bioavailability. This disorder is characterized by plasma triglyceride (TG) levels above 10 mmol/L, increased acute pancreatitis risk, and features of familial chylomicronemia syndrome (FCS). Evinacumab is an angiopoietin-like protein 3 (ANGPTL3) monoclonal antibody, and its efficacy in decreasing plasma TG levels depends on LPL bioavailability. To identify FCS-causing pathogenic variants in patients with persistent chylomicronemia treated with evinacumab. A phase II clinical trial was conducted with evinacumab in patients with severe hypertriglyceridemia. Plasma TG values were measured at baseline and every 2 weeks for 24 weeks. Three FCS patients homozygotes for a P234L pathogenic variant in the LPL gene (HoLPL P234L) known to be associated with low postheparin LPL activity (proven LPLD) participated in the study and were used as tracers. The genotype-specific efficacy of evinacumab to decrease TG levels in other participants was compared to that achieved in HoLPL P234L patients. After 24 weeks of evinacumab treatment, TG levels decreased <20% in HoLPL P234L patients known to lack LPL. Similarly, a participant homozygote for a E282X variant in the exon 6 of the LPL gene that was suspected to be pathogenic due to its location did not respond to evinacumab (TG decreased <10% and remained >10 mmol/L). The efficacy of ANGPTL3 inhibitors in decreasing TG levels is LPL-dependent. Poor response to evinacumab supports the evidence that the E282X variant in the LPL gene is pathogenic and associated with persistent chylomicronemia (FCS phenotype).
2023-11-07 | Severe hypertriglyceridemia: Existing and emerging therapies.
Severe hypertriglyceridemia (sHTG), defined as a triglyceride (TG) concentration ≥ 500 mg/dL (≥ 5.7 mmol/L) is an important risk factor for acute pancreatitis. Although lifestyle, some medications, and certain conditions such as diabetes may lead to HTG, sHTG results from a combination of major and minor genetic defects in proteins that regulate TG lipolysis. Familial chylomicronemia syndrome (FCS) is a rare disorder caused by complete loss of function in lipoprotein lipase (LPL) or LPL activating proteins due to two homozygous recessive traits or compound heterozygous traits. Multifactorial chylomicronemia syndrome (MCS) and sHTG are due to the accumulation of rare heterozygous variants and polygenic defects that predispose individuals to sHTG phenotypes. Until recently, treatment of sHTG focused on lifestyle interventions, control of secondary factors, and nonselective pharmacotherapies that had modest TG-lowering efficacy and no corresponding reductions in atherosclerotic cardiovascular disease events. Genetic discoveries have allowed for the development of novel pathway-specific therapeutics targeting LPL modulating proteins. New targets directed towards inhibition of apolipoprotein C-III (apoC-III), angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like protein 4 (ANGPTL4), and fibroblast growth factor-21 (FGF21) offer far more efficacy in treating the various phenotypes of sHTG and opportunities to reduce the risk of acute pancreatitis and atherosclerotic cardiovascular disease events.
2023-08-11 | Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype–phenotype relationship for variants reported to date
Lipoprotein lipase (LPL) is the rate-limiting enzyme for triglyceride hydrolysis. Homozygous or compound heterozygous LPL variants cause autosomal recessive familial chylomicronemia syndrome (FCS), whereas simple heterozygous LPL variants are associated with hypertriglyceridemia (HTG) and HTG-related disorders. LPL frameshift coding sequence variants usually cause complete functional loss of the affected allele, thereby allowing exploration of the impact of different levels of LPL function in human disease.All exons and flanking intronic regions of LPL were Sanger sequenced in patients with HTG-related acute pancreatitis (HTG-AP) or HTG-AP in pregnancy. Previously reported LPL frameshift coding sequence variants were collated from the Human Gene Mutation Database and through PubMed keyword searching. Original reports were manually evaluated for the following information: zygosity status of the variant, plasma LPL activity of the variant carrier, disease referred for genetic analysis, patient's age at genetic analysis, and patient's disease history. SpliceAI was employed to predict the potential impact of collated variants on splicing.Two novel rare variants were identified, and 53 known LPL frameshift coding sequence variants were collated. Of the 51 variants informative for zygosity, 30 were simple heterozygotes, 12 were homozygotes, and 9 were compound heterozygotes. Careful evaluation of the 55 variants with respect to their clinical and genetic data generated several interesting findings. First, we conclude that 6-7% residual LPL function could significantly delay the age of onset of FCS and reduce the prevalence of FCS-associated syndromes. Second, whereas a large majority of LPL frameshift coding sequence variants completely disrupt gene function through their "frameshift" nature, a small fraction of these variants may act wholly or partly as "in-frame" variants, leading to the generation of protein products with some residual LPL function. Third, we identified two candidate LPL frameshift coding sequence variants that may retain residual function based on genotype-phenotype correlation or SpliceAI-predicted data.This study reported two novel LPL variants and yielded new insights into the genotype-phenotype relationship as it pertains to LPL frameshift coding sequence variants.
gene therapies
2026-04-04 | Lipoprotein lipase DNA methylation in the adipose tissue of patients with persistent chylomicronemia.
Persistent chylomicronemia (PC) is a rare condition characterized by plasma triglyceride concentration persistently >10 mmol/L despite treatment, reflecting a lack of lipoprotein lipase (LPL) bioavailability. PC encompasses patients with the familial chylomicronemia syndrome (FCS) and patients with multifactorial PC. Life habits and environmental factors are known modulators of DNA methylation (DNAme), which can influence access to the LPL gene and possibly contribute to the expression of PC. To compare LPL DNAme in blood and adipose tissue of patients with PC or other causes of hypertriglyceridemia (HTG) and normotriglyceridemic controls. DNA was extracted from blood and adipose tissue in 186 participants: 31 with PC (21 FCS, 10 multifactorial PC), 125 with HTG, and 30 controls. DNAme was measured using pyrosequencing at 22 cytosine-phosphate-guanine sites (CpGs) located in the promoter and between the first exons of the LPL gene. Differences in LPL DNAme were assessed according to the genotype and severity of HTG. No difference in LPL DNAme was observed in blood samples. In adipose tissues, patients with FCS were significantly less methylated at 2 CpGs located in the LPL gene body compared with other genotypes (Δϐ = 2.85% and 3.78%, P = .011). When DNAme was analyzed according to HTG severity, the same CpGs were less methylated in patients with PC of any cause compared with other groups (Δϐ = 4.55%, P = .002; Δϐ = 7.70%, P < .001). In this study, the LPL DNAme signature in adipose tissue differed in patients with PC compared with others, highlighting that different factors might contribute to PC and its associated risks.
2026-03-30 | Milky blood in a middle-aged man with Diabetes mellitus: Familial chylomicronemia syndrome due to GPIHBP1 mutation
Milky blood in a middle-aged man with Diabetes mellitus: Familial chylomicronemia syndrome due to GPIHBP1 mutation1Mukti Nath Sankhi, 2Naresh Bansal,3Samir Samadarshi, 4Santosh Kumar Singh2Rohit Vashisht1Nepalese Army Institute of Health Sciences College of MedicineKathmandu, Bagmati, Nepal2Army Hospital, Research and ReferralNew Delhi, Delhi, India3Command Hospital Air ForceBangalore, India4Armed Forces Medical CollegePune, IndiaCorresponding author: Mukti Nath Sankhi, Lecturer, Nepalese Army Institute of Health Sciences College of Medicine Kathmandu, Bagmati, Nepal. Email: muktinath.sankhi@naihs.edu.np
2026-02-09 | Case Report: Clinical and genetic analysis of a family with hereditary spherocytosis combined with familial chylomicronemia syndrome.
This study was conducted to investigate the clinical and genetic characteristics of a family affected by hereditary spherocytosis (HS) combined with familial chylomicronemia syndrome (FCS), identify the pathogenic cause, and provide a basis for the clinical diagnosis, treatment, and genetic counseling of affected children. Clinical data were collected from family members. High-throughput sequencing was performed to identify pathogenic variants in genes associated with HS and FCS in the proband. Suspected pathogenic mutations were confirmed in family members via PCR-Sanger sequencing. Bioinformatics analysis and three-dimensional protein structure prediction were also conducted. The proband presented with severe anemia, splenomegaly, and jaundice. Genetic testing revealed a heterozygous mutation, c.6005G>A (p.Trp2002*), in the spectrin beta chain (SPTB)gene (NM_001355436.2) and a missense mutation, c.292G>A (p.Ala98Thr), in the lipoprotein lipase (LPL) gene (NM_000237.3). The SPTB c.6005G>A (p.Trp2002*) mutation was inherited from the mother, who exhibited mild anemia, jaundice, and splenomegaly. The LPL c.292G>A (p.Ala98Thr) mutation was inherited from the father, who had hypertriglyceridemia. The SPTB c.6005G>A (p.Trp2002*) mutation is extremely rare in the general population. The heterozygous mutations SPTB c.6005G>A (p.Trp2002*) and LPL c.292G>A (p.Ala98Thr) are the pathogenic causes in this family and provide a basis for clinical management and genetic counseling. Based on the HGMD, 1000G, and ExAC databases, the SPTB c.6005G>A (p.Trp2002*) mutation is reported here for the first time, enriching the mutation spectrum of the SPTB gene.
2025-11-03 | Abstract 4370295: Single dose of a novel CRISPR-CasX editor potently reduces triglycerides in preclinical models and efficiently edits APOC3 in non-human primates
Background: Severe hypertriglyceridemia (SHTG) and familial chylomicronemia syndrome (FCS) are marked by extreme triglyceride (TG) elevations, raising the risk for acute pancreatitis and cardiovascular complications. Apolipoprotein C-III (APOC3) impairs TG catabolism and clearance. Loss-of-function APOC3 mutations are linked to lower TGs and reduced atherosclerotic risk, highlighting APOC3 as a promising therapeutic target. CRISPR-CasXE (XE) is an engineered gene editing platform with improved potency and specificity over natural systems. Here, we report the development of STX-1400, the first liver-targeted XE gene editing therapy designed to disrupt APOC3 expression and reduce circulating TGs. Approach: STX-1400 consists of an mRNA encoding an engineered XE editor and a single APOC3-targeting gRNA delivered via lipid nanoparticles. We evaluated the efficacy of a STX-1400 prototype in multiple in vitro and in vivo models. Specificity was assessed using a comprehensive off-target strategy to nominate potential off-target sites, followed by deep sequencing evaluation in primary human hepatocytes (PHHs) treated at 10xEC90. A non-human primate (NHP) surrogate was also tested in cynomolgus monkeys at escalating doses, with APOC3 editing measured in liver biopsies 18 days post-dose. Results: In PHHs, a STX-1400 prototype showed dose-dependent APOC3 editing (up to 90%) with >70% decrease in secreted APOC3 protein. In human APOC3 transgenic mice, hepatic editing at the APOC3 locus exceeded >70%, reducing circulating APOC3 by 80%. In hypertriglyceridemic mice, the STX-1400 prototype reduced APOC3 mRNA by >90% and protein by >95%, which corresponded with decreasing plasma TGs by >95% and total cholesterol by >80%. No off-target editing was observed in PHHs treated at 10xEC90. Notably, a single administration of the NHP analog of the STX-1400 prototype in cynomolgus monkeys achieved saturated editing levels (>70%) in the liver at 1mg/kg, with liver enzyme profiles comparable to controls. Conclusions: Our findings demonstrate that the STX-1400 prototype potently and specifically edits APOC3 across human cells, mouse models, and non-human primates. This study is the first demonstration that a CRISPR-based therapy has achieved saturated in vivo editing of the APOC3 locus in NHP liver. These results provide strong preclinical evidence supporting the potential of STX-1400 as a first-in class genome editing therapy for hypertriglyceridemia in patients with SHTG and FCS.
2025-07-05 | Heterozygous pathogenic PPARG variants in patients with severe hypertriglyceridemia.
Heterozygous pathogenic variants in PPARG cause familial partial lipodystrophy type 3 (FPLD3, Mendelian Inheritance in Man [MIM] #604367), a heritable form of insulin resistance with multiple metabolic disturbances including hypertriglyceridemia. We investigated the prevalence of FPLD3 individuals in our cohort of patients with multifactorial chylomicronemia syndrome (MCS). We used our targeted DNA sequencing panel to screen the PPARG gene in 182 clinically diagnosed MCS patients. We found that 3.3% of MCS patients (6/182) had a heterozygous pathogenic PPARG variant, consistent with a diagnosis of FPLD3. The variants were PPARG p.Lys186fs (ClinVar identifier 8132), p.Glu217Lys, p.Pro454fs (ClinVar identifier 436405), p.Met284Ile, p.Ser383Arg, and p.Arg181Trp. None of these patients had previously been diagnosed with FPLD3 and their clinical and biochemical features were otherwise comparable to those of the entire MCS cohort. A small but clinically relevant subgroup of individuals with MCS has FPLD3. Clinical features in FPLD3 are subtle but the phenotype can be metabolically severe. Genetic screening of patients with severe hypertriglyceridemia should include assessment of lipodystrophy genes, since management of lipodystrophy patients is distinct from that of typical MCS patients.
cell therapies
2026-01-01 | Sequential Continuous Renal Replacement Therapy and Therapeutic Plasma Exchange in Pediatric Necrotizing Hypertriglyceridemia-Induced Pancreatitis with Suspected Familial Chylomicronemia Syndrome: A Case Report
Background: Hypertriglyceridemia-induced acute pancreatitis (HTG-AP) is a severe and underrecognized etiology of pancreatitis, accounting for 1% - 4% of all cases in adults, with extreme triglyceridemia raising the risk of fulminant multi-organ failure. When underlying lipoprotein lipase (LPL) deficiency is suspected—as in familial chylomicronemia syndrome (FCS)—conventional pharmacologic strategies are inherently limited, and therapeutic plasma exchange (TPE) represents the most effective currently available approach for the rapid removal of chylomicrons and triglyceride-rich lipoproteins from the circulation. Case Summary: We report a 14-year-old girl presenting with triglycerides > 14,000 mg/dL, severe necrotizing pancreatitis, acute kidney injury (AKI), mild acute respiratory distress syndrome (ARDS), and metabolic encephalopathy. No prior medical history was identified. Despite aggressive pharmacologic therapy with intravenous insulin, heparin, and fibrates, triglyceride levels remained critically elevated. Continuous renal replacement therapy (CRRT) was initiated for AKI, metabolic acidosis, and hemodynamic instability, achieving significant physiologic stabilization. However, because CRRT does not effectively clear chylomicrons, lipid levels remained dangerously high. Two urgent sessions of TPE reduced triglycerides from >14,000 mg/dL to approximately 300 mg/dL, with subsequent normalization of pancreatic enzymes and full recovery of renal, respiratory, and neurological function. The patient was discharged in good clinical condition. Conclusion: This case illustrates that CRRT and TPE fulfill distinct, non-overlapping roles in severe HTG-AP. CRRT provides essential metabolic bridge support, and TPE achieves definitive lipid clearance. When LPL deficiency is suspected, early escalation to TPE is potentially lifesaving. A high index of clinical suspicion and timely decision-making are the key determinants of outcome in this rare but catastrophic condition.
2025-07-01 | Experience with apheretic treatment in the chronic management of severe hypertriglyceridemia: case series.
Chylomicronemia Syndrome (CS) refers to a group of lipid disorders characterized by the accumulation of chylomicrons in the plasma due to impaired lipolytic clearance. It encompasses various clinical features, including Familial Chylomicronemia Syndrome (FCS) and Multifactorial Chylomicronemia Syndrome (MCS). Diagnosing CS is a significant clinical challenge, as it is essential for identifying patients at highest risk of acute pancreatitis, preventing recurrence, and improving cardiovascular outcomes. Methods and Case Descriptions. Since 2008, we have identified eight patients residing in the same geographical area of Central Italy (Tuscany Region), all referred to us for severe and treatment-resistant hypertriglyceridemia. During this time, new therapeutic agents such as volanesorsen and lomitapide became available. However, none of these patients met the reimbursement criteria set by the Italian Medicines Agency (AIFA). We describe the clinical management and follow-up of these patients, in whom plasma and lipoprotein apheresis remain an effective therapy for reducing the risk of pancreatitis.
2024-03-27 | Exchange Transfusion: A Good Option for the Acute Treatment of Familial Chylomicronemia Syndrome in the Neonatal Period
Familial chylomicronemia syndrome (FCS) is one of the rare causes of hypertriglyceridemia. Plasmapheresis is recommended in patients with triglyceride levels greater than 2000 mg/dL. However, plasmapheresis is difficult to perform in most centers due to technical inadequacies in the neonatal period. There are some reports in the literature on the efficacy of exchange transfusion. The index case involves a 20-day-old male patient who was admitted to the emergency department for restlessness and poor feeding. He was born at term with a birth weight of 4000 g. He was exclusively breastfed. The patient was taken to the neonatal intensive care unit due to his plasma being in the form of excessive lipemia. The first measurable triglyceride level was 5100 mg/dL (57.6 mmol/L). Breast milk was restricted, and intravenous hydration was started. However, his triglyceride level did not decrease despite this treatment. Other laboratory values could not be read due to excessive lipemic serum. On the third day of hospitalization, an exchange transfusion was decided upon in this case due to the development of respiratory distress (oxygen support, tachypnea). After exchange transfusion, the patient's triglyceride level reduced dramatically to 592 mg/dL (6.6 mmol/L), and his respiratory symptoms resolved. The aim of this case report is to demonstrate that exchange transfusion therapy is a safe and effective treatment modality in the neonatal period for the acute management of FCS. Furthermore, dietary therapy restricted to long-chain fatty acids combined with medium-chain fatty acid supplementation is highly effective in the chronic management of these patients.
2023-11-13 | Acute pancreatitis in pregnancy and familial chylomicronemia syndrome: case report and literature review
Acute pancreatitis rarely occurs in pregnancy, with hypertriglyceridemia being the fourth leading cause during pregnancy. Hypertriglyceridemia, of which Familial Chylomicronemia Syndrome is the most severe form, ranks among the four principal causes of pancreatitis in pregnancy. Total Plasma exchange (TPE) has been found to be an effective and safe intervention both as a therapeutic and a prophylactic act. A 22-year-old female with FCS presented at the 21st week of gestation with acute hypertriglyceridemia pancreatitis. Despite medical management, she was then started on TPE at the two-week follow-up after serum triglyceride level was out of control. The triglyceride dropped from 55.0 % to 77.5 % during these sessions. Despite these interventions, pancreatitis recurred in week 34. An emergency C-section was carried out after a drop in the fetal heart rate. Postpartum triglycerides dropped by 57 % but remained above 1,000 mg/dl. FCS is difficult to manage during pregnancy, and it frequently fails to respond to various pharmacologic lines. TPE can help prolong a pregnancy, but it is not a definite treatment. Novel therapies for hypertriglyceridemia in pregnancy await additional safety testing.
2022-08-16 | Plasma exchange therapy for familial chylomicronemia syndrome in infant: A case report.
Familial chylomicronemia syndrome (FCS) is a rare genetic disease. FCS usually manifests by the age of 10 years, and 25% of cases of FCS occur during infancy. Here we present a case of FCS in a male infant and summarize our experiences on the diagnosis and therapy of this case. A male infant aged 1 month and 8 days had recurrent hematochezia and hyperchylomicronemia. FCS based on symptoms and genetic test. Plasma exchange therapy. His development was normal with a good spirit and satisfactory weight gain, and no hematochezia occurred again. Genetic test is important for accurate diagnosis of FCS, and we identified a new mutation of lipoprotein lipase gene c.88C>A which conformed to autosomal recessive inheritance. Plasma exchange therapy can be applied to infants with FCS with low risk and good outcomes.
small molecules
2026-08-05 | Monogenic Familial Chylomicronemia Syndrome in Children: Clinical Divergences and Management Paradigms
Monogenic familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder caused by disrupted intravascular lipoprotein lipase (LPL) pathways. Phenotypic variation often leads to diagnostic delays. We contrast two unique pediatric presentations of FCS, highlighting distinct pathophysiology. Case 1 describes a 21-month-old girl with eruptive xanthomas, which was initially misdiagnosed as an infectious rash, later revealed to be secondary to severe hypertriglyceridemia of 100.6 mmol/L (reference range < 0.8 mmol/L). Molecular testing confirmed a genetic mutation in the GPIHBP1 gene. Case 2 describes a 2-day-old neonate with incidental finding of lipemia during jaundice evaluation, subsequently revealing a fasting triglyceride level of 8.5 mmol/L. Genetic analysis identified compound heterozygous mutations in the LPL gene. Case 1 required intensive insulin therapy, strict dietary fat restriction and adjunctive gemfibrozil. Case 2 was managed via dietary restriction and medium-chain triglyceride formula supplementation. This two-case series illustrates the diagnostic challenges of FCS in pediatric practice and the contribution of molecular confirmation to establishing the underlying aetiology and informing counselling and long-term management.
2026-08-01 | EP1843 - LBA_ECE_1388 - Resistant hypertriglyceridaemia associated with low-molecular-weight heparin in heterozygous LPL variant carriers
Abstract Introduction and Objective Biallelic pathogenic variants in the apolipoprotein (APO) C2, APOA5l, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation factor 1 (LMF1), and lipoprotein lipase (LPL) genes cause familial chylomicronemia syndrome (FCS). Although heterozygous carriers typically exhibit a milder phenotype, severe hypertriglyceridemia (HTG) may develop in the presence of secondary triggers. Low-molecular-weight heparin (LMWH) can increase the release of LPL from the endothelium, potentially leading to an initial transient reduction in triglyceride (TG) levels; however, with continued use, rapid clearance of circulating LPL and limited resynthesis capacity may result in depletion of the functional LPL pool. In this report, we present a possible association between enoxaparin use and resistant HTG in a patient carrying a heterozygous pathogenic LPL variant. Case Presentation A 49-year-old man presented with a TG level of 5502 mg/dL (63.3 mmol/L), without a history of alcohol consumption. His medical history was notable for myocardial infarction 14 years earlier, 11 episodes of pancreatitis, and portal and splenic vein thrombosis following a severe pancreatitis episode six months prior, as well as pancreatitis-related secondary diabetes mellitus. Glycemic control was stable, with a hemoglobin A1c level of 6.4% at presentation. Genetic analysis identified a heterozygous pathogenic variant in the LPL gene, c.347G>C (p.Arg116Pro). Although the patient's sister carried the same heterozygous variant, her TG levels had been reported to be no higher than 500 mg/dL (5.6 mmol/L). Despite treatment with fenofibrate, rosuvastatin, nicotinic acid, orlistat, and intravenous insulin infusion, the TG level remained elevated at 4770 mg/dL (53.9 mmol/L), without a meaningful reduction. After treatment reassessment, LMWH was discontinued due to its potential contributory role, and rivaroxaban was initiated. Following this modification, the TG level decreased to 1516 mg/dL (17.1 mmol/L). Discussion and Conclusion The marked interindividual variability in phenotypic severity among heterozygous LPL variant carriers suggests a substantial contribution of secondary modifiers. In our patient, persistently elevated TG levels despite intensive lipid-lowering therapy and adequate glycemic control suggested an ongoing precipitating factor. The substantial decline in TG levels following discontinuation of LMWH suggests that anticoagulant therapy may have had a clinically relevant impact in the setting of genetically limited LPL activity. This observation underscores the importance of carefully reviewing not only metabolic determinants but also concomitant pharmacologic treatments in patients with severe and refractory HTG. In individuals with an underlying genetic predisposition, LMWH use should be assessed on an individual basis for its potential contributory role.
2026-06-18 | A Case of Familial Chylomicronemia Syndrome Caused by a Novel Homozygous GPIHBP1 Mutation Successfully Treated with the Selective PPARα Modulator Pemafibrate.
Familial chylomicronemia syndrome (FCS) is a rare disorder characterized by the accumulation of chylomicrons in the circulation due to genetic defects or autoantibodies affecting lipoprotein lipase (LPL), the key enzyme responsible for the metabolism of chylomicrons and very-low-density lipoproteins (VLDL), or its associated proteins, including apolipoprotein (apo) C-II, apoA-V, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), and lipase maturation factor 1 (LMF1). This condition is associated with markedly elevated serum triglyceride (TG) levels and, in severe cases, recurrent episodes of pancreatitis and eruptive xanthomas. Among these etiologies, genetic deficiency of GPIHBP1 is exceedingly rare. We aimed to clarify the clinical and genetic basis and treatment strategies of a patient with GPIHBP1 deficiency. A 47-year-old woman with a childhood diagnosis of FCS presented with severe epigastric pain and was admitted to Rinku General Medical Center for emergency management of acute pancreatitis secondary to severe chylomicronemia. She had a history of severe hypertriglyceridemia complicated by pancreatitis during her first pregnancy and extreme hypertriglyceridemia exceeding 6,000 mg/dL during her second pregnancy without the development of pancreatitis. DNA sequence analysis was performed as a clinical diagnostic test and outsourced to KUBIX Inc. (Hakusan, Ishikawa, Japan). Laboratory evaluation revealed marked hypertriglyceridemia (1,262 mg/dL) with a type V hyperlipoproteinemia pattern. Serum preheparin LPL mass was markedly reduced, and circulating GPIHBP1 was undetectable. Genetic analysis identified a novel homozygous frameshift mutation in the GPIHBP1 gene (NM_178172.4:c.20del [p.Val7AlafsTer73]), which has not been previously reported in public databases. No pathogenic variants were detected in other LPL-related genes. Acute pancreatitis improved rapidly with fasting and intravenous fluid therapy. Strict dietary fat restriction, followed by the addition of the selective PPARα modulator pemafibrate, successfully maintained TG levels below 500 mg/dL during follow-up. We report an extremely rare case of FCS caused by a novel homozygous mutation in the GPIHBP1 gene, in which pregnancy served as a major trigger for severe hypertriglyceridemia. Early diagnosis and strict lipid control are essential to prevent recurrent pancreatitis in patients with GPIHBP1 deficiency.
2026-06-17 | Heterozygosity for pathogenic variants in familial chylomicronemia syndrome genes: from carrier state to complex trait.
Biallelic loss-of-function (LOF) variants in any of five canonical genes - LPL, GPIHBP1, APOA5, APOC2 , and LMF1 - cause familial chylomicronemia syndrome (FCS), a rare and severe Mendelian disorder. Heterozygosity for these same variants is far more common but its clinical implications have only recently come into focus. Here, the past 18months of evidence on the monoallelic carrier state across the FCS genes is synthesized. Longitudinal studies of LPL and APOA5 heterozygotes have demonstrated that triglyceride phenotypes vary widely both between individuals and within the same individual over time, ranging from completely normal levels to severe hypertriglyceridemia. Heterozygosity contributes to 15-25% of multifactorial chylomicronemia syndrome (MCS) cases. Mechanistic data implicate dominant-negative effects for some truncating variants and saturation of compromised lipolytic reserve as unifying explanations, rather than simple haploinsufficiency. Common intermediate-effect risk alleles such as LPL p.D36N and p.N318S, and APOA5 p.S19W and p.G185C, behave differently and should not be conflated with rare LOF variants. The phenotype of FCS-gene heterozygotes is best understood as a complex trait modulated by polygenic background and secondary factors. This understanding has practical implications for cascade screening, counseling, and selection of patients who may benefit from emerging apolipoprotein C-III-targeted therapies, particularly those in the refractory MCS subgroup.
2026-06-15 | Multifactorial Chylomicronemia Syndrome With a Rare APOA5 Variant and Recurrent Acute Pancreatitis: A Case Report From Rural Colombia
Severe hypertriglyceridemia (triglycerides ≥ 500 mg/dL) carries a high risk of recurrent acute pancreatitis and cardiovascular disease. Pathogenic variants in the APOA5 gene are associated with hyperlipoproteinemia type V and familial hypertriglyceridemia; however, detailed case reports involving variants of uncertain significance (VUS) with a severe clinical phenotype and documented therapeutic response are rarely published. A 46-year-old woman from rural Supía, Caldas, Colombia, presented with persistent very severe hypertriglyceridemia (peak: 2,170 mg/dL), three hospitalizations for acute pancreatitis, and inadequate response to statins and fibrates. Targeted exome sequencing identified a heterozygous APOA5 VUS: c.694T>C, p.Ser232Pro (NM_052968.5), classified as PM2/PP3 per ACMG criteria (ClinVar: VCV002617654.3). An off-label PCSK9 inhibitor regimen achieved a greater than 90% triglyceride reduction (nadir: 118 mg/dL), though adherence has been intermittent due to economic and healthcare access barriers. This case highlights the diagnostic value of targeted genetic testing in severe familial hypertriglyceridemia and illustrates how an APOA5 VUS may underlie a severe multifactorial chylomicronemia phenotype. Segregation analysis and functional studies in first-degree relatives are warranted to support variant reclassification. This report also underscores the impact of healthcare access barriers on rare metabolic disease outcomes in rural Latin America.
oligonucleotides
2026-09-30 | Gapmers: Invention and Early History.
Gapmers are antisense oligonucleotides composed of a central DNA segment flanked by nucleotides of modified chemistry. Hybridizing with transcripts by sequence complementarity, gapmers recruit ribonuclease H and induce target RNA degradation. Since its concept first emerged in the 1980s, much work has gone into developing gapmers for use in basic research and therapy. These include improvements in gapmer chemistry, delivery, and therapeutic safety. Gapmers have also successfully entered clinical trials for various genetic disorders, with two approved by the US Food and Drug Administration for the treatment of familial hypercholesterolemia and transthyretin amyloidosis-associated polyneuropathy, and one approved by the European Commission for the treatment of familial chylomicronemia syndrome. Here, we review the events surrounding the early development of gapmers, from conception to their maturity, and briefly conclude with perspectives on their use in therapy.
2026-09-30 | Olezarsen for the Treatment of Hypertriglyceridemia.
Hypertriglyceridemia (HTG) is a common dyslipidemic disorder characterized by fasting serum triglyceride (TG) concentrations exceeding 150 mg/dL. Elevated TG levels contribute substantially to cardiovascular risk, as remnant lipoprotein particles derived from triglyceride-rich lipoproteins (TRL) exhibit marked atherogenicity. Conventional therapies, such as statins and fibrates, often fail to adequately lower TG levels or improve clinical outcomes. Advances in antisense technology have enabled the development of precise oligonucleotide-based therapies that reduce TG levels by targeting key regulators of lipid metabolism. Apolipoprotein C-III (ApoC-III) is a key regulator of TLR clearance, positioning it as a critical therapeutic target. Olezarsen, a next-generation N-acetylgalactosamine-conjugated antisense oligonucleotide (ASO) designed to induce RNase H-mediated degradation of APOC3 mRNA, received FDA approval in December 2024 as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). In this chapter, we review the pharmacological mechanism, clinical development, and safety profile of olezarsen for FCS and broader hypertriglyceridemia-related indications.
2026-07-31 | Olezarsen for hypertriglyceridemia and familial chylomicronemia syndrome: A Next-generation APOC3-targeted RNA therapy
Abstract: Olezarsen is a next-generation N acetylgalactosamine-conjugated antisense oligonucleotide (ASO) designed to selectively suppress the synthesis of apolipoprotein C-III (ApoC-III), hence reducing triglyceride (TG)-rich lipoproteins and reducing the metabolic burden of familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (HTG). Olezarsen achieves highly efficient ApoC-III inhibition and substantial, sustained TG lowering, simultaneously minimizing systemic exposure and related adverse eventsas observed with earlier ASO therapies. Evidence accumulated from Phase 2 and pivotal Phase 3 clinical trials, namely ESSENCE–TIMI 73b, CORE–TIMI 72a/72b, and BALANCE which established consistent ~ 50%–70% reductions in plasma TGs and 60%–80% decline in ApoC-III levels among patients with severe HTG. These lipid level improvements extend to remnant cholesterol and nonhigh-density lipoprotein cholesterol, and importantly, resulted in meaningful reductions in acute pancreatitis risk in population groups who are predisposed to recurrent episodes. Compared with conventional therapy, Olezarsen exhibits enhanced hepatoselectivity and a distinctly favorable platelet safety profile, allowing its suitability for long-term management. The once-monthly subcutaneous dosing regimen further enhances adherence potential and real-world feasibility experience. With the United States Food and Drug Administration approval granted in 2024 for the treatment of FCS, Olezarsen stands as a major evolution in precision lipid therapeutics. Regulatory review is ongoing globally for broader HTG indications. Although cardiovascular outcome data and extended postmarketing surveillance results are still awaited, present clinical evidence establishes Olezarsen as a transformative therapy for patients with FCS, severe HTG, and treatment-refractory TG elevation, efficiently addressing an unmet clinical need in reducing both metabolic risk and pancreatitis-related morbidity.
2026-07-06 | Olezarsen and Plozasiran: Novel apoC-III targeting medications for the treatment of hypertriglyceridemia.
Hypertriglyceridemia is a prevalent lipid disorder associated with residual atherosclerotic cardiovascular disease (ASCVD) risk and increased risk of acute pancreatitis at triglyceride (TG) levels above 1000 mg/dL. Causes of hypertriglyceridemia are multifactorial and may be a result of secondary causes (Western diet, alcohol, medications, uncontrolled diseases/disorders), genetic disorders, or a combination of both. Two novel medications (olezarsen, plozasiran), which inhibit hepatic production of apoC-III mRNA and increase TG clearance, have recently been approved to reduce TG levels in adults with familial chylomicronemia syndrome (FCS). Both olezarsen and plozasiran have been evaluated in randomized, placebo-controlled, clinical trials in patients with varying degrees of hypertriglyceridemia. In this review, we report the lipid-lowering effects and safety of both olezarsen and plozasiran from clinical trials in patients with hypertriglyceridemia. Based on available data, both agents are associated with significant TG-lowering effects via reductions in apoC-III, as well as favorable effects on other lipid parameters. Overall, both agents appear generally well tolerated, although monitoring of liver enzymes and glycemic control is warranted for both agents, and additional monitoring of platelet counts for olezarsen. Future clinical trials are needed to assess whether the TG-lowering effects of each agent are associated with reduced risk of pancreatitis and ASCVD events.
2026-06-19 | Comparative efficacy and safety of olezarsen versus volanesorsen for familial chylomicronemia syndrome: a matching-adjusted indirect comparison.
Background: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder characterized by severe hypertriglyceridemia causing recurrent acute pancreatitis (AP). Since FCS is a genetic deficiency in functional lipoprotein lipase, conventional triglyceride-lowering therapies are ineffective in this metabolic disorder. Apolipoprotein C-III (apoC-III) inhibitors, including volanesorsen and olezarsen, have emerged as targeted treatments for FCS. Aim: To compare the efficacy and safety of olezarsen 80 mg every four weeks (Q4W) versus volanesorsen 300 mg weekly (QW) in patients with FCS using an anchored matching-adjusted indirect comparison. Materials & methods: Individual patient data from the Balance trial of olezarsen (n = 45) were weighted to match baseline characteristics reported in the APPROACH trial of volanesorsen (n = 66). Outcomes included percent change in fasting triglycerides (TG) and apoC-III at 26 and 52 weeks, and risks of AP events and adverse events at 52 weeks. Results: At 52 weeks, mean differences in fasting TG and apoC-III were -27.4% (95% CI: -69.4, 14.5) and -21.3% (95% CI: -61.9, 19.3). Relative risks of AP, treatment-emergent adverse events, and serious adverse events were 0.23 (95% CI: 0.01, 5.02), 0.87 (95% CI: 0.66, 1.13) and 0.50 (95% CI: 0.08, 3.26) at week 52. The rate ratio for AP events per patient-year was 0.06 (95% CI: 0.003, 1.41). No comparisons were statistically significant. Conclusion: In this matching-adjusted indirect comparison, no statistically significant differences in outcomes were observed between olezarsen and volanesorsen in patients with FCS. These findings provide important comparative context in a setting where head-to-head evidence is unavailable.
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2026-09-10 | Clinical and functional evidence supporting pathogenicity of a novel APOA5 variant in familial chylomicronemia syndrome.
This study aimed to evaluate the clinical and functional impact of a novel apolipoprotein A5 (ApoA5) variant by assessing lipoprotein lipase (LPL) activity. Demographic and clinical data, including blood lipid levels and body mass index, were retrospectively collected from an endocrinology clinic registry. Ten individuals with familial chylomicronemia syndrome (FCS) carrying a novel APOA5 variant were included. Whole-exome sequencing was performed using the latest generation DNB-SEQ400 platform. LPL activity was measured in post-heparin plasma using a radiometric assay. Statistical analysis: Categorical variables were summarized as frequencies and percentages, and continuous variables as mean ± standard deviation or median (range), as appropriate. Group comparisons were performed using the Mann-Whitney U test or chi-square test. Analyses were conducted using the Statistical Package for the Social Sciences software (v. 25.0). A p-value < 0.05 was considered statistically significant. We report ten cases of FCS with a homozygous missense variant of uncertain significance in APOA5: c.694T>C; p.(Ser232Pro), located in exon 3. In six patients assessed for LPL activity, levels remained consistently below 20% compared to normotriglyceridemic controls. The addition of exogenous serum containing APOA5 restored LPL activity to above 20% in all cases, indicating functional rescue. Measurement of LPL activity demonstrated the functional impact of the APOA5 c.694T>C; p.(Ser232Pro) variant. These findings support reclassification of the variant as likely pathogenic and enable differentiation from multifactorial chylomicronemia syndrome.
2026-03-15 | Post-heparin plasma lipase activities in patients with severe hypertriglyceridemia treated with evinacumab.
Patients with severe hypertriglyceridemia (sHTG) have variable lipoprotein lipase (LPL) activity levels that may influence therapeutic response. This exploratory analysis investigated post-heparin triglyceride lipase and phospholipase activities in three cohorts of patients with sHTG who received evinacumab (angiopoietin-like 3 inhibitor) for 12 or 24 weeks during a phase 2 trial: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function (LOF) LPL pathway mutations; cohort 2, multifactorial chylomicronemia syndrome (MCS) with heterozygous LOF LPL pathway mutations; and cohort 3, MCS without LPL pathway mutations. Post-heparin plasma samples were obtained at baseline and at week 24 (end of the treatment period). Triglyceride lipase activities (LPL and hepatic lipase [HL]) were measured using both a colorimetric and a scintillation assays. Phospholipase activities (HL and endothelial lipase [EL]) were measured using a colorimetric assay. Baseline post-heparin LPL triglyceride lipase activity was lowest in cohort 1; treatment with evinacumab for 12 or 24 weeks did not alter activity at week 24 versus baseline across cohorts using the colorimetric assay. Non-HL triglyceride lipase activity (mostly LPL) assessed using the scintillation assay showed a significant increase in cohort 1 at 24 weeks versus baseline (P = 0.04). Neither HL nor EL phospholipase activities differed among cohorts or changed with evinacumab treatment. High intra- and inter-patient variability in lipase activity was observed with all methods. Post-heparin LPL triglyceride lipase activity was lower in patients with sHTG with bi-allelic LPL pathway mutations and increased in that group with evinacumab. The high variability in lipase activities observed via differing methods supports the need for more robust assays.
2025-03-06 | Treatment With Evinacumab Links a New Pathogenic Variant in the LPL Gene to Persistent Chylomicronemia.
Persistent chylomicronemia is caused by lipoprotein lipase deficiency (LPLD) or lack of lipoprotein lipase (LPL) bioavailability. This disorder is characterized by plasma triglyceride (TG) levels above 10 mmol/L, increased acute pancreatitis risk, and features of familial chylomicronemia syndrome (FCS). Evinacumab is an angiopoietin-like protein 3 (ANGPTL3) monoclonal antibody, and its efficacy in decreasing plasma TG levels depends on LPL bioavailability. To identify FCS-causing pathogenic variants in patients with persistent chylomicronemia treated with evinacumab. A phase II clinical trial was conducted with evinacumab in patients with severe hypertriglyceridemia. Plasma TG values were measured at baseline and every 2 weeks for 24 weeks. Three FCS patients homozygotes for a P234L pathogenic variant in the LPL gene (HoLPL P234L) known to be associated with low postheparin LPL activity (proven LPLD) participated in the study and were used as tracers. The genotype-specific efficacy of evinacumab to decrease TG levels in other participants was compared to that achieved in HoLPL P234L patients. After 24 weeks of evinacumab treatment, TG levels decreased <20% in HoLPL P234L patients known to lack LPL. Similarly, a participant homozygote for a E282X variant in the exon 6 of the LPL gene that was suspected to be pathogenic due to its location did not respond to evinacumab (TG decreased <10% and remained >10 mmol/L). The efficacy of ANGPTL3 inhibitors in decreasing TG levels is LPL-dependent. Poor response to evinacumab supports the evidence that the E282X variant in the LPL gene is pathogenic and associated with persistent chylomicronemia (FCS phenotype).
2023-11-07 | Severe hypertriglyceridemia: Existing and emerging therapies.
Severe hypertriglyceridemia (sHTG), defined as a triglyceride (TG) concentration ≥ 500 mg/dL (≥ 5.7 mmol/L) is an important risk factor for acute pancreatitis. Although lifestyle, some medications, and certain conditions such as diabetes may lead to HTG, sHTG results from a combination of major and minor genetic defects in proteins that regulate TG lipolysis. Familial chylomicronemia syndrome (FCS) is a rare disorder caused by complete loss of function in lipoprotein lipase (LPL) or LPL activating proteins due to two homozygous recessive traits or compound heterozygous traits. Multifactorial chylomicronemia syndrome (MCS) and sHTG are due to the accumulation of rare heterozygous variants and polygenic defects that predispose individuals to sHTG phenotypes. Until recently, treatment of sHTG focused on lifestyle interventions, control of secondary factors, and nonselective pharmacotherapies that had modest TG-lowering efficacy and no corresponding reductions in atherosclerotic cardiovascular disease events. Genetic discoveries have allowed for the development of novel pathway-specific therapeutics targeting LPL modulating proteins. New targets directed towards inhibition of apolipoprotein C-III (apoC-III), angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like protein 4 (ANGPTL4), and fibroblast growth factor-21 (FGF21) offer far more efficacy in treating the various phenotypes of sHTG and opportunities to reduce the risk of acute pancreatitis and atherosclerotic cardiovascular disease events.
2023-08-11 | Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype–phenotype relationship for variants reported to date
Lipoprotein lipase (LPL) is the rate-limiting enzyme for triglyceride hydrolysis. Homozygous or compound heterozygous LPL variants cause autosomal recessive familial chylomicronemia syndrome (FCS), whereas simple heterozygous LPL variants are associated with hypertriglyceridemia (HTG) and HTG-related disorders. LPL frameshift coding sequence variants usually cause complete functional loss of the affected allele, thereby allowing exploration of the impact of different levels of LPL function in human disease.All exons and flanking intronic regions of LPL were Sanger sequenced in patients with HTG-related acute pancreatitis (HTG-AP) or HTG-AP in pregnancy. Previously reported LPL frameshift coding sequence variants were collated from the Human Gene Mutation Database and through PubMed keyword searching. Original reports were manually evaluated for the following information: zygosity status of the variant, plasma LPL activity of the variant carrier, disease referred for genetic analysis, patient's age at genetic analysis, and patient's disease history. SpliceAI was employed to predict the potential impact of collated variants on splicing.Two novel rare variants were identified, and 53 known LPL frameshift coding sequence variants were collated. Of the 51 variants informative for zygosity, 30 were simple heterozygotes, 12 were homozygotes, and 9 were compound heterozygotes. Careful evaluation of the 55 variants with respect to their clinical and genetic data generated several interesting findings. First, we conclude that 6-7% residual LPL function could significantly delay the age of onset of FCS and reduce the prevalence of FCS-associated syndromes. Second, whereas a large majority of LPL frameshift coding sequence variants completely disrupt gene function through their "frameshift" nature, a small fraction of these variants may act wholly or partly as "in-frame" variants, leading to the generation of protein products with some residual LPL function. Third, we identified two candidate LPL frameshift coding sequence variants that may retain residual function based on genotype-phenotype correlation or SpliceAI-predicted data.This study reported two novel LPL variants and yielded new insights into the genotype-phenotype relationship as it pertains to LPL frameshift coding sequence variants.
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Drug Discovery Landscape
10 orphan drug designations for Familial chylomicronemia syndrome, including 5 approved therapies.
10 orphan drug designations for Familial chylomicronemia syndrome, including 5 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Olezarsen sodium [Tryngolza] | oligonucleotides | EMA | Approved | Swedish Orphan Biovitrum AB (publ) |
olezarsen [Tryngolza] | RNAs | FDA | Approved | Ionis Pharmaceuticals |
Synthetic double-stranded siRNA oligonucleotide directed against apolipoprotein C-III mRNA and covalently linked to a ligand containing three N-acetylgalactosamine residues [Redemplo] | RNAs | EMA | Approved | Arrowhead Pharmaceuticals Ireland Limited |
plozasiran [Redemplo] | RNAs | FDA | Approved | Arrowhead Pharmaceuticals, Inc. |
volanesorsen sodium, apolipotrotein C-III antisense oligonucleotide | oligonucleotides | FDA | Akcea Therapeutics, Inc. | |
Phosphorothioate oligonucleotide targeted to apolipoprotein C-III [Waylivra] | oligonucleotides | EMA | Approved | Akcea Therapeutics Ireland Limited |
Pradigastat | small molecules | EMA | Novartis Europharm Limited | |
selective deacylglycerol acyltransferase 1 inhibitor | small molecules | FDA | Novartis Pharmaceuticals Corporation | |
lomitapide | small molecules | FDA | Chiesi Farmaceutici S.p.A. | |
Lomitapide | small molecules | EMA | Chiesi Farmaceutici S.p.A. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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