JIMD Reports, Journal Year: 2024, Volume and Issue: 65(4), P. 239 - 248
Published: June 2, 2024
Familial chylomicronemia syndrome (FCS) is a rare disorder of triglyceride (TG) metabolism caused by loss function variants in one five known canonical genes involved chylomicron lipolysis and clearance-
Language: Английский
Current Atherosclerosis Reports, Journal Year: 2023, Volume and Issue: 25(10), P. 701 - 709
Published: Aug. 29, 2023
Abstract Purpose of Review To provide an insight into the new pharmacological options for treatment severe hypertriglyceridemia (sHTG). Recent Findings sHTG is difficult to treat. The majority traditional agents available have limited success in both robustly decreasing triglyceride levels and/or reducing incidence acute pancreatitis (AP), most complication sHTG. Therapeutic with novel mechanisms action been developed, such as antisense oligonucleotides (ASO) and small interfering RNA (siRNA) targeting APOC3 ANGPTL3 . review discusses also 2 abandoned drugs treatment, evinacumab vupanorsen. Summary ASO , volanesorsen, approved use patients familial chylomicronemia syndrome (FCS) Europe. Olezarsen, N-acetylgalactosamine (GalNAc)-conjugated same target, seems a better safety efficacy profile. siRNA namely ARO-APOC3 ARO-ANG3, are promising However, ultimate clinical goal any decrease risk AP, has not definitively achieved till now by pharmacotherapy, either or development.
Language: Английский
Citations
34
The Journal of Clinical Endocrinology & Metabolism, Journal Year: 2024, Volume and Issue: unknown
Published: Sept. 6, 2024
Abstract Context Patients with rare familial chylomicronemia syndrome (FCS) and relatively common multifactorial (MCS) both express severe hypertriglyceridemia, defined as plasma triglyceride concentration ≥10 mmol/L (≥885 mg/dL). Clinically there can be confusion between the 2 conditions. Objective To compare clinical biochemical phenotypes in patients genotypically characterized FCS MCS. Methods We performed targeted sequencing of DNA from 193 classified them having either or MCS, compared characteristics. Results were significantly younger than MCS (31.4 ± 16.7 vs 51.0 11.3 years; P = .003), earlier age at symptom onset (15.0 15.8 37.8 8.8 .00066), lower body mass index (23.3 3.1 30.7 5.0 kg/m2; .000016), higher prevalence pancreatitis events (81.8% 35.2%; .003). Furthermore, had a ratio to total cholesterol (ie, 4.18 0.92 1.08 0.51; < .0001) apolipoprotein B 0.56 0.15 1.02 0.43 g/L; heterozygous pathogenic variants more presentation other genetic subgroups. Conclusion have notable phenotypic differences although is overlap. While analysis persistent hypertriglyceridemia definitively diagnose FCS, 8.8% sustained refractory behave functionally if they which should influence their eligibility for novel therapies hypertriglyceridemia.
Language: Английский
Citations
7
Expert Review of Endocrinology & Metabolism, Journal Year: 2024, Volume and Issue: 19(4), P. 299 - 306
Published: June 7, 2024
Introduction Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive condition. Effective treatment important as patients are at risk for severe and potentially fatal acute pancreatitis. We review recent developments in pharmacologic FCS, namely biological inhibitors of apolipoprotein (apo) C-III angiopoietin-like protein 3 (ANGPTL3).
Language: Английский
Citations
6
Cells, Journal Year: 2023, Volume and Issue: 12(12), P. 1648 - 1648
Published: June 16, 2023
Since the discovery of LDL receptor in 1973 by Brown and Goldstein as a causative protein hypercholesterolemia, tremendous amounts effort have gone into finding ways to manage high cholesterol familial hypercholesterolemic (HoFH HeFH) individuals with loss-of-function mutations (LDLR) gene. Statins proved be first blockbuster drug, helping both HoFH HeFH inhibiting synthesis pathway rate-limiting enzyme HMG-CoA reductase inducing receptor. However, statins could not achieve therapeutic goal LDL. Other therapies targeting LDLR include PCSK9, which lowers promoting degradation. Inducible degrader (IDOL) also controls protein, but an IDOL-based therapy is yet developed. Among LDLR-independent pathways, such angiopoietin-like 3 (ANGPTL3), apolipoprotein (apo) B, apoC-III CETP, only ANGPTL3 offers advantage treating patients showing relatively better preclinical clinical efficacy animal models individuals, respectively. While loss-of-LDLR-function been known for decades, gain-of-LDLR-function recently identified some individuals. The new information on gain function, together CRISPR-Cas9 genome/base editing technology target ANGPTL3, promise who are at higher risk developing atherosclerotic cardiovascular disease (ASCVD).
Language: Английский
Citations
16
Current Opinion in Lipidology, Journal Year: 2023, Volume and Issue: 34(2), P. 59 - 69
Published: Feb. 1, 2023
Purpose of review Not all patients with severe hypertriglyceridemia develop acute pancreatitis. We surveyed recent literature on inter-individual genetic variation in susceptibility to Recent findings Genetic determinants pancreatitis include: rare Mendelian disorders caused by highly penetrant pathogenic variants genes involved trypsinogen activation; uncommon activation, protein misfolding as well calcium metabolism and cystic fibrosis, that have variable penetrance show a range odds ratios for pancreatitis; common polymorphisms many the same only small effect risk. The role these modulating risk is unclear. However, among plasma triglycerides, those predisposing more associated chylomicronemia appear higher Summary Currently, hypertriglyceridemia, most consistent predictor triglyceride level. Furthermore, appears be modulated burden factors greater magnitude elevation. itself this metabolic context
Language: Английский
Citations
14
Journal of clinical lipidology, Journal Year: 2023, Volume and Issue: 17(5), P. 659 - 665
Published: Aug. 7, 2023
Language: Английский
Citations
11
Expert Opinion on Pharmacotherapy, Journal Year: 2024, Volume and Issue: unknown
Published: Sept. 21, 2024
Apolipoprotein (apo)C-III, a key regulator of plasma triglyceride (TG) levels, is prime candidate for the treatment hypertriglyceridemia (HTG), prevention acute pancreatitis, and reduction future atherosclerotic cardiovascular disease (ASCVD) events.
Language: Английский
Citations
4
Cellular Signalling, Journal Year: 2025, Volume and Issue: 131, P. 111706 - 111706
Published: March 2, 2025
Language: Английский
Citations
0
Current Atherosclerosis Reports, Journal Year: 2025, Volume and Issue: 27(1)
Published: April 21, 2025
This review discusses new treatment approaches for familial chylomicronemia syndrome (FCS), a rare disorder affecting triglyceride metabolism. The focus is on antisense oligonucleotides (ASO) and small-interfering RNA (siRNA) therapies targeting APOC3 angiopoietin-like protein 3 (ANGPTL3). Volanesorsen, an ASO APOC3, has shown effectiveness in managing FCS, multifactorial chylomicronemia, partial lipodystrophy, but its use limited by thrombocytopenia. Emerging therapies, Olezarsen (ASO anti-APOC3) Plozasiran (siRNA anti-APOC3), both conjugated with GalNAc, show promise reducing acute pancreatitis risk without platelet concerns. ANGPTL3 inhibition requires residual lipoprotein lipase (LPL) activity, only siRNA-based therapies-zodasiran solbinsiran-under investigation. Suppressing expression via siRNA offer significant potential, long-term studies are needed to confirm their efficacy safety. Future research may explore gene-editing strategies using lipid nanoparticle-based CRISPR-Cas9 delivery more durable outcomes.
Language: Английский
Citations
0
Journal of clinical lipidology, Journal Year: 2022, Volume and Issue: 17(1), P. 87 - 93
Published: Nov. 22, 2022
Language: Английский
Citations
17