👤 Miriam Larouche

Persistent chylomicronemia is associated with severe hypertriglyceridemia (sHTG) and plasma triglycerides (TG) levels sustainably > 10 mmol/L (880 mg/dL) despite lipid lowering therapies. The main risk of persistent chylomicronemia is acute pancreatitis (AP). During the second and third trimester of pregnancy, TG levels significantly increase, which represents a serious risk of AP in women with preexisting chylomicronemia. New emerging therapies such as plozasiran, a GalNAc-conjugated small interfering RNA (siRNA) against ApoC3, are developed to manage persistent chylomicronemia, but no data are currently available on their safety and efficacy during pregnancy. We report herein the case of a woman with persistent chylomicronemia randomized in the PALISADE study to receive plozasiran 25 mg quarterly, who had an unplanned pregnancy during the clinical trial. The 34-year-old patient received one dose of plozasiran 8 weeks before conception and the experimental treatment was ceased afterwards. The pregnancy went well, TG levels did not rise above 10 mmol/L (880 mg/dL) during the whole pregnancy, even during the last two trimesters where TG levels usually increase two- to four-fold from baseline and she did not experience any AP episode. She delivered a healthy baby at 39 weeks. This case suggests that plozasiran might be safe for the mother and the fetus and could prevent incremental pregnancy-driven TG elevation and occurrence of AP in women with sHTG. This is consistent with the long duration of action and hepatic half-life of plozasiran in clinical studies where TG levels remained sustainably lower than baseline > 9 months after the last injection. Show less

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. Show less

Chylomicronemia is characterized by extreme hypertriglyceridemia (triglyceride values >10 mmol/L). It may be caused by a biallelic combination of a pathogenic variant [familial chylomicronemia syndrome (FCS)] or by genetic susceptibility combined with comorbidities and environmental factors [multifactorial chylomicronemia syndrome (MCS)]. Acute pancreatitis (AP) is the most serious complication of chylomicronemia. In the general population, the prevalence of AP during pregnancy is estimated to be <0.35%. As triglyceride levels significantly increase during pregnancy, it may affect the course of pregnancy and further increase the risk of AP in women with chylomicronemia. One hundred sixteen pregnancies involving 49 European and North American women with a history of chylomicronemia (20 FCS, 29 MCS) were retrospectively reviewed. The occurrence of AP, the course of pregnancy, fetal development, and delivery were evaluated. Forty-two percent of FCS and 10% of MCS women experienced at least 1 AP episode during pregnancy (P = .01). Compared to MCS, women with FCS presented a higher percentage of pregnancies with AP (17% vs 5%, P = .02). Among all reviewed pregnancy-related AP, 56% occurred in primigravida FCS women compared to 0% in MCS. Premature deliveries were elevated in both groups, although they were more frequent in FCS (56%) vs MCS (19%) (P = .01). The percentages of miscarriages (11.8% vs 10.7%) and fetal failure to thrive (5.9% vs 9.2%) were not significantly different between the 2 cohorts. In this study, pregnant women with chylomicronemia had a 30-fold (MCS) to 120-fold (FCS) higher occurrence of AP compared to the general population. Chylomicronemia per se does not seem to influence fetal development. Show less

Severe hypertriglyceridemia (HTG) is characterized by plasma triglyceride (TG) levels >500 mg/dL (SI: 5.7 mmol/L) (reference range, <150 mg/dL [SI: <1.7 mmol/L]) and is linked to cardiovascular disease and pancreatitis risk. Treatment typically involves dietary restrictions and lipid-lowering medications. Glycerol kinase deficiency (GKD) is a rare genetic disorder that causes pseudo-HTG. In SHASTA-2, a study of patients with severe HTG, most subjects (>90%) treated with plozasiran, an apolipoprotein C-III (APOC3) small interfering RNA (siRNA), achieved TG levels <500 mg/dL (SI: 5.7 mmol/L), below the risk threshold for acute pancreatitis. We report herein a case study of a 65-year-old male apparently not responding to plozasiran. The patient was shown to carry a loss-of-function variant in the Show less

Oncogenic alterations in fibroblast growth factor receptor (FGFR)-family proteins occur across cancers, including pediatric gliomas. Our genomic analysis of 11,635 gliomas across ages finds that 5.3% of all gliomas harbor FGFR alterations, with an incidence of almost 9% in pediatric gliomas. Alterations in FGFR proteins are differentially enriched by age, tumor grade, and histology, with FGFR1 alterations associated with glioneuronal histologies. Leveraging isogenic systems, we confirm FGFR1 alterations to induce downstream Mitogen Activated Protein Kinase (MAPK) and mTOR signaling pathways, drive gliomagenesis, activate neuronal transcriptional programs and exhibit sensitivity to MAPK pathway and pan-FGFR inhibitors. Finally, we perform a retrospective analysis of clinical responses in children diagnosed with FGFR-altered gliomas and find that treatment with currently available inhibitors is largely associated with stability of disease. This study provides key insights into the biology of FGFR1-altered gliomas, therapeutic strategies to target them and associated challenges that still need to be overcome. Show less

The angiopoietin-like protein 3/8 complex (ANGPTL3/8) inhibits lipoprotein lipase (LPL) activity, primarily in oxidative tissues, and does so more potently than ANGPTL3, making ANPTL3/8 an attractive target for treating dyslipidemia. This study enrolled 48 adults (36 men, 12 women) with mixed hyperlipidemia to assess the primary outcome of safety and the secondary outcomes of pharmacokinetics and pharmacodynamics of ascending doses of LY3475766, a human monoclonal antibody that specifically blocks ANGPTL3/8-mediated inhibition of LPL activity. Participants received a single dose of LY3475766 or placebo. LY3475766 was well tolerated with no severe adverse events or adverse event-related discontinuations. Compared with placebo, LY3475766 dose-dependently reduced the concentration of triglycerides (-70%), remnant cholesterol (-86%), low-density lipoprotein cholesterol (-32%), non-high-density lipoprotein cholesterol (non-HDL-C) (-35%) and apolipoprotein B (-29%) while increasing HDL-C (+27%). LY3475766 thus significantly reduced atherogenic lipoprotein levels while increasing HDL-C levels; however, the effects on cardiovascular risk remain to be established. ClinicalTrials.gov registration: NCT04052594 . Show less

Extreme hypertriglyceridemia, defined as triglyceride (TG) levels ≥1000 mg/dL, is almost always indicative of chylomicronemia. The current diagnostic approach categorizes individuals with chylomicronemia into familial chylomicronemia syndrome (FCS; prevalence 1-10 per million), caused by the biallelic combination of pathogenic variants that impair the lipolytic action of lipoprotein lipase (LPL), or multifactorial chylomicronemia syndrome (MCS, 1 in 500). A pragmatic framework should emphasize the severity of the phenotype and the risk of complications. Therefore, we endorse the term "persistent chylomicronemia (PC)" defined as TG ≥1000 mg/dL in more than half of the measurements to encompass patients with the highest risk for pancreatitis, regardless of their genetic predisposition. We suggest classification of PC into 4 subtypes: (1) genetic FCS, (2) clinical FCS, (3) PC with "alarm" features, and (4) PC without alarm features. Although patients with FCS most likely have PC, the vast majority with PC do not have genetic FCS. Proposed alarm features are: (a) history of recurrent TG-induced acute pancreatitis, (b) recurrent hospitalizations for severe abdominal pain without another identified cause, (c) childhood pancreatitis, (d) family history of TG-induced pancreatitis, and/or (e) postheparin LPL activity <20% of normal value. Alarm features constitute the strongest risk factors for future acute pancreatitis risk. Patients with PC and alarm features have very high risk of pancreatitis, comparable to that in patients with FCS. Effective, innovative treatments for PC, like apolipoprotein C-III inhibitors, have been developed. Combined with lifestyle modifications, these agents markedly lower TG levels and risk of pancreatitis in the very-high-risk groups, irrespective of the monogenic etiology. Pragmatic definitions, education, and focus on patients with PC, specifically those with alarm features, could help mitigate the risk of acute pancreatitis and other complications. Show less

Extreme hypertriglyceridemia, defined as triglyceride (TG) levels ≥1000 mg/dL, is almost always indicative of chylomicronemia. The current diagnostic approach categorizes individuals with chylomicronemia into familial chylomicronemia syndrome (FCS; prevalence 1-10 per million), caused by the biallelic combination of pathogenic variants that impair the lipolytic action of lipoprotein lipase (LPL), or multifactorial chylomicronemia syndrome (MCS, 1 in 500). A pragmatic framework should emphasize the severity of the phenotype and the risk of complications. Therefore, we endorse the term "persistent chylomicronemia" defined as TG ≥1000 mg/dL in more than half of the measurements to encompass patients with the highest risk for pancreatitis, regardless of their genetic predisposition. We suggest classification of PC into four subtypes: 1) genetic FCS, 2) clinical FCS, 3) PC with "alarm" features, and 4) PC without alarm features. Although patients with FCS most likely have PC, the vast majority with PC do not have genetic FCS. Proposed alarm features are: (a) history of recurrent TG-induced acute pancreatitis, (b) recurrent hospitalizations for severe abdominal pain without another identified cause, (c) childhood pancreatitis, (d) family history of TG-induced pancreatitis, and/or (e) post-heparin LPL activity <20 % of normal value. Alarm features constitute the strongest risk factors for future acute pancreatitis risk. Patients with PC and alarm features have very high risk of pancreatitis, comparable to that in patients with FCS. Effective, innovative treatments for PC, like apoC-III inhibitors, have been developed. Combined with lifestyle modifications, these agents markedly lower TG levels and risk of pancreatitis in the very-high-risk groups, irrespective of the monogenic etiology. Pragmatic definitions, education, and focus on patients with PC specifically those with alarm features could help mitigate the risk of acute pancreatitis and other complications. Show less

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). Show less

The aim of this review is to provide an overview of severe hypertriglyceridemia presenting in the form of chylomicronemia that persists despite treatment of secondary causes and the use of conventional lipid-lowering treatment. Persistent chylomicronemia is a rare syndromic disorder that affects carriers of bi-allelic combinations of pathogenic gene variants impairing lipoprotein lipase (LPL) activity, as well as a significant number of individuals who do not meet this genetic criterion. It is associated with a high risk of acute pancreatitis and other morbidities. Effective innovative treatments for severe hypertriglyceridemia are being developed and are becoming available. Patients with persistent chylomicronemia of any cause respond equally to next-generation therapies with LPL-independent mechanisms of action and do not generally respond to conventional LPL-dependent treatments. Not all individuals with persistent chylomicronemia carry a proven pathogenic combination of gene variants that impair LPL activity. Documenting the clinical characteristics of people with persistent chylomicronemia and their response to emerging therapies is essential to correctly establish their risk trajectory and ensure equitable access to personalized treatment. Show less

The aim of this review is to present the clinical indications of apolipoprotein C-III (apoC3) inhibition in the therapeutic arsenal for the treatment of lipid disorders and associated risks and to compare the most advanced modalities of apoC3 inhibition currently available or in development, specifically APOC3 antisense oligonucleotides (ASO) and small interfering RNA (siRNA). ApoC3 inhibition significantly decreases triglyceride levels by mechanisms coupling both lipoprotein lipase (LPL) upregulation and LPL-independent mechanisms. The main apoC3 inhibitors in advanced clinical development are the GalNAc-ASO olezarsen and the GalNAc-siRNA plozasiran. Clinical studies conducted with volanesorsen, the olezarsen precursor, showed a favorable effect on hepatic steatosis (nonalcoholic fatty liver disease, NAFLD). Olezarsen does not appear to be associated with the main side effects attributed to volanesorsen including thrombocytopenia. Plozasiran is in advanced clinical development and requires subcutaneous injection every 3 months and present to-date an efficacy and safety profile comparable to that of the monthly ASO. Inhibition of apoC3 is effective across all the spectrum of hypertriglyceridemia, might have a favorable effect on hepatic steatosis (NAFLD) and the effect of apoC3 inhibition on cardiovascular risk is not limited to its effect on plasma triglycerides. APOC3 GalNAc-conjugated ASO and siRNA are both effective in decreasing plasma apoC3 and triglyceride levels. Show less

The role of the inhibition of ANGPTL3 in severe or refractory hypercholesterolemia is well documented, less in severe hyperTG. This review focuses on the preclinical and clinical development of ApoC-III inhibitors and ANGPTL3, 4, and 3/8 complex inhibitors for the treatment of severe or refractory forms of hypertriglyceridemia to prevent cardiovascular disease or other morbidities. APOC3 and ANGPTL3 became targets for drug development following the identification of naturally occurring loss of function variants in families with a favorable lipid profile and low cardiovascular risk. The inhibition of ANGPTL3 covers a broad spectrum of lipid disorders from severe hypercholesterolemia to severe hypertriglyceridemia, while the inhibition of ApoC-III can treat hypertriglyceridemia regardless of the severity. Preclinical and clinical data suggest that ApoC-III inhibitors, ANGPTL3 inhibitors, and inhibitors of the ANGPTL3/8 complex that is formed postprandially are highly effective for the treatment of severe or refractory hypertriglyceridemia. Inhibition of ANGPTL3 or the ANGPTL3/8 complex upregulates LPL and facilitates the hydrolysis and clearance of triglyceride-rich lipoproteins (TRL) (LPL-dependent mechanisms), whereas ApoC-III inhibitors contribute to the management and clearance of TRL through both LPL-dependent and LPL-independent mechanisms making it possible to successfully lower TG in subjects completely lacking LPL (familial chylomicronemia syndrome). Most of these agents are biologicals including monoclonal antibodies (mAb), antisense nucleotides (ASO), small interfering RNA (siRNA), or CRISPR-cas gene editing strategies. Show less

The familial chylomicronemia syndrome (FCS) is an ultra rare disease caused by lipoprotein lipase (LPL) deficiency associated with potentially lethal acute pancreatitis risk. Thrombocytopenia (platelet count < 150,000 × 10 To evaluate post-prandial fluctuations in the platelet count (PLC) and functional defects of hemostasis in FCS. PLC, functional defects in hemostasis and hematologic variables were measured up-to 5 h after a meal in 6 homozygotes for FCS causing gene variants (HoLPL), 6 heterozygotes for LPL loss-of-function variants (HeLPL) and 7 normolipidemic controls. Hourly post-prandial PLC was significantly lower in HoLPL than in controls (P < 0.009). Compared to the other groups, the PLC tended to decrease rapidly (in the first hour) post-meal in HoLPL (P = 0.03) and remained lower than baseline 5-h post-meal (P = 0.02) whereas it tended to slightly increase in normolipidemic controls (P = 0.02). Platelet function was not affected by the prandial status. In HoLPL, post-prandial fluctuations in the PLC positively correlated with the lymphocyte count (P = 0.005) and negatively with neutrophil/lymphocyte ratio (NLR). The PLC decreases post-prandially in FCS (HoLPL), is not associated with changes in functional defects of hemostasis and correlates with the NLR, a marker of acute pancreatitis severity. Show less