Several mouse models have already proved valuable for investigating hypertrophic responses to cardiac stress. Here, we characterize one caused by a well defined single copy transgene, RenTgMK, that genetically clamps plasma renin and thence angiotensin II at high levels. All of the transgenic males develop concentric cardiac hypertrophy with fibrosis but without dilatation. Over half die suddenly aged 6 -8 months. Telemetry showed disturbances in diurnal rhythms a few days before death and, later, electrocardiographic disturbances comparable to those in humans with congestive heart failure. Expression of seven hypertrophyrelated genes in this and two categorically different models (lack of atrial natriuretic peptide receptor A; overexpression of calsequestrin) were compared. Statistical analyses show that ventricular expressions of the genes coding for atrial natriuretic peptide,  myosin heavy chain, medium chain acyl-CoA dehydrogenase, and adrenomedullin correlate equally well with the degree of hypertrophy, although their ranges of expression are, respectively, 50-, 30-, 10-, and 3-fold.
Background Elevated LDL-C and triglyceride rich lipoproteins (TRLs) are independent risk factors for cardiovascular disease (CVD). Genetic deficiency of angiopoietin-like protein 3 (ANGPTL3) is associated with reduced circulating levels of LDL-C, triglycerides (TGs), VLDL-C, HDL-C and reduced CVD risk, with no described adverse phenotype. ARO-ANG3 is a RNA interference drug designed to silence expression of ANGPTL3. Single doses of ARO-ANG3 have been shown to reduce ANGPTL3, TGs, VLDL-C and LDL-C in healthy volunteers (HVs, AHA 2019). We report the effects of multiple doses of ARO-ANG3 in HVs with a focus on the duration of action. Methods ARO-ANG3 was administered subcutaneously to HVs on days 1 and 29 at doses of 100, 200 or 300 mg (n=4 per group). Measured parameters included ANGPTL3, LDL-C, TGs, VLDL-C and HDL-C. Follow up is ongoing. Results All HVs have received both doses and follow-up is currently through week 16 (12 weeks after second dose). Mean nadir for ANGPTL3 levels occurred 2 weeks after the second dose (−83–93%) with minimal change for 200 and 300 mg but 16% recovery for 100 mg at week 16. Mean TGs and VLDL-C reached nadir earlier (3 wks, −61–65%) without apparent dose response and minimal change for any dose at wk 16. LDL-C nadir occurred 4–6 wks after the second dose (−45–54%), again with minimal evidence for dose response or change through wk 16. HDL-C was reduced 14–37% at wk 16. ARO-ANG3 was well tolerated without serious or severe adverse events or dropouts related to drug. The most common adverse events have been headache and upper respiratory infections. Conclusions Genetic deficiency of ANGPTL3 is a cause of familial combined hypolipemia and is associated with a decreased risk of CVD. Using RNAi to selectively suppress ANGPTL3 production reproduces these genetic effects with a duration of at least 12 weeks following a second dose and with good tolerability over 16 wks. ANGPTL3 inhibition results in lowering of LDL-C and TRLs which may confer protection against CVD in patients with atherogenic mixed dyslipidemia. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Arrowhead Pharmaceuticals
Background: Hypertriglyceridemia (HTG) increases the risk of acute pancreatitis and atherosclerosis. In a Phase 1 study (NCT03783377), single subcutaneous doses of investigational RNA interference (RNAi) therapeutic ARO-APOC3 (10, 25, 50, and 100 mg; N=24) demonstrated deep and prolonged reductions in apolipoprotein C3 (APOC3) and triglycerides (TG) and increases in HDL-C in healthy volunteers with good tolerability, compared with placebo (N=16). Purpose: We report initial results of the effects of ARO-APOC3 in patients with HTG (fasting TG ≥ 300 mg/dL) or multifactorial chylomicronemia (MCM; fasting TG ≥ 880 mg/dL). Methods: Up to 40 subjects with HTG and 20 subjects with MCM will receive ARO-APOC3 or placebo on days 1 and 29. Pharmacodynamic responses include serum APOC3, TG, and other lipid parameters reported up to week 4 prior to the 2 nd dose. Results: At the data cutoff (16 March 2020), the first 4 enrolled patients with HTG and 6 enrolled patients with MCM were administered ARO-APOC3 50 mg. ARO-APOC3 substantially reduced mean (range) APOC3 levels by 96% (88-99%) in both patient groups at Week 4 (Table). ARO-APOC3 substantially reduced mean (range) TG by 78% (67-87%) in HTG patients and by 92% (90-95%) in MCM patients at Week 4. Three of 4 HTG patients and 3 of 6 MCM patients had TG levels below 150 mg/dL. All MCM patients had TG ≤ 500 mg/dL. To date, ARO-APOC3 has been generally well tolerated with no reports of treatment-related serious or severe adverse events. Two of the 6 unblinded MCM patients experienced a transient ALT elevation to >3X ULN that returned to approximate pre-dose baseline by Day 113. Conclusions: Preliminary results indicate that a single dose of ARO-APOC3 reduces APOC3 levels by >90% and TG by ~80% 4 weeks after treatment in patients with HTG and MCM. The magnitude of treatment effect was similar in both populations and ARO-APOC3 had a favorable safety profile. Using RNAi to silence expression of APOC3 appears promising for treating patients with HTG and MCM.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.