Explore the vast range of titles available.

Osteoarthritis (OA) is a common, debilitating, chronic disease with no disease-modifying drug approved to date. We discovered LNA043—a derivative of angiopoietin-like 3 (ANGPTL3)—as a potent chondrogenesis inducer using a phenotypic screen with human mesenchymal stem cells. We show that LNA043 promotes chondrogenesis and cartilage matrix synthesis in vitro and regenerates hyaline articular cartilage in preclinical OA and cartilage injury models in vivo. LNA043 exerts at least part of these effects through binding to the fibronectin receptor, integrin α 5 β 1 on mesenchymal stem cells and chondrocytes. In a first-in-human (phase 1), randomized, double-blinded, placebo-controlled, single ascending dose, single-center trial ( NCT02491281 ; sponsored by Novartis Pharmaceuticals), 28 patients with knee OA were injected intra-articularly with LNA043 or placebo (3:1 ratio) either 2 h, 7 d or 21 d before total knee replacement. LNA043 met its primary safety endpoint and showed short serum pharmacokinetics, cartilage penetration and a lack of immunogenicity (secondary endpoints). Post-hoc transcriptomics profiling of cartilage revealed that a single LNA043 injection reverses the OA transcriptome signature over at least 21 d, inducing the expression of hyaline cartilage matrix components and anabolic signaling pathways, while suppressing mediators of OA progression. LNA043 is a novel disease-modifying OA drug candidate that is currently in a phase 2b trial ( NCT04864392 ) in patients with knee OA. The mechanism of action of LNA043—a novel disease-modifying osteoarthritis treatment candidate—is characterized in preclinical studies and through transcriptomic profiling of cartilage from patients with osteoarthritis in a phase 1 trial.

Angiopoietin-like 3 (ANGPTL3) inhibits endothelial lipase and lipoprotein lipase. Injection of antisense oligonucleotides targeting ANGPTL3 messenger RNA effects a reduction of atherogenic lipoproteins in humans and mice and a slowing of progression of atherosclerosis in mice.

Angiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. loss-of-function carriers have lower levels of triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol and a lower risk of atherosclerotic cardiovascular disease than noncarriers. Zodasiran is an RNA interference (RNAi) therapy targeting expression of in the liver. We conducted a double-blind, placebo-controlled, dose-ranging phase 2b trial to evaluate the safety and efficacy of zodasiran in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). Eligible patients were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24. A total of 204 patients underwent randomization. At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, -54 percentage points with 50 mg, -70 percentage points with 100 mg, and -74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, -51 percentage points, -57 percentage points, and -63 percentage points, respectively) (P<0.001 for all comparisons). Other differences in change from baseline as compared with placebo included the following: for non-HDL cholesterol level, -29 percentage points with 50 mg, -29 percentage points with 100 mg, and -36 percentage points with 200 mg; for apolipoprotein B level, -19 percentage points, -15 percentage points, and -22 percentage points, respectively; and for LDL cholesterol level, -16 percentage points, -14 percentage points, and -20 percentage points, respectively. We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran. In patients with mixed hyperlipidemia, zodasiran was associated with significant decreases in triglyceride levels at 24 weeks. (Funded by Arrowhead Pharmaceuticals; ARCHES-2 ClinicalTrials.gov number, NCT04832971.).

Among 65 patients with homozygous familial hypercholesterolemia, the use of evinacumab, a monoclonal antibody against ANGPTL3, resulted in a reduction from baseline in the LDL cholesterol level, as compared with a small increase with placebo, for a between-group difference of 49.0 percentage points at 24 weeks.

Purpose of Review Dyslipidemia is a casual risk factor for atherosclerotic cardiovascular disease (ASCVD). There is an unmet need for more effective treatments for patients with dyslipidemias. Angiopoietin-like protein 3 (ANGPTL3) and ANGPTL8 play key roles in triglyceride trafficking and energy balance in humans. We review the functional role of these ANGPTL proteins in the regulation of lipoprotein metabolism, and recent clinical trials targeting ANGPTL3 and ANGPTL3/8 with monoclonal antibody and/or nucleic acid therapies, including antisense oligonucleotides and small interfering RNA. Recent Findings Cumulative evidence supports the roles of ANGPTL3 and ANGPTL8 in lipid metabolism through inhibition of lipoprotein lipase and endothelial lipase activity. ANGPTL3 and ANGPTL3/8 inhibitors are effective in lowering plasma triglycerides and low-density lipoprotein (LDL)-cholesterol, with the possible advantage of raising high-density lipoprotein (HDL)-cholesterol with the inhibition of ANGPTL3/8. Therapeutic inhibition of ANGPTL3 and ANGPTL3/8 can lower plasma triglyceride and LDL-cholesterol levels possibly by lowering production and upregulating catabolism of triglyceride-rich lipoprotein and LDL particles. However, the effect of these novel agents on HDL metabolism remains unclear. The cardiovascular benefits of ANGPTL3 and ABGPTL3/8 inhibitors may also include improvement in vascular inflammation, but this requires further investigation. Summary Inhibition of ANGPTL3 and ANGPTL3/8 can broadly correct atherogenic dyslipidemia in patients with hypertriglyceridemia, familial hypercholesterolemia, mixed hyperlipidemia and metabolic syndrome. Whether these agents can improve cardiovascular outcomes remains to be demonstrated.

Necrosis in the tumor interior is a common feature of aggressive cancers that is associated with poor clinical prognosis and the development of metastasis. How the necrotic core promotes metastasis remains unclear. Here, we report that emergence of necrosis inside the tumor is correlated temporally with increased tumor dissemination in a rat breast cancer model and in human breast cancer patients. By performing spatially focused transcriptional profiling, we identified angiopoietin-like 7 (Angptl7) as a tumor-specific factor localized to the perinecrotic zone. Functional studies showed that Angptl7 loss normalizes central necrosis, perinecrotic dilated vessels, metastasis, and reduces circulating tumor cell counts to nearly zero. Mechanistically, Angptl7 promotes vascular permeability and supports vascular remodeling in the perinecrotic zone. Taken together, these findings show that breast tumors actively produce factors controlling central necrosis formation and metastatic dissemination from the tumor core.

Angiopoietin-like protein 2 (ANGPTL2) maintains tissue homeostasis by inducing inflammation and angiogenesis. It is produced in infiltrating immune cells or resident cells, such as adipocytes, vascular endothelial cells, and tumor cells. We hypothesized that ANGPTL2 might play an important role as a unique mediator in both systemic and periodontal disease. We demonstrated an increased ANGPTL2 concentration in gingival crevicular fluid from chronic periodontitis patients. Porphyromonas gingivalis lipopolysaccharide (LPS) treatment strongly induced ANGPTL2 mRNA and protein levels in Ca9-22 human gingival epithelial cells. Recombinant human ANGPTL2 increased interleukin 1β (IL-1β), IL-8, and tumor necrosis factor-α (TNF-α) mRNA and protein levels in Ca9-22 cells. Small-interfering (si)RNA-mediated ANGPTL2 knockdown in Ca9-22 cells reduced IL-1β, IL-8 and TNF-α mRNA and protein levels compared with control siRNA (p<0.01) in P. gingivalis LPS-stimulated Ca9-22 cells. Antibodies against integrin α5β1, an ANGPTL receptor, blocked induction of these inflammatory cytokines in P. gingivalis LPS-treated Ca9-22 cells, suggesting that secreted ANGPTL induces inflammatory cytokines in gingival epithelial cells via an autocrine loop. The classic sequential cascade of P. gingivalis LPS → inflammatory cytokine induction is well established. However, in the current study, we reveal a novel cascade comprising sequential P. gingivalis LPS → ANGPTL2 → integrin α5β1 → inflammatory cytokine induction, which might be responsible for inducing potent periodontal disorganization activity in gingival epithelial cells. Via this pathway, ANGPTL2 functions in the pathogenesis of periodontitis and contributes to prolonging chronic inflammation in patients with systemic disease.

Angiopoietin-like 3 is an inhibitor of lipoprotein lipase. Evinacumab is a monoclonal antibody that inhibits angiopoietin-like 3, activating lipoprotein lipase. In patients with hypercholesterolemia that is refractory to statin and PCSK9 inhibitor therapy, the use of evinacumab reduced plasma lipid levels by more than 50% at the maximum dose.

This study showed an association of loss-of-function mutations in ANGPTL4 with low triglyceride levels and protection against coronary artery disease. Inhibition of Angptl4 in mice and monkeys with a monoclonal antibody reduced triglyceride levels. The level of serum triglycerides is, in part, heritable, and elevated levels are associated with a risk of ischemic cardiovascular disease. 1 – 3 Mendelian randomization studies of genetically determined triglyceride levels have suggested that this association is causal. 4 Two lines of genetic evidence have further established a causal role for serum triglycerides in the risk of cardiovascular disease. First, inactivating mutations in the gene encoding apolipoprotein C3 ( APOC3 ), a component of remnant particles, were reported to be associated with decreased serum triglyceride levels, a decreased burden of subclinical atherosclerosis, and a reduced risk of ischemic cardiovascular disease, which suggests . . .

Loss-of-function variants in ANGPTL3 were associated with lower plasma levels of lipids and lower rates of coronary disease. A monoclonal antibody against ANGPTL3 reduced the atherosclerotic lesion area in mice and reduced levels of triglycerides and LDL cholesterol in human volunteers.