👤 Jacob J Basson

Genetic studies have established angiopoietin-related protein 4 (ANGPTL4) as a key regulator of triglyceride metabolism and a promising target to reduce atherosclerotic cardiovascular disease (ASCVD) risk beyond traditional risk factors. Human ANGPTL4 loss-of-function shows no adverse consequences and is associated with reduced triglycerides and remnant cholesterol, and a reduced risk of type 2 diabetes and ASCVD. Nonetheless, development of ANGPTL4 inhibitors has been delayed due to adverse findings in ANGPTL4-knockout mice fed a high saturated fat diet, including lipid accumulation in mesenteric lymph nodes, systemic inflammation, adverse clinical signs, and reduced survival. We previously reported the development and preclinical characterisation of MAR001, an ANGPTL4 inhibitory antibody. Here, we report a comprehensive safety assessment of ANGPTL4 inhibition, including novel analysis of genetic ANGPTL4 loss on mesenteric lymph node architecture in humans and two early-phase clinical trials. MAR001 was evaluated in a first-in-human, randomised, placebo-controlled, single-ascending-dose phase 1 study with three parts in which participants received a single subcutaneous injection of MAR001 or placebo. The study was developed and conducted by Novartis Biomedical Research (Cambridge, MA, USA). Eligible participants enrolled in part 1A were healthy men and women aged between 18 years and 65 years with a bodyweight of at least 50 kg and a BMI of 18-30 kg/m We found no evidence of clinical adversity in human germline ANGPTL4 loss-of-function, adding to preclinical support for initiating human studies. Between Nov 20, 2017, and Sept 10, 2019, in the first-in-human, randomised, placebo-controlled, single-ascending-dose phase 1 study, part 1A enrolled 32 healthy participants: six each received 15 mg, 50 mg, 150 mg, or 450 mg of MAR001, and eight received placebo. Part 1B enrolled 12 participants: nine received 450 mg of MAR001 and three received placebo. Part 1C enrolled 12 participants: eight received 450 mg of MAR001 and four received placebo. Between Nov 24, 2013, and July 1, 2024, in the multidose phase 1b/2a randomised, double-blind, placebo-controlled study, 55 participants were randomly assigned to receive subcutaneous injections of placebo (19 participants) or MAR001 at doses of 150 mg (ten participants), 300 mg (nine participants), or 450 mg (17 participants), followed by a 12-week safety follow-up period. MAR001 was safe and generally well tolerated, and we observed no treatment-related systemic inflammatory biomarker elevations or changes in mesenteric lymph node size or inflammation assessed by MRI. MAR001 (450 mg) yielded placebo-adjusted week 12 mean reductions in triglycerides of 52·7% (90% CI -77·0 to -28·3) and in remnant cholesterol of 52·5% (-76·1 to -28·9). ANGPTL4 inhibition with MAR001 can safely and effectively reduce circulating triglycerides and remnant cholesterol. The findings of these trials support further research and development of MAR001 as a promising potential lipid-lowering therapy to reduce risk of ASCVD. Marea Therapeutics. Show less

Schlafen12 (SLFN12) promotes human intestinal and prostatic epithelial differentiation. We sought to determine whether SLFN12 reduces triple-negative breast cancer (TNBC) aggressiveness. We validated bioinformatics analyses of publicly available databases by staining human TNBC. After virally overexpressing or siRNA-reducing SLFN12 in TNBC cell lines, we measured proliferation by CCK-8 assay, invasion into basement-membrane-coated pores, mRNA by q-RT-PCR and protein by Western blotting. Flow cytometry assessed proliferation and stem cell marker expression, and sorted CD44+/CD24- cells. Stemness was also assessed by mammosphere formation, and translation by click-it-AHA chemistry. SLFN12 expression was lower in TNBC tumors and correlated with survival. SLFN12 overexpression reduced TNBC MDA-MB-231, BT549, and Hs578T proliferation. In MDA-MB-231 cells, AdSLFN12 reduced invasion, promoted cell cycle arrest, increased E-cadherin promoter activity, mRNA, and protein, and reduced vimentin expression and protein. SLFN12 knockdown increased vimentin. AdSLFN12 reduced the proportion of MDA-MB-231 CD44 SLFN12 may reduce TNBC aggressiveness and improve survival in part by a post-transcriptional decrease in ZEB1 that promotes TNBC cancer stem cell differentiation. Show less

Single genetic loci offer little predictive power for the identification of depression. This study examined whether an analysis of gene-gene (G × G) interactions of 78 single nucleotide polymorphisms (SNPs) in genes associated with depression and age-related diseases would identify significant interactions with increased predictive power for depression. A retrospective cohort study. A survey of participants in the Wisconsin Longitudinal Study. A total of 4811 persons (2464 women and 2347 men) who provided saliva for genotyping; the group comes from a randomly selected sample of Wisconsin high school graduates from the class of 1957 as well as a randomly selected sibling, almost all of whom are non-Hispanic white. Depression as determine by the Composite International Diagnostic Interview-Short-Form. Using a classification tree approach (recursive partitioning (RP)), the authors identified a number of candidate G × G interactions associated with depression. The primary SNP splits revealed by RP (ANKK1 rs1800497 (also known as DRD2 Taq1A) in men and DRD2 rs224592 in women) were found to be significant as single factors by logistic regression (LR) after controlling for multiple testing (p=0.001 for both). Without considering interaction effects, only one of the five subsequent RP splits reached nominal significance in LR (FTO rs1421085 in women, p=0.008). However, after controlling for G × G interactions by running LR on RP-specific subsets, every split became significant and grew larger in magnitude (OR (before) → (after): men: GNRH1 novel SNP: (1.43 → 1.57); women: APOC3 rs2854116: (1.28 → 1.55), ACVR2B rs3749386: (1.11 → 2.17), FTO rs1421085: (1.32 → 1.65), IL6 rs1800795: (1.12 → 1.85)). The results suggest that examining G × G interactions improves the identification of genetic associations predictive of depression. 4 of the SNPs identified in these interactions were located in two pathways well known to impact depression: neurotransmitter (ANKK1 and DRD2) and neuroendocrine (GNRH1 and ACVR2B) signalling. This study demonstrates the utility of RP analysis as an efficient and powerful exploratory analysis technique for uncovering genetic and molecular pathway interactions associated with disease aetiology. Show less