👤 Michael Moriarty

Neurodegenerative diseases such as Huntington's Disease (HD) have a significant impact on healthcare accessibility and costs. A fatal genetic condition, characterized by the progressive loss of striatal neurons, HD is hindered by the lack of endogenous repair in the adult brain. Recent efforts toward protecting neural circuits through neurotrophic support using brain-derived neurotrophic factor (BDNF) have been suboptimal due to the protein's short half-life and limited diffusion. Addressing this, adeno-associated viral vectors (AAV) can be employed as a delivery tool to spatially transduce cells, enabling the localised production of BDNF with consequential neuron protection and/or plasticity, yet present their own constraints. To overcome these known challenges of AAV gene delivery, an injectable, physiologically stable hydrogel-mimic of the brain's extracellular matrix was fabricated to encapsulate the AAVs. This smart system both shielded and constrained the AAV; optimising transfection and therefore elevated and sustained BDNF presentation at the target site. Here, we achieved high neuroprotection using AAVDJ-BDNF delivered through a hydrogel formed via self-assembling peptide nanoscaffolds. These findings support the notion that the spatiotemporal release of BDNF to striatal neurons, facilitated by engineered biomaterial delivery systems, demonstrates tremendous promise by enhancing the efficacy of gene therapy targeted at slowing neurodegenerative disease progression. Show less

Lipoprotein(a) (Lp[a]) is an apolipoprotein B100 (apoB)-containing lipoprotein with a single apolipoprotein(a) (apo[a]) covalently bound to apoB via a disulfide bond and oxidized phospholipids linked to apoB and apo(a), which is associated with proinflammatory, prothrombotic, and proatherogenic mechanisms. Elevated Lp(a) (≥125 nmol/L [≥50 mg/dL]) is an independent, causal, genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD), affecting >1.4 billion individuals worldwide. There are no pharmacological Lp(a)-lowering therapies approved in the United States; however, lipoprotein apheresis may be considered under certain circumstances. Germany is the only country where apheresis is approved for patients with elevated Lp(a) and progressing ASCVD. Existing lipid-lowering therapies including proprotein convertase subtilisin/kexin type 9 inhibitors have shown modest effects on Lp(a) levels but fallen short of clinically meaningful reductions of >50 to 100 mg/dL. Several Lp(a)-lowering, RNA-targeted agents are in development, including antisense oligonucleotides (ASOs) and small interfering RNAs. Pelacarsen is a second-generation ASO that targets the production of apo(a) and includes chemical modifications such as triantennary N-acetylgalactosamine that improve biostability, decrease off-target toxicity compared with unmodified ASOs, and allow rapid, specific uptake by hepatocytes, the site of apo(a) synthesis. A phase 2b study of pelacarsen showed ≥80% reduction in Lp(a) concentration with a favorable safety profile in patients with established ASCVD. The ongoing phase 3 Lp(a)HORIZON study is evaluating whether the Lp(a)-lowering effects of pelacarsen translate into reductions in the incidence of major cardiovascular events, also in patients with established ASCVD. Herein, we review the mechanism of action of pelacarsen and evidence for its Lp(a)-lowering effects. Show less

Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III (apoC-III) production, in lowering triglyceride levels in patients at high risk for or with established cardiovascular disease. A randomized, double-blind, placebo-controlled, dose-ranging study was conducted in 114 patients with fasting serum triglycerides 200-500 mg/dL (2.26-5.65 mmol/L). Patients received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6-12 months. The primary endpoint was the percent change in fasting triglyceride levels from baseline to Month 6 of exposure. Baseline median (interquartile range) fasting triglyceride levels were 262 (222-329) mg/dL [2.96 (2.51-3.71) mmol/L]. Treatment with olezarsen resulted in mean percent triglyceride reductions of 23% with 10 mg every 4 weeks, 56% with 15 mg every 2 weeks, 60% with 10 mg every week, and 60% with 50 mg every 4 weeks, compared with increase by 6% for the pooled placebo group (P-values ranged from 0.0042 to <0.0001 compared with placebo). Significant decreases in apoC-III, very low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were also observed. There were no platelet count, liver, or renal function changes in any of the olezarsen groups. The most common adverse event was mild erythema at the injection site. Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established cardiovascular disease. NCT03385239. Show less

Most lung cancers are diagnosed too late for curative treatment to be possible, therefore early detection is crucial. Serum proteins are a rich source of biomarkers and have the potential to be used as diagnostic and prognostic indicators for lung cancer. In order to examine differences in serum levels of specific proteins associated with human lung squamous carcinoma, immunodepletion of albumin and five other high-abundant serum proteins followed by 2-D difference gel electrophoresis (DIGE) analysis and subsequent MS was used to generate a panel of proteins found to be differentially expressed between the cancer and normal samples. Proteins found to have increased abundance levels in squamous cell carcinoma sera compared to normal sera included apolipoprotein A-IV precursor, chain F; human complement component C3c, haptoglobin, serum amyloid A protein precursor and Ras-related protein Rab-7b. Proteins found to have lower abundance levels in squamous cell carcinoma sera compared to normal sera included alpha-2-HS glycoprotein, hemopexin precursor, proapolipoprotein, antithrombin III and SP40; 40. The data presented here demonstrate that high-abundant protein removal combined with 2-D DIGE is a powerful strategy for the discovery of potential biomarkers. The identification of lung cancer-specific biomarkers is crucial to early detection, which in turn could lead to a dramatic increase in survival rates. Show less