Delving into the Latest Updates on APOCIII program (Biocrine) with Synapse

Overview

Basic Info

Drug Type

Biological products

Synonyms-

Target

APOC3

Mechanism

APOC3 inhibitors(Apolipoprotein C-III inhibitors)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication

Diabetes Mellitus

Inactive Indication-

Originator Organization

BioCrine AB

Active Organization

BioCrine AB

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Familial chylomicronemia syndrome (FCS) is a very rare, underdiagnosed disorder that can cause abdominal pain and recurrent pancreatitis from childhood -potentially life-threatening- and chronic complications such as diabetes mellitus and exocrine pancreatic insufficiency. FCS affects the quality of life and mental health of those who suffer from it, aspects that must be taken into account in its treatment, based on a strict low-fat diet, which is difficult to adhere to and persist. People with FCS lack the lipolytic capacity to hydrolyze triglycerides (TG) and have a minimal or null response to conventional lipid-lowering treatments. ApoCIII antagonists, specifically volanesorsen, olezarsen and ARO-APOC3, are the most promising drugs to reduce TG concentrations in patients with FCS. Anti-ANGPTL3 therapies appear to be less effective. More clinical trials and new pharmacological treatments are needed to improve the quality of life and prognosis of people with FCS.

01 Dec 2018·Lipids in health and disease

Increased inflammation, endoplasmic reticulum stress and oxidative stress in endothelial and macrophage cells exacerbate atherosclerosis in ApoCIII transgenic mice

Article

Author: Yingchun, Han ; Xiaohong, Zhang ; Yahong, Ma ; Jiangping, Wen ; Xiaokui, He

BACKGROUND:

Overexpression of apolipoprotein CIII (ApoCIII) leads to hypertriglyceridemia (HTG) which promotes atherosclerosis development. However, it remains unclear whether ApoCIII affects the atherosclerosis alone by promoting the inflammation and endoplasmic reticulum (ER) stress, or in combination with HTG.

METHODS:

Transgenic (ApoCIIItg) mouse models were used to investigate the atherogenic role of ApoCIII. Since endothelial cells and macrophages play crucial roles in atherosclerosis, we examined whether triglyceride-rich lipoproteins (TRLs), the major lipoproteins, in plasma of ApoCIIItg mice affect inflammation and ER stress levels in these cells. To further investigate the role of ApoCIII and triglyceride, we incubated HUVECs cells and peritoneal macrophages with TRLs with or without ApoCIII.

RESULTS:

Increased inflammation and ER stress were found in the aorta of ApoCIIItg mice. TRLs increased ER stress and oxidative stress in HUVECs and macrophages in a dose dependent. Moreover, TRLs together with ApoCIII could induce a higher inflammation level than TRLs alone in these cells.

CONCLUSIONS:

Both TRLs and ApoCIII contribute to the progression of atherosclerosis, and the modulation of TRLs and ApoCIII may represent a novel therapeutic approach against HTG induced atherosclerosis.

01 Nov 2017·DiabetologiaQ1 · MEDICINE

VLDL and apolipoprotein CIII induce ER stress and inflammation and attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal muscle cells

Q1 · MEDICINE

Article

Author: Li, Diana ; Escolà-Gil, Joan Carles ; Botteri, Gaia ; Gumà, Anna ; Kohan, Alison B ; Barroso, Emma ; Pizarro, Javier ; Montori, Marta ; Palomer, Xavier ; Vázquez-Carrera, Manuel ; Cedó, Lídia

AIM/HYPOTHESIS:

Here, our aim was to examine whether VLDL and apolipoprotein (apo) CIII induce endoplasmic reticulum (ER) stress, inflammation and insulin resistance in skeletal muscle.

METHODS:

Studies were conducted in mouse C2C12 myotubes, isolated skeletal muscle and skeletal muscle from transgenic mice overexpressing apoCIII.

RESULTS:

C2C12 myotubes exposed to VLDL showed increased levels of ER stress and inflammatory markers whereas peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and AMP-activated protein kinase (AMPK) levels were reduced and the insulin signalling pathway was attenuated. The effects of VLDL were also observed in isolated skeletal muscle incubated with VLDL. The changes caused by VLDL were dependent on extracellular signal-regulated kinase (ERK) 1/2 since they were prevented by the ERK1/2 inhibitor U0126 or by knockdown of this kinase by siRNA transfection. ApoCIII mimicked the effects of VLDL and its effects were also blocked by ERK1/2 inhibition, suggesting that this apolipoprotein was responsible for the effects of VLDL. Skeletal muscle from transgenic mice overexpressing apoCIII showed increased levels of some ER stress and inflammatory markers and increased phosphorylated ERK1/2 levels, whereas PGC-1α levels were reduced, confirming apoCIII effects in vivo. Finally, incubation of myotubes with a neutralising antibody against Toll-like receptor 2 abolished the effects of apoCIII on ER stress, inflammation and insulin resistance, indicating that the effects of apoCIII were mediated by this receptor.

CONCLUSIONS/INTERPRETATION:

These results imply that elevated VLDL in diabetic states can contribute to the exacerbation of insulin resistance by activating ERK1/2 through Toll-like receptor 2.

100 Deals associated with APOCIII program (Biocrine)

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