Engineering of a GLP-1 analogue peptide/anti-PCSK9 antibody fusion for type 2 diabetes treatment.

Type 2 diabetes (T2D) is a complex and progressive disease requiring polypharmacy to manage hyperglycaemia and cardiovascular risk factors. However, most patients do not achieve combined treatment goals. To address this therapeutic gap, we have developed MEDI4166, a novel glucagon-like peptide-1 (GLP-1) receptor agonist peptide fused to a proprotein convertase subtilisin/kexin type 9 (PCSK9) neutralising antibody that allows for glycaemic control and low-density lipoprotein cholesterol (LDL-C) lowering in a single molecule.

Superior reductions in hepatic steatosis and fibrosis with co-administration of a glucagon-like peptide-1 receptor agonist and obeticholic acid in mice.

Objective: Nonalcoholic steatohepatitis (NASH) is an unmet need associated with metabolic syndrome. There are no approved therapies for NASH; however, glucagon-like peptide-1 receptor (GLP-1R) and farnesoid-X receptor (FXR) agonists are promising drug targets. We investigated the therapeutic effects of co-administration of a GLP-1R agonist, IP118, with FXR agonist obeticholic acid (OCA) in mice.

Novel therapeutics and targets for the treatment of diabetes.

The microvascular complications of insufficiently controlled diabetes (neuropathy, retinopathy and nephropathy) and the marked increased risk of macrovascular events (e.g., stroke and myocardial infarction) have a dire impact on society in both human and economic terms.

Bone morphogenetic proteins and growth differentiation factors as drug targets in cardiovascular and metabolic disease.

Bone morphogenetic proteins (BMPs) and growth differentiation factors (GDFs) control the development and homeostasis of multiple tissue types in many organisms, from humans to invertebrates. These morphogens are expressed in a tissue-specific manner and they signal by binding to serine-threonine kinase receptors, resulting in coordinated changes in gene expression that regulate the differentiation and development of multiple tissue types. In addition, these proteins are regulated post-transcriptionally through binding to several soluble proteins.

Myostatin, a negative regulator of muscle mass: implications for muscle degenerative diseases.

Myostatin is a secreted protein that negatively regulates skeletal muscle mass determining both muscle fiber number and size. The myostatin pathway is conserved and regulates muscle mass in a number of animal species ranging from fish to humans. Inhibition of myostatin using a variety of therapeutic approaches can increase muscle mass in a number of animal models of human disease, including muscular dystrophy.

Requirement of BMP-2-induced phosphatidylinositol 3-kinase and Akt serine/threonine kinase in osteoblast differentiation and Smad-dependent BMP-2 gene transcription.

The mechanism by which bone morphogenetic protein-2 (BMP-2) induces osteoblast differentiation is not precisely known. We investigated the involvement of the phosphatidylinositol (PI) 3-kinase/Akt signal transduction pathway in modulation of this process. BMP-2 stimulated PI 3-kinase activity in osteogenic cells.