Development of a First ‐in‐Class Unimolecular Dual GIP/GLP‐2 Analogue, GL‐0001, for the Treatment of Bone Fragility

The first-in-class unimolecular dual GIP/GLP-2 analogue GL-0001 activates both GIPr and GLP-2r, resulting in cAMP production and lysyl oxidase expression. Then lysyl oxidase increases collagen cross-linking and bone material strength. ABSTRACTDue to aging of the population, bone frailty is dramatically increasing worldwide. Although some therapeutic options exist, they do not fully protect or prevent against the occurrence of new fractures. All current drugs approved for the treatment of bone fragility target bone mass. However, bone resistance to fracture is not solely due to bone mass but relies also on bone extracellular matrix (ECM) material properties, i.e., the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-2 (GIP/GLP-2) analogue, GL-0001, that activates simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagon-like peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cyclic adenosine monophosphate-lysyl oxidase pathway to enhance collagen maturity. Furthermore, bilateral ovariectomy was performed in 32 BALB/c mice at 12  weeks of age prior to random allocation to either saline, dual GIP/GLP-2 analogues (GL-0001 or GL-0007) or zoledronic acid groups (n = 8/group). Treatment with dual GIP/GLP-2 analogues was initiated 4 weeks later for 8 weeks. At the organ level, GL-0001 modified biomechanical pa...

Source: Journal of Bone and Mineral Research - March 10, 2023 Category: Orthopaedics Authors: Benoit Gobron, Malory Couchot, Nigel Irwin, Erick Legrand, B éatrice Bouvard, Guillaume Mabilleau Tags: Research Article Source Type: research