Development of a First-in-Class Unimolecular Dual GIP/GLP-2 Analogue, GL-0001, for the Treatment of Bone Fragility
Benoit Gobron1,2, Malory Couchot1,3, Nigel Irwin4
1Univ Angers, Nantes Université, ONIRIS, Inserm, RMeS, UMR 1229, SFR ICAT, Angers, France.
Abstract:
Due 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 parameters by increasing ultimate load, postyield displacement, and energy-to-fracture of cortical bone. GL-0001 also prevented excess trabecular bone degradation at the appendicular skeleton and enhanced bone ECM material properties in cortical bone through a reduction of the mineral-to-matrix ratio and augmentation in enzymatic collagen cross-linking. These results demonstrate that targeting bone ECM material properties is a viable option to enhance bone strength and opens an innovative pathway for the treatment of patients suffering from bone fragility. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Insights
A novel dual GIP/GLP-2 analogue, GL-0001, enhances bone strength by improving extracellular matrix quality, not just bone mass. This offers a new therapeutic avenue for combating bone fragility and preventing fractures.
Area of Science:
- Bone biology and material science
- Pharmacology and drug discovery
- Biomedical engineering
Background:
- Bone frailty is a growing global health issue, with current treatments primarily focusing on bone mass, often failing to prevent new fractures.
- Bone's resistance to fracture depends on both mass and the material properties of its extracellular matrix (ECM).
Purpose of the Study:
- To introduce and evaluate a novel unimolecular dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-2 (GIP/GLP-2) analogue, GL-0001, for treating bone fragility.
- To investigate GL-0001's mechanism of action on bone ECM material properties and its therapeutic potential.
Main Methods:
- Development of a first-in-class dual GIP/GLP-2 analogue (GL-0001) activating both GIPr and GLP-2r.
- In vivo study using an ovariectomized mouse model, comparing GL-0001 to saline and zoledronic acid.
- Assessment of bone biomechanical parameters, trabecular bone degradation, and ECM material properties (mineral-to-matrix ratio, collagen cross-linking).
Main Results:
- GL-0001 significantly enhanced cortical bone biomechanical parameters, including ultimate load, postyield displacement, and energy-to-fracture.
- The dual analogue prevented excessive trabecular bone loss and improved ECM quality by reducing the mineral-to-matrix ratio and increasing collagen cross-linking.
- GL-0001 acts synergistically via a cAMP-lysyl oxidase pathway to mature collagen.
Conclusions:
- Targeting bone ECM material properties represents a viable strategy for improving bone strength and treating bone fragility.
- GL-0001 demonstrates potential as an innovative therapeutic agent for patients suffering from bone fragility, offering a new approach beyond bone mass enhancement.
