Controlable RNA expressing Scaffold for Bone Regeneration – CreaBone

The need for bone repair is exponentially rising due to increases in life expectancy and accidents. Natural bone grafts either autografts or allografts (from cadavers) are traditionally used as replacements. Yet, they present limited availability, morbidity of donor and acceptor sites and variability.
The advantages of bone graft synthetic substitutes (mainly calcium phosphate-based materials) are as follows: unlimited sources, similar lot-to-lot performance, either implantable and/or injectable for minimally invasive surgery. However, these materials are hampered by improper bone tissue integration and vascularization issues; in fact, they are at best osteoconductive but not/weakly osteoinductive. To enhance their bone-forming ability, these bone substitutes may be associated with osteoprogenitor cells, most frequently Multipotent Stromal Cells (MSC) from bone marrow. So far, compared to the benchmark for bone repair (i.e., autologous bone graft), therapeutic effectiveness of MSC-based constructs is lower than autologous bone grafts.
Currently, orthobiologics made of implantable carriers combined with bioactive molecules such as growth factors, peptides or small molecules, represent the most promising class of therapeutic medical products for bone regeneration. Signalling of these molecules mimics endogenous repair mechanisms by recruiting and programming the patient's own progenitor cells. Three growth factors have already been approved in clinics. However, these proteins require supra-physiological dosage resulting in side effects in humans: massive protein leakage from the carrier sponge into the soft tissue and then systemic diffusion leading to occurrence of inflammation, osteolysis, bone cyst and ectopic bone formation.
More recently, there is much interest in the use of messenger RNA (mRNA) as an alternative to both protein delivery and gene therapy for tissue regeneration. Indeed, the mRNA approach is safer, as, unlike DNA, RNA does not need to traffic to the nucleus of the cell; thus, there is no possibility of undesirable genetic events. By locally delivering mRNA to produce active BMPs in situ by host cells, we should provide a safe, efficient and tunable platform of novel orthobiologics for tissue regeneration.
In this project, we aim at developing innovative orthobiologics for bone regeneration as an alternative to recombinant proteins. We will provide an adaptable platform for bone regeneration where the morphogenetic mRNA can be tuned to patient-specific disease characteristics, contributing to the development of personalized nanomedicine and advancing the field of regenerative medicine.
The strategy of using mRNA-based therapy offers a great and, so far, untapped, opportunity to assess the osteogenic and bone healing potential of BMPs other than BMP-2, a molecule that has been shown to cause adverse side-effects. More specifically, we will compare the established osteogenic potential of BMP2/2, 6/6 or 9/9 homodimers to osteogenic 2/7 heterodimers and yet to be evaluated 4/7 heterodimers.
Aims:
The overall aim of the project is to use hydrogel and macromolecule assemblies to formulate scaffolds enabling a safe, local and transitory expression of BMP dimers and to validate their performance for bone regeneration. We propose to:
1) Identify the best BMP homodimer (2, 6 or 9) and heterodimer (2/7 or 4/7) for the osteogenic differentiation of osteoprogenitors in vitro and ectopic bone induction in vivo
2) Optimize the combination of mRNA constructs with hydrogels (CreaBone) for controlled diffusion and MSC transfection in vitro and in vivo
3) Validate the potential of CreaBone to heal large defect in long bone and generate vertical bone tissue apposition (a crucial issue in oral implantology)
Partners with complementary skills and long-term expertise will tackle the project: mRNA therapeutics delivery (CBM), protein- and cell-based bone regeneration (B3OA) and smart bone graft substitute development (RMeS).