Efficient healing of large osseous segmental defects using optimized chemically modified messenger RNA encoding BMP-2

Abstract

Large segmental osseous defects heal poorly. Recombinant, human bone morphogenetic protein-2 (rhBMP-2) is used clinically to promote bone healing, but it is applied at very high doses that cause adverse side effects and raise costs while providing only incremental benefit. We describe a previously unexplored, alternative approach to bone regeneration using chemically modified messenger RNA (cmRNA). An optimized cmRNA encoding BMP-2 was delivered to critical-sized femoral osteotomies in rats. The cmRNA remained orthotopically localized and generated BMP locally for several days. Defects healed at doses ≥25 μg of BMP-2 cmRNA. By 4 weeks, all animals treated with 50 μg of BMP-2 cmRNA had bridged bone defects without forming the massive callus seen with rhBMP-2. Moreover, such defects recovered normal mechanical strength quicker and initiated bone remodeling faster. cmRNA regenerated bone via endochondral ossification, whereas rhBMP-2 drove intramembranous osteogenesis; cmRNA provides an innovative, safe, and highly translatable technology for bone healing.

The role of the immune microenvironment in bone, cartilage, and soft tissue regeneration: from mechanism to therapeutic opportunity

“…A major advancement in the field of bone regeneration has been the development of mRNA-based BMP-2 therapy. For example, to avoid the high costs and adverse effects of rhBMP-2, such as inflammatory complications, ectopic bone formation, and tumor formation [ 39 ], De La Vega et al [ 40 ] have reported that using a modified mRNA encoding BMP-2 is another approach to bone regeneration. This novel approach, compared with the recombinant protein approach, results in significantly better healing of large, critically sized, segmental osseous defects of long bones and has no adverse effects, possibly because of its transient and anatomically restricted expression of BMP-2 [ 40 ]…”

Rational Design of Bisphosphonate Lipid-like Materials for mRNA Delivery to the Bone Microenvironment

“…Bisphosphonate (BP) and BP derivatives have been used as targeting ligands for bone microenvironment-targeted delivery of therapeutic cargoes such as HER-2 targeting Trastuzumab antibody, BMP-2 growth factor, calcium phosphate–DNA plasmid, and parathyroid hormone for disease treatments. − Unlike traditional gene delivery of DNA, which needs first to translocate to the nucleus of the cell before expression, mRNA can almost immediately be translated into its cognate proteins after delivery to cells without any risk of insertional mutagenesis or genetic damage. Very recently, De La Vega and co-workers used chemically modified mRNA encoding BMP-2 for efficient healing of large osseous segmental defects, providing an innovative and potentially translatable technology for bone healing application . Although these studies made drastic improvements for bone targeting applications, efficient and specific delivery of mRNA to the bone microenvironment still remains a challenge.…”

Periosteum and fascia lata: Are they so different?

“…Although most other BMP were found to be significantly less present in HFL than HP, these two last ones were known to be the most important factors for osteo-induction ( White et al, 2007 ; Even et al, 2012 ; Wang et al, 2014 ). Non-recombinant or recombinant BMP-2 and -7, which were both approved by the Food and Drug Administration for some human uses, such as in spinal fusion and tibial pseudarthrosis, are currently employed in off-label uses, including CSBD ( Ong et al, 2010 ; Even et al, 2012 ; De La Vega et al, 2022 ). They both play a key role in osteoblast differentiation and initiating facture healing ( White et al, 2007 ; Wang et al, 2014 ).…”