TY - JOUR
T1 - Efficient healing of large osseous segmental defects using optimized chemically modified messenger RNA encoding BMP-2
AU - De La Vega, Rodolfo E
AU - van Griensven, Martijn
AU - Zhang, Wen
AU - Coenen, Michael J
AU - Nagelli, Christopher V
AU - Panos, Joseph A
AU - Peniche Silva, Carlos J
AU - Geiger, Johannes
AU - Plank, Christian
AU - Evans, Christopher H
AU - Balmayor, Elizabeth R
N1 - Funding Information:
We acknowledge the support provided by C. Dohmen during the nonviral lipidoid vector production and by V. Joris and N. Roumans during the protein quantification and ELISA assays. This project was supported by NIH (R01 AR074395 from NIAMS to C.H.E. and E.R.B.) and the John and Posy Krehbiel Professorship in Orthopedics (C.H.E.). Partial support was received by NIAMS (T32AR56950 to C.V.N.).
Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
PY - 2022/2/18
Y1 - 2022/2/18
N2 - 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.
AB - 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.
KW - BONE
KW - DELIVERY
KW - THERAPEUTICS
U2 - 10.1126/sciadv.abl6242
DO - 10.1126/sciadv.abl6242
M3 - Article
C2 - 35171668
SN - 2375-2548
VL - 8
JO - Science advances
JF - Science advances
IS - 7
M1 - 6242
ER -