Applying mRNA to healing broken bones

Messenger RNA technology could have broad applications beyond preventing COVID-19 with vaccines. Besides the infectious disease and cancer areas that industry leaders BioNTech and Moderna are already exploring, a research team at Mayo Clinic found mRNA holds promise for regenerating bones.

Sending a low dose of an optimized mRNA instructing for the protein BMP-2 could heal bone defects in rats, helping the animals grow new bone with mechanical properties comparable to those of native bone, scientists at Mayo Clinic reported in a new study published in the journal Science Advances.

Because the mRNA treatment effect appeared better than existing recombinant human BMP-2, mRNA “provides an innovative, safe and highly translatable technology for bone healing,” the researchers wrote in the study.

BMP-2 is a natural protein in the body that promotes the development of bone and cartilage. In 2002, the FDA greenlit Medtronic’s recombinant human BMP-2 implant, known as Infuse, as a bone graft material. But the product comes with less-than-ideal efficacy and side effects such as unintended bone formation, the Mayo Clinic researchers noted.

The team figured local delivery of genetic information coding for BMP-2 could be an alternative way to generate bone.

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In experiments conducted in a rat model of bone defects, an injection within the bone lesion of 50-mcg engineered mRNA encoding BMP-2, delivered via a lipid vector, led to significant BMP-2 production. The protein expression decayed to low levels by day 5 after administration. By comparison, the effects of a clinically equivalent dose of recombinant human BMP-2 tapered off more slowly after hitting a high on the first day.

As early as four weeks after treatment, all animals treated with the 50-mcg mRNA product had bridged bone defects indicating complete healing, the researcher found.

Further analysis found the tissue grown from the mRNA was biomechanically superior to that spurred on by the recombinant protein. On a torque failure test, which measures how much external force can be applied before a part fails, the mRNA group had recovered to native bone levels at four weeks, whereas the recombinant group remained significantly lower than normal.

Bone remodeling, a process key to bone healing, was also “visibly superior” in the mRNA group, the team found. Probably thanks to this trait and its transient presence, the mRNA didn’t cause the large, abnormal bone callus that formed in mice treated with the recombinant BMP-2 protein.

Almost no mRNA drug was detected in blood, lung, spleen, liver or kidney during the experiment period, as the BMP-2 protein production was limited to the bone lesion, the team reported.

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The team picked mRNA because, compared with DNA therapies, it’s relatively easy to produce and can be delivered into the cell with less expensive nonviral vectors. mRNA won’t integrate into the human genome and is only present in the body for a short period of time, making it a safe option, the researchers said.

The success of mRNA COVID-19 vaccines has encouraged scientists to explore other uses of mRNA. In another regenerative medicine application of mRNA, scientists at the University of Pennsylvania recently designed an mRNA to express a chimeric antigen receptor that can recognize the fibroblast activation protein on the surface of heart fibroblast cells, which form scars from cardiac injury. Targeted delivery of the mRNA to T cells formed CAR-T cells that removed the diseased fibroblast cells, leading to a significant improvement in heart function in mice.

Overall, the Mayo Clinic team argues that in bone healing, mRNA “promises to couple affordability with efficacy, and clinical expediency with safety, while presenting fewer barriers than traditional gene therapy to clinical translation.”