Innovative Approach Combines Stem Cell Therapy and Drug Treatment to Combat Abnormal Bone Growth

A research team at Kyoto University has pioneered a new treatment strategy for fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterized by abnormal bone formation. The study, led by Associate Professor Makoto Ikeya, effectively combines low-dose rapamycin with mesenchymal stem/stromal cells (MSCs) derived from induced pluripotent stem (iPS) cells, as detailed in the journal JBMR Plus.

FOP is triggered by mutations in the ACVR1 gene, which leads to excessive bone morphogenetic protein (BMP) signaling. This abnormal signaling causes a condition known as heterotopic ossification (HO), wherein soft tissues, including muscles and tendons, gradually convert into bone. Even minor injuries or infections can instigate HO, ultimately leading to joint fusion and significant mobility impairment. Currently, there are no approved therapies available that can effectively halt or reverse this debilitating condition.

In prior research, the team demonstrated that iPS cell-derived MSCs engineered to produce ACVR2B-Fc--a decoy receptor that neutralizes excess BMP ligands--could mitigate HO in FOP model mice. However, the therapeutic effectiveness was limited due to the swift clearance of transplanted cells by the host immune system, which restricted the continuous production of the therapeutic protein.

To address this challenge, the researchers incorporated low-dose rapamycin, an immunosuppressant commonly utilized in transplant medicine. Rapamycin not only modulates immune responses but has also been shown to inhibit abnormal cartilage formation and BMP signaling in cells affected by FOP. This dual functionality made it a suitable candidate to enhance the survival and efficacy of engineered MSCs.

The investigation revealed that while rapamycin alone could diminish HO, its combination with ACVR2B-Fc-producing MSCs yielded significantly improved therapeutic results. This integrated approach effectively reduced both initial and recurrent HO in mouse models, with observed enhancements in motor performance as assessed through rotarod and treadmill tests.

Further examination indicated that rapamycin prolonged the survival of transplanted cells by decreasing inflammation and inhibiting immune-related cytokines. This extended survival facilitated sustained production of ACVR2B-Fc, confirmed by increased Fc fragment levels in the bloodstream. Histological evaluations also illustrated reduced bone and cartilage formation, further validating the treatment's effectiveness.

These findings indicate that the combination of stem cell therapy with targeted immunosuppression can overcome immune barriers, potentially leading to improved treatment outcomes for genetic disorders like FOP. This study represents a significant step forward in demonstrating that immunomodulation can amplify the efficacy of engineered stem cell treatments, which could have implications for various conditions involving abnormal tissue repair, immune rejection, or chronic inflammation.

For further details, refer to the publication: Pan Gao et al., Combined rapamycin and mesenchymal stem/stromal cells derived from induced pluripotent stem cells-mediated delivery of ACVR2B-Fc fusion protein reduces heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva, JBMR Plus (2025). DOI: 10.1093/jbmrpl/ziaf068.