Innovative Approach Using Stem Cells and Drug Therapy to Combat Abnormal Bone Growth in FOP

A groundbreaking study led by Associate Professor Makoto Ikeya at Kyoto University introduces a novel therapeutic strategy for treating fibrodysplasia ossificans progressiva (FOP), a rare genetic disorder characterized by progressive abnormal bone formation in soft tissues. The research combines low doses of rapamycin, an immunosuppressant, with mesenchymal stem/stromal cells (MSCs) derived from induced pluripotent stem cells (iPS cells) to effectively reduce heterotopic ossification (HO), the process where muscles, tendons, and ligaments are transformed into bone.

FOP results from mutations in the ACVR1 gene, causing excessive bone morphogenetic protein (BMP) signaling and leading to HO, often triggered by minor injuries or infections. This leads to joint fusion and severe mobility restrictions, with no current treatments able to prevent or reverse the condition. Previous research demonstrated that MSCs engineered to produce ACVR2B-Fc, a decoy receptor neutralizing BMP ligands, could diminish HO in mouse models. However, immune rejection limited the longevity of these cells and their therapeutic efficacy.

To address this challenge, the team incorporated low-dose rapamycin, a drug well-known for its immunosuppressive and regenerative properties, which had been shown to suppress abnormal cartilage formation and BMP signaling in FOP cells. The combination of rapamycin with MSCs producing ACVR2B-Fc resulted in significantly enhanced outcomes, reducing both initial and recurring HO in mice. Treated mice also exhibited improved motor function, demonstrated through rotarod and treadmill tests.

Mechanistically, rapamycin prolonged the survival of transplanted MSCs by mitigating inflammation and cytokine activity, enabling sustained production of the therapeutic ACVR2B-Fc protein, confirmed by elevated blood levels. Histological assessments further confirmed reduced bone and cartilage formation, underscoring the treatment’s effectiveness.

This approach highlights the potential of combining stem cell therapy with targeted immunomodulation to overcome immune barriers, offering promising insights for treating genetic disorders like FOP. The findings suggest that immunosuppressants like rapamycin can significantly enhance the delivery and efficacy of engineered stem cell therapies, opening pathways for future therapies addressing abnormal tissue growth and immune rejection in various medical conditions.

For more information, see the original research published in JBMR Plus (2025): DOI: 10.1093/jbmrpl/ziaf068