A research team led by Associate Professor Makoto Ikeya in the Department of Clinical Application at Kyoto University has developed a promising new therapeutic strategy for fibrodysplasia ossificans progressiva (FOP)—a rare and severely disabling genetic disorder—by combining low-dose rapamycin with mesenchymal stem/stromal cells (MSCs) derived from induced pluripotent stem (iPS) cells. The paper is published in the journal JBMR Plus.

FOP is caused by mutations in the ACVR1 gene, resulting in overactive bone morphogenetic protein (BMP) signaling. This dysregulation leads to heterotopic ossification (HO), a pathological process in which soft tissues such as muscles, tendons, and ligaments progressively transform into bone.

Even minor injuries or infections can trigger HO, eventually leading to joint fusion and severe immobility. Currently, there are no approved treatments that can effectively prevent or reverse this debilitating condition.

In previous work, the team demonstrated that iPS cell-derived MSCs engineered to produce ACVR2B-Fc—a decoy receptor that binds and neutralizes excess BMP ligands—could reduce HO in FOP model mice. However, the therapeutic benefit was constrained by the rapid clearance of transplanted cells by the host immune system, which limited the sustained production of the therapeutic protein.

To overcome this limitation, the researchers introduced low-dose rapamycin, an immunosuppressant widely used in transplant medicine. Rapamycin was selected not only for its ability to modulate immune responses but also because the team had previously shown that it suppresses abnormal cartilage formation and BMP signaling in FOP-derived cells. This dual functionality made it an ideal candidate to support the survival and function of the engineered MSCs.

The study found that rapamycin alone could reduce HO, but its combination with ACVR2B-Fc-producing MSCs significantly enhanced therapeutic outcomes. This dual approach effectively reduced both primary and recurrent HO in the mouse model, with mice exhibiting improvements in motor performance, as measured by rotarod and treadmill tests.

Further analysis revealed that rapamycin extended the survival of transplanted cells by reducing inflammation and suppressing immune-related cytokines. This prolonged survival enabled sustained production of ACVR2B-Fc, confirmed by elevated Fc fragment levels in the blood. Histological analysis also showed reduced bone and cartilage formation, further supporting the treatment’s efficacy.

These findings suggest that combining stem cell therapy with targeted immunosuppression can overcome immune barriers and improve therapeutic outcomes in genetic diseases such as FOP. This study is among the first to demonstrate that immunomodulation can enhance the effectiveness of engineered stem cell therapies, potentially informing future treatments for other conditions involving abnormal tissue repair, immune rejection, or chronic inflammation.