By using patient iPS cells, Prof. Junya Toguchida has become a global leader in fibrodysplasia ossificans progressiva (FOP) research. Three years ago, Toguchida announced a drug trial to test the effects of rapamycin, a common immunosuppressant, on FOP patients. In his latest study on FOP, published in Orphanet Journal of Rare Diseases, Toguchida and his colleagues report that a prophylactic regimen may have the best therapeutic effect.

FOP is a rare genetic disease in which bone replaces soft tissue. Gradually patients become immobile and eventually die of asphyxiation because the chest cavity will not move. It is also a difficult disease to give a prognosis.

"FOP is a progressive disease, but with a step-wise progression. In other diseases, patients will get worse over time, and that can be seen with each visit. FOP patients, however, may seem stable, but then incur a major setback," explains Toguchida.

The majority of FOP patients will show a flare-up, which describes localized swelling indicative of abnormal bone growth, usually following some sort of trauma. Ironically, the only way to remove the abnormal bone growth is through surgery, which itself is a form of trauma that risks exasperating the disease. Still, 40% of patients will not show a flare-up and not recall when the disease started to significantly worsen. Thus, Toguchida worried that different FOP patients could respond differently in the rapamycin trial.

"The inability to follow the disease progression has a serious influence on the design of a clinical trial. We decided to investigate different regimens on mice that mimic flare-up and no flare-up FOP," he says.

The abnormal bone growth seen in FOP was induced in mice through a chemical treatment. A rapamycin regimen of once a day, five times a week, began one week later and was maintained for four weeks. These mice showed a dramatic drop in abnormal bone growth compared to the untreated group.

In a follow-up study, the scientists added physical trauma, in which muscle was directly pinched, two weeks after the chemical induction. Mice were further divided into those that received rapamycin regimen beginning one week after the chemical treatment (therefore, one week before the pinch) and those that received the rapamycin regimen the day of the pinch. Both drug treatments similarly suppressed abnormal bone growth at the traumatized site.

However, trauma in FOP induces bone growth at untraumatized sites too. It was here where the prophylactic had a bigger effect. Abnormal bone growth began to form in untraumatized sites following the pinch in untreated mice. While rapamycin treatment the day of the pinch suppressed some of this growth, the suppression was much greater if the treatment began one week earlier.

"Many FOP patients will require surgery to remove the heterotrophic ossification. This surgery is trauma and risks more heterotrophic ossification. Our findings suggest a prophylactic regimen reduces the risk," notes Toguchida.

Indeed, a third set of experiments in which the mice underwent surgery to remove bone had the same effect. These findings have important implications not only for on drug treatment programs, but also on pre-operative preparation when surgically removing bone.

"Both early and episode-initiated rapamycin treatment suppressed episode-induced heterotrophic ossification, but early seemed more effective," says Toguchida.

• doi: 10.1186/s13023-020-01406-8