Disease activity in Fibrodysplasia Ossificans Progressiva: The role of Activin A & [18F]NaF PET/CT as a biomarker

We used primary dermal fibroblasts from FOP patients to study Activin A production and its regulation by inflammatory cytokines in FOP in a cell model. Remarkably, FOP fibroblasts exhibited higher Activin A production compared to healthy controls, both under standard culture conditions and during osteogenic transdifferentiation. We identified TGFβ1 as a specific stimulant of Activin A in FOP, which led to increased INHBA gene expression and protein levels. Both Activin A and TGFβ1 were induced by BMP4 in fibroblasts from FOP patients and controls. However, treatment with TNFα and IL6 resulted in minimal Activin A and TGFβ1 production in both FOP and control fibroblasts. Our findings reveal that TGFβ1 triggers Activin A production in FOP. Since TGFβ1 can promote the main driver of FOP, it may also be considered a potential therapeutic target for FOP treatment. After that we performed a further exploration of the clinical pharmacology data from LUMINA-1 (NCT03188666), a phase 2 trial investigating garetosmab (a monoclonal antibody against activin A) in FOP patients. No significant differences were observed in PK or BMP9 concentration-time profiles between patients who did or did not experience serious adverse events. Comparative exposure-response analyses showed no link between trough concentration (Ctrough) and either efficacy or safety. There were no trends indicating that higher serum exposures to garetosmab were associated with a difference in reduction of heterotopic ossification (HO) or increased adverse events. Chapter 5 is also based on outcomes from the Lumina-1 trial. Here we analysed the dynamic [18F]NaF PET/CTs performed during the trial to study the use of [18F]NaF uptake parameters for routine assessment of disease activity in FOP patients. The uptake was quantified using nonlinear regression (NLR) analysis, standardized uptake value (SUV), and target-to-blood ratio (TBR). The correlation with NLR-derived Ki was higher for TBR (r = 0.92, 95% CI 0.85 – 0.96) than that for SUV (r = 0.81, 95% CI 0.64 – 0.90). This correlation remained consistent at baseline and after one year, supporting the use of TBR for assessing fluoride uptake in PET-active lesions in FOP, with SUV as an acceptable alternative. Later we used the [18F]NaF PET/CT together with other advanced bone imaging techniques such as the micro-CT, quantitative backscatter electron imaging (qBEI) and circular polarised light (CPL) imaging to investigate the pathophysiology of Eagle syndrome. Eagle syndrome is a rare bone condition characterized by the elongation of the styloid process, causing throat and neck pain, and in severe cases, neurovascular symptoms like syncope and neuralgia. With these techniques we demonstrated that the elongated styloid processes in Eagle syndrome consist of mature bone, capable of endochondral repair, likely growing from the base through endochondral ossification, rather than being a secondary calcification of the stylohyoid ligament as previously speculated.