Targeting TGF-β for treatment of osteogenesis imperfecta

BACKGROUND. Currently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-beta signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-beta signaling in children with OI and conducted a phase I clinical trial of TGF-beta inhibition in adults with OI. METHODS. Histology and RNA-Seq were performed on bones obtained from children. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify dysregulated pathways. Reverse-phase protein array, Western blot, and IHC were performed to evaluate protein expression. A phase I study of fresolimumab, a TGF-beta neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed. RESULTS. OI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated GO molecular event. GSEA identified the TGF-beta pathway as the top activated signaling pathway, and IPA showed that TGF-beta 1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD. CONCLUSION. Increased TGF-beta signaling is a driver pathogenic mechanism in OI. Anti-TGF-beta therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover. TRIAL REGISTRATION. ClinicalTrials.gov NCT03064074.

Automated summary

The study found that there is excessive TGF-beta signaling in patients with osteogenesis imperfecta (OI). TGF-beta signaling may be a driver pathogenic mechanism in OI. Anti-TGF-beta therapy could be a potential disease-specific therapy.