Targeting transforming growth factor- β (TGF-β) for treatment of osteogenesis imperfecta.

Currently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies have shown that excessive TGF-β signaling is a driver of pathogenesis in OI. Here, we evaluated TGF-β signaling in children with OI and translated this discovery by conducting a phase 1 clinical trial of TGF-β inhibition in adults with OI.Histology and RNASeq were performed on bones obtained from children affected (n=10) and unaffected (n=4) by OI. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify key dysregulated pathways. Reverse-phase protein array (RPPA), Western blot (WB), and Immunohistochemistry (IHC) were performed to evaluate changes at the protein level. A phase 1 study with a single administration of fresolimumab, a pan-anti-TGF-β neutralizing antibody, was conducted in 8 adults with OI. Safety and effects of fresolimumab on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed.OI bone demonstrated woven structure, increased osteocyte density, high turnover, and reduced bone maturation. SMAD phosphorylation was the most significantly up-regulated GO molecular event. GSEA identified TGF-β pathway as top activated signaling pathway in OI. IPA showed that TGF-β was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increase in LS aBMD in participants with OI type IV, while those with more severe OI type III and VIII had unchanged or decreased LS aBMD.Our data confirm that TGF-β signaling is a driver pathogenic mechanism in OI bone and that anti-TGF-β therapy could be a potential disease-specific therapy with dose-dependent effects on bone mass and turnover.NCT03064074 FUNDING. This work was supported by the Brittle Bone Disorders Consortium (BBDC) (U54AR068069). The BBDC is a part of the National Center for Advancing Translational Science's (NCATS') RDCRN. The BBDC is funded through a collaboration between the Office of Rare Disease Research (ORDR) of NCATS, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute of Dental and Craniofacial Research (NIDCR), National Institute of Mental Health (NIMH) and National Institute of Child Health and Human Development (NICHD). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The BBDC was also supported by the OI Foundation. The work was supported by The Clinical Translational Core of BCM IDDRC (P50HD103555) from the Eunice Kennedy Shriver NICHD. Funding from the USDA/ARS under Cooperative Agreement No. 58-6250-6-001 also facilitated analysis for the study procedures. The contents of this publication do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The study was supported by a research agreement with Sanofi Genzyme.