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

Authors: SONG, I - Baylor College Of Medicine; NAGAMANI, SANDESH - Baylor College Of Medicine; NGUYEN, DIANNE - Baylor College Of Medicine; GRAFE, INGO - Dresden University; SUTTON, VERNON - Baylor College Of Medicine; GANNON, FRANCIS - Baylor College Of Medicine; MUNIVEZ, ELDA - Baylor College Of Medicine; JIANG, MING - Baylor College Of Medicine; TRAN, ALYSSA - Baylor College Of Medicine; WALLACE, MAEGAN - University Of Nebraska; ESPOSITO, PAUL - University Of Nebraska; MUSAAD, SALMA - Children'S Nutrition Research Center (CNRC); STRUDTHOFF, ELIZABETH - University Of Nebraska; MCGUIRE, SHARON - University Of Nebraska; THORNTON, MICHELE - University Of Nebraska; SHENAVA, VINITHA - Baylor College Of Medicine; ROSENFELD, SCOTT - Baylor College Of Medicine; SHYPAILO, ROMAN - Children'S Nutrition Research Center (CNRC); ORWOLL, ERIC - Oregon Health & Science University; LEE, BRENDAN - Baylor College Of Medicine

Submitted to: Journal of Clinical Investigation
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/23/2022
Publication Date: 2/3/2022
Citation: Song, I.W., Nagamani, S.C., Nguyen, D., Grafe, I., Sutton, V.R., Gannon, F.H., Munivez, E., Jiang, M.M., Tran, A., Wallace, M., Esposito, P., Musaad, S., Strudthoff, E., McGuire, S., Thornton, M., Shenava, V., Rosenfeld, S., Shypailo, R., Orwoll, E., Lee, B. 2022. Targeting TGF-beta for treatment of osteogenesis imperfecta. Journal of Clinical Investigation. 132(7). Article e152571. https://doi.org/10.1172/JCI152571.
DOI: https://doi.org/10.1172/JCI152571

Interpretive Summary: Osteogenesis Imperfect (OI) is a genetic disorder that causes bone and muscle weakness, among other effects. Studies in mice showed that OI can be caused by too much of a protein called transforming growth factor-beta (TGF-beta). In this study, we wanted to understand whether reducing TGF-beta activity in humans can improve bone health. So we tested the safety of therapy with fresolimumab, a TGF-beta antibody, and explored its effects on bone health in adults with OI. Results in humans confirm that increased TGF-beta activity causes bone problems in OI, and that anti-TGF-beta therapy could be used to improve bone health in individuals with OI. This research helps to further our understanding of bone and muscle biology and the prevention of disease.

Technical Abstract: Currently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies have shown that excessive TGF-beta signaling is a driver of pathogenesis in OI. Here, we evaluated TGF-beta signaling in children with OI and translated this discovery by conducting a phase 1 clinical trial of TGF-beta 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-beta 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-beta pathway as top activated signaling pathway in OI. IPA showed that TGF-beta 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-beta signaling is a driver pathogenic mechanism in OI bone and that anti-TGF-beta therapy could be a potential disease-specific therapy with dose-dependent effects on bone mass and turnover.