Targeting TGFb In Osteogenesis Imperfecta

点击翻译按钮获取中文摘要

PROJECT SUMMARY Osteogenesis Imperfecta (OI) is a group of heterogeneous brittle bone disorders. Over 95% of patients harbor dominantly inherited structural mutations in the type I procollagen genes (COL1A1 and COL1A2) or recessively inherited mutations in the protein complexes important in type I collagen post-translational assembly and hydroxylation. Currently, there are no FDA-approved treatments for OI. While off-label use of anti-resorptive bisphosphonates has become a de facto standard of care especially in children with OI, their clinical impact on fracture incidence, mild OI type I (> 50% of patients), and adult, severe OI with lower bone formation is unclear. This highlights the critical need of therapeutic innovations for OI. Taking anabolic approaches, we have shown in adult OI that teriparatide (PTH 1-34) increases lumbar spine BMD in mild OI type I, but surprisingly, had no significant effect in severe OI, suggesting the possibility of combinatorial therapy to overcome PTH insensitivity. We and others have shown that collagen over-modification and altered cross-linking lead to abnormal mineralization and altered extracellular matrix (ECM)-to-cell signaling, in particular, excessive TGFβ signaling in OI in mice (Col1a2G610C/+ and Crtap-/-). Pan-anti-TGFβ treatment rescued the skeletal phenotype in these mice. In primary fetal rat osteoblasts, TGFβ downregulates PTH 1 receptor, which led us to hypothesize that TGFβ signaling contributes to PTH insensitivity in moderate and severe OI (Aim 1). On the severe end of the spectrum, others have shown that Col1a1Jrt/+ mice also have increased TGFβ; however, they did not respond to anti-TGFβ at doses that were effective in the moderate OI models. In our phase 1 anti-TGFβ clinical trial, increase lumbar spine BMD was observed in moderate but not severe OI participants after a single dose. Our unpublished preliminary data also showed increase TGFβ in our mild Col1a1+/- OI mice. We therefore hypothesize a wide dose/frequency range requirement for anti-TGFβ among different OI severities and a bone-targeted antibody can improve efficacy and safety across all types (Aim 2). TGFβ is also critical in fracture healing. We previously found delayed fracture healing with reduced callus size in Col1a2G610C/+ and Crtap-/- mice and anti-TGFβ further reduced this. This observation underscores the importance for studying the effects of anti-TGFβ in the course of fracture repair for future clinical management (Aim 3). Finally, understanding the mechanism of TGFβ excess in OI bone could potentially lead to new therapeutic targets. One hypothesis for this is decreased interaction between abnormal collagen and small leucine rich proteoglycans, like Decorin, which sequester mature TGFβ (Aim 4). Our overall goal is to answer the questions and unmet needs around targeting TGFβ in OI. Aim 1. Is PTH insensitivity in mice and patients with OI type III/IV due to excessive TGFβ? Aim 2. Develop a bone- targeted anti-TGFβ antibody and determine the dose range for mild, moderate, and severe OI. Aim 3. Assess the short and long-term effects of anti-TGFβ treatment in OI fracture repair. Aim 4. Determine the genetic requirement of Decorin in modulating excessive TGFβ in OI.