Targeting TGFb In Osteogenesis Imperfecta

项目总结 成骨不全(OI)是一组异质性脆性骨病。超过95%的患者 港湾主要遗传的I型前胶原基因(COL1A1和COL1A2)或 I型胶原翻译后组装中重要的蛋白质复合体的隐性遗传突变 和羟化作用。目前，还没有FDA批准的OI治疗方法。同时非标签使用抗吸收药 双膦酸盐已成为事实上的护理标准，特别是在OI儿童中，它们对临床的影响 骨折的发生率，轻度OI(50%的患者)和成人，重度OI伴较低的骨形成尚不清楚。 这突显了OI治疗创新的迫切需要。采取合成代谢的方法，我们已经证明 在成人OI中，Teriparatide(PTH1-34)增加了轻度OI I型患者腰椎骨密度，但令人惊讶的是，没有 对重度OI有显著疗效，提示联合治疗有可能克服甲状旁腺激素不敏感。 我们和其他人已经证明了胶原蛋白的过度修饰和改变的交联会导致异常 矿化和改变细胞外基质到细胞的信号，特别是过度的转化生长因子β信号。 小鼠OI(Col1a2G610C/+和CRTAP-/-)。PAN-抗转化生长因子β治疗挽救了这些小鼠的骨骼表型。 在原代胎鼠成骨细胞中，转化生长因子β下调甲状旁腺素受体，这导致我们推测转化生长因子β 信号转导导致中、重度OI患者甲状旁腺激素不敏感(目标1)。在光谱的最严重的一端， 其他研究表明，Col1a1Jrt/+小鼠也增加了转化生长因子β；然而，它们对抗转化生长因子β没有反应 在中度OI模型中有效的剂量。在我们的1期抗转化生长因子β临床试验中，增加腰椎 在单次给药后，观察到中度但不严重的OI参与者的脊柱骨密度。我们未出版的 初步数据还显示，在轻度COL1a1+/-OI小鼠中，转化生长因子β升高。因此，我们假设一个广泛的 不同OI和骨靶向抗体抗转化生长因子β的剂量/频率范围要求 可提高所有类型的有效性和安全性(目标2)。转化生长因子β在骨折愈合中也起关键作用。我们之前 在COL1a2G610C/+和CRTAP-/-小鼠中发现骨折愈合延迟，骨痂尺寸减小，并进一步抗转化生长因子β 减少了这个。这一观察结果强调了研究抗转化生长因子β在血管内皮细胞损伤过程中作用的重要性。 骨折修复为未来的临床管理(目标3)。最后，了解转化生长因子β过度表达的机制。 OI骨可能会带来新的治疗靶点。对此的一个假设是互动减少 在异常的胶原和小的富含亮氨酸的蛋白多糖之间，如核心蛋白聚糖，它隔离了成熟的转化生长因子β (目标4)。我们的总体目标是回答围绕OI转化生长因子β的问题和未得到满足的需求。目标1.是 转化生长因子β过多致OI III/IV型小鼠和患者甲状旁腺素不敏感目标2.发展骨骼- 靶向抗转化生长因子β抗体，并确定轻、中、重度OI的剂量范围。目标3. 评价抗转化生长因子β治疗OI骨折的近期和远期疗效。目标4.确定 粘附素在调节OI过度转化生长因子β中的遗传需求。

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.