Targeting TGFb In Osteogenesis Imperfecta

靶向 TGFb 治疗成骨不全症

• 批准号: 10736736
• 负责人: Brendan Lee
• 金额: $ 62.59万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-07 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736736
• 关键词: Adult; Affect; Antibodies; Architecture; Binding; Biomechanics; Bone Development; Bone callus; COL1A1 gene; COL1A2 gene; Child; Chondrocytes; Clinical; Clinical Management; Clinical Trials; Collagen; Collagen Type I; Coupling; Data; Developmental Bone Diseases; Dose; Extracellular Matrix; FDA approved; Forteo; Fracture; Frequencies; Future; Genes; Genetic; Goals; Histology; Human; Hydroxylation; Impaired healing; Incidence; Inflammation; Inherited; Lead; Leucine; Long-Term Effects; Measures; Modeling; Modification; Mus; Mutation; Osteoblasts; Osteoclasts; Osteogenesis; Osteogenesis Imperfecta; Outcome; Participant; Pathway interactions; Patients; Phase; Phenotype; Physiologic Ossification; Procollagen; Proteoglycan; Rattus; Recurrence; Regimen; Safety; Sampling; Serology; Severities; Signal Transduction; Testing; Therapeutic; Thick; Tibial Fractures; Toxicology; Transforming Growth Factor beta; Type I Procollagen; United States National Institutes of Health; Vertebral column; angiogenesis; bisphosphonate; bone; bone fracture repair; bone mass; bone repair; bone turnover; combinatorial; crosslink; decorin; effective therapy; effectiveness study; fetal; healing; improved; inflammatory marker; innovation; mineralization; mouse model; neoplastic cell; new therapeutic target; novel therapeutics; off-label use; overexpression; phase I trial; protein complex; receptor; safety testing; skeletal; standard of care; targeted treatment; trafficking

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.

项目摘要 成骨不完美（OI）是一组异质的脆性骨骼疾病。超过95％的患者 I型Procollagen基因（COL1A1和COL1A2）或 在I型胶原蛋白胶原蛋白复合物中的隐性遗传突变，翻译后组装 和羟基化。目前，没有FDA批准的OI治疗方法。同时使用反应的标签 双膦酸盐已成为事实上的护理标准，尤其是在有OI的儿童中，他们对 骨折事件，轻度OI I型（> 50％的患者）和成人，骨形成较低的成人，尚不清楚。 这突出了OI治疗创新的迫切需要。采用合成代谢方法，我们已经表明 在成年OI中，Teriparatide（PTH 1-34）在轻度I型中增加了腰椎BMD，但令人惊讶的是没有 在严重的OI中的显着影响，表明合并治疗克服PTH不敏感的可能性。 我们和其他人已经表明，胶原蛋白过度修饰和交联改变导致异常 矿化和细胞外基质（ECM）至细胞信号的改变，尤其是过量的TGFβ信号传导 小鼠中的OI（COL1A2G610C/+和CRTAP - / - ）。 pan-anti-TGFβ处理营救了这些小鼠的骨骼表型。 在原发性胎儿大鼠成骨细胞中，TGFβ下调了PTH 1受体，这使我们假设TGFβ 信号传导导致中度和重度OI的PTH不敏感（AIM 1）。在频谱的严重端， 其他人则表明，col1a1jrt/+小鼠的TGFβ也增加了。但是，他们没有对抗TGFβ做出反应 以中等OI模型有效的剂量。在我们的1阶段抗TGFβ临床试验中，增加腰 单剂量后，在中度但严重的OI参与者中观察到脊柱BMD。我们未发表的 初步数据还显示了我们轻度COL1A1 +/- OI小鼠中TGFβ的增加。因此，我们假设一个宽阔的 抗TGFβ在不同的OI严重程度和骨靶向抗体之间的剂量/频率范围要求 可以提高所有类型的效率和安全性（AIM 2）。 TGFβ在断裂愈合中也很重要。我们以前 发现COL1A2G610C/+和CRTAP - / - 小鼠和抗TGFβ进一步延迟裂缝愈合，愈伤组织的大小降低 减少了这一点。该观察结果强调了研究抗TGFβ在过程中的影响的重要性 未来临床管理的断裂修复（AIM 3）。最后，了解TGFβ的机制超过 OI骨可能会导致新的治疗靶标。一个假设是减少相互作用 在异常胶原蛋白和富含亮氨酸的小蛋白聚糖之间 （目标4）。我们的总体目标是回答针对OI中TGFβ的问题和未满足的需求。 AIM 1。是 由于TGFβ过量而导致的小鼠和OI III/IV型患者的PTH不敏感性？目标2。发展骨 - 靶向抗TGFβ抗体，并确定轻度，中度和重度OI的剂量范围。目标3。 评估抗TGFβ治疗在OI断裂修复中的短期和长期影响。目标4。确定 在调节OI中过量的TGFβ时，Decorin的遗传需求。