Small Molecule Inhibition of Noggin to Induce Spinal Fusion

Noggin 的小分子抑制诱导脊柱融合

• 批准号: 10367281
• 负责人: SCOTT D. BODEN
• 金额: $ 33.29万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-20 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367281
• 关键词: Address; Animals; BMP2 gene; Binding; Biocompatible Materials; Biological Assay; Bone Morphogenetic Proteins; Clinical; Collagen; Data; Dose; Drops; Engineering; Enzyme-Linked Immunosorbent Assay; Feedback; Formulation; Gene Expression Profiling; Glycolates; Harvest; Hematoma; Histologic; Histology; Hybrids; Implant; In Vitro; Inflammation; Inflammatory; Kinetics; Measures; Mechanics; Mediating; Minerals; Modeling; Nanostructures; Nerve; Operative Surgical Procedures; Oryctolagus cuniculus; Osteoblasts; Osteogenesis; Palpation; Plant Roots; Porifera; Procedures; Process; Production; Proteins; Rattus; Residual state; Safety; Scanning; Seroma; Signal Pathway; Signal Transduction; Site; Spinal Fusion; System; Testing; Time; Toxicology; Vascular Permeabilities; Vertebral column; Work; antagonist; bioscaffold; bone; bone morphogenetic protein receptors; collagen scaffold; design; extracellular; improved; in vivo; innovation; irritation; mineralization; new technology; novel; osteogenic; osteoprogenitor cell; pre-clinical; prevent; radiological imaging; receptor binding; recombinant human bone morphogenetic protein-2; recruit; response; scaffold; side effect; small molecule; small molecule inhibitor; soft tissue; spatiotemporal; spine bone structure; subcutaneous

Abstract This application proposes to address one of the major translational limitations of using Bone Morphogenetic Proteins (BMPs) for local bone induction in spine fusion. Since the FDA approval of recombinant human BMP- 2, it has consistently induced bone formation in widespread clinical use, but also has been associated with several local side effects including inflammation, vascular permeability, seromas, hematomas, and nerve root irritation. Our overall strategy is to locally inhibit the primary natural BMP antagonist, noggin, creating a BMP- privileged zone that allows for lower BMP levels to induce bone formation. We propose to engineer a hybrid scaffold combining a collagen sponge and a poly(lactic-co-glycolic acid) (PLGA) or a nanostructured mineral coating to deliver a novel small molecule that blocks noggin activity. In compelling preliminary data from rabbit spine fusion studies, we show a significant increase in noggin production in surrounding soft tissue, an auto- induction of local BMP-2 production in the fusion site, and a subsequent increase in noggin production in the fusion site. To blunt the noggin negative feedback loop, we computationally designed a novel Small Molecule Inhibitor (SMI) of noggin that blocks its binding to BMP-2 and enhances activity of exogenous and endogenous BMPs. To provide spatiotemporal control of the noggin SMI, we engineered a hybrid collagen scaffold with either a nanostructured mineral or a PLGA coating. This innovative noggin SMI strategy will allow lower BMP levels to locally induce bone formation through enhanced cellular responsiveness. We hypothesize that locally blocking the activity of noggin will disrupt/uncouple the negative feedback loop and allow the positive feedback loop to prevail, thereby resulting in greater signal amplification of BMP-2 within the delivery scaffold. We propose the following Specific Aims: Aim 1: To determine the noggin SMI to BMP-2 ratio and dose windows to maximize the positive and minimize the negative BMP feedback signaling loops in vitro and osteogenesis in vivo. Aim 2: To engineer a hybrid biomaterial delivery system to control spatial and temporal release of the noggin SMI to potentiate BMP-2 responsiveness. Aim 3: To demonstrate that a hybrid noggin SMI scaffold can lower the dose of BMP-2 required to produce spine fusion. The potential impact of a decreased BMP dose is substantial for improving the safety of activating the BMP signaling pathway for spinal fusion clinically.

摘要 该应用程序旨在解决使用骨形态发生技术的主要翻译限制之一 脊柱融合中局部骨诱导的蛋白质(BMPs)。自从FDA批准了重组人BMP- 2、它在临床上一直被广泛使用，但也与诱导骨形成有关 几种局部副作用，包括炎症、血管通透性、血清肿、血肿和神经根 令人恼火。我们的总体策略是局部抑制主要的天然BMP拮抗剂noggin，创建BMP- 允许较低的BMP水平诱导骨形成的特权区。我们计划设计一种混合动力车 胶原海绵与聚乳酸-乙醇酸(PLGA)或纳米结构矿物复合的支架 涂层以提供一种新型的小分子，阻止脑豆蛋白活性。在来自兔子的令人信服的初步数据中 脊柱融合研究表明，周围软组织中noggin的产生显著增加，这是一种自动- 在融合部位诱导局部BMP-2产生，并随后在融合部位增加noggin产量 聚变地点。为了钝化noggin负反馈回路，我们通过计算设计了一种新的小分子 Noggin的抑制剂(SMI)，阻断其与BMP-2的结合，并增强外源性和内源性的活性 BMPS。为了提供对noggin SMI的时空控制，我们设计了一种混合型胶原支架，其中 一种纳米结构的矿物或PLGA涂层。这一创新的noggin SMI战略将允许更低的BMP水平 局部通过增强细胞反应性诱导骨形成。我们假设局部阻塞 Noggin的活动将扰乱/分离负反馈环，并允许正反馈环 从而导致BMP-2在输送支架内的信号放大更大。我们建议 以下具体目标：目标1：确定noggin SMI与BMP-2的比率和剂量窗口，以最大化 在体外和体内成骨时，正性和最小化负性骨形态发生蛋白反馈信号环。目标2：实现 设计一种混合生物材料递送系统以控制noggin SMI的空间和时间释放 增强BMP-2的反应性。目的3：证明一种混合的noggin SMI支架可以降低剂量 产生脊柱融合所需的骨形态发生蛋白-2。减少BMP剂量的潜在影响对 提高临床激活BMP信号通路用于脊柱融合的安全性。