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: 10666349
• 负责人: SCOTT D. BODEN
• 金额: $ 33.08万
• 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/10666349
• 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; Euthanasia; 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; 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.

抽象的 该应用旨在解决使用骨形态发生的主要翻译限制之一 用于脊柱融合中局部骨诱导的蛋白质 (BMP)。自FDA批准重组人BMP以来 2、它在广泛的临床应用中始终诱导骨形成，但也与 一些局部副作用，包括炎症、血管通透性、血清肿、血肿和神经根 刺激。我们的总体策略是局部抑制主要的天然 BMP 拮抗剂 noggin，从而产生 BMP- 允许较低 BMP 水平诱导骨形成的特权区。我们建议设计一种混合动力 结合胶原海绵和聚乳酸乙醇酸 (PLGA) 或纳米结构矿物质的支架 涂层可传递一种新型小分子，阻止头蛋白活性。来自兔子的令人信服的初步数据 脊柱融合研究表明，周围软组织的头蛋白产量显着增加，这是一种自动 诱导融合位点局部 BMP-2 的产生，随后增加融合位点头蛋白的产生 融合位点。为了削弱头负反馈循环，我们通过计算设计了一种新颖的小分子 头蛋白抑制剂 (SMI)，阻断其与 BMP-2 的结合并增强外源性和内源性的活性 BMP。为了提供 noggin SMI 的时空控制，我们设计了一种混合胶原支架 纳米结构矿物或 PLGA 涂层。这种创新的 noggin SMI 策略将允许降低 BMP 水平 通过增强细胞反应性局部诱导骨形成。我们假设局部阻塞 noggin 的活动将破坏/解耦负反馈循环并允许正反馈循环 占优势，从而导致递送支架内 BMP-2 的信号放大更大。我们建议 具体目标如下： 目标 1：确定头 SMI 与 BMP-2 的比率和剂量窗口，以最大化 体外和体内成骨作用中的正反馈信号环路和最小化负反馈信号环路。目标 2： 设计混合生物材料输送系统来控制 noggin SMI 的空间和时间释放 增强 BMP-2 反应能力。目标 3：证明混合 noggin SMI 支架可以降低剂量 产生脊柱融合所需的 BMP-2。减少 BMP 剂量的潜在影响对于 提高临床上激活BMP信号通路进行脊柱融合的安全性。