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.

抽象的 该应用建议解决使用骨形态发生的主要翻译局限性之一 蛋白质（BMP）用于脊柱融合中的局部骨诱导。由于FDA批准重组人BMP- 2，它一直在广泛的临床用途中始终诱导骨形成，但也与 几种局部副作用，包括炎症，血管通透性，血清瘤，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，形成BMP- 特权区域允许较低的BMP水平诱导骨形成。我们建议设计混合动力 脚手架结合胶原蛋白海绵和聚乳糖 - 乙醇酸）（PLGA）或纳米结构矿物 涂层提供一种新型的小分子，可阻止Noggin活性。在引人入胜的兔子初步数据中 脊柱融合研究，我们显示了周围软组织的Noggin产生显着增加，这是自动的 在融合部位诱导局部BMP-2产生，随后Noggin的产生增加 融合网站。为了钝化Noggin负反馈循环，我们在计算上设计了一个新型的小分子 Noggin的抑制剂（SMI）阻断了其与BMP-2的结合并增强了外源性和内源性的活性 BMP。为了提供Noggin SMI的时空控制 纳米结构的矿物或PLGA涂层。这种创新的Noggin SMI策略将使BMP级别降低 通过增强的细胞反应能力，局部诱导骨形成。我们假设本地阻止 Noggin的活性将破坏/脱离负面反馈回路，并允许正反馈循环 盛行，从而导致递送支架内BMP-2的更大信号扩增。我们建议 以下特定目的：目标1：确定Noggin SMI与BMP-2比率和剂量窗口以最大化 阳性并最大程度地减少了体内体外和成骨的负反馈信号回路。目标2：到 工程师一种混合生物材料输送系统，以控制Noggin SMI的空间和时间释放 增强BMP-2响应能力。目的3：证明混合型noggin smi脚手架可以降低剂量 产生脊柱融合所需的BMP-2。降低BMP剂量的潜在影响对于 提高激活BMP信号通路的安全性在临床上。