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.

摘要 本申请提出解决使用骨形态发生学的主要翻译限制之一， 脊柱融合中用于局部骨诱导的骨形成蛋白。自从FDA批准重组人BMP-1以来， 2，它在广泛的临床应用中一直诱导骨形成，但也与 几种局部副作用，包括炎症、血管通透性、血清肿、血肿和神经根 过敏我们的总体策略是局部抑制主要的天然BMP拮抗剂，noggin，创造一个BMP- 这是一个特权区，允许较低的BMP水平诱导骨形成。我们打算设计一种混合动力车 结合胶原海绵和聚（乳酸-共-乙醇酸）（PLGA）或纳米结构矿物的支架 包被以递送阻断头蛋白活性的新型小分子。在令人信服的初步数据从兔子 脊柱融合研究中，我们发现周围软组织中noggin的产生显著增加， 在融合部位诱导局部BMP-2产生，随后在融合部位增加头蛋白产生。 融合点为了钝化noggin负反馈回路，我们通过计算设计了一种新型的小分子 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 BMP。为了提供对头蛋白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策略将允许较低的BMP水平， 通过增强的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/断开负反馈回路，并允许正反馈回路 因此导致递送支架内BMP-2的更大的信号放大。我们建议 以下具体目的：目的1：确定头蛋白SMI与BMP-2的比率和剂量窗，以最大化 在体外和体内成骨中，正性和最小化负性BMP反馈信号循环。目标2： 设计混合生物材料递送系统以控制头蛋白SMI的空间和时间释放， 增强BMP-2反应性。目的3：证明杂交头蛋白SMI支架可以降低剂量， 骨形态发生蛋白-2的合成。降低BMP剂量的潜在影响对于 提高了激活BMP信号通路用于脊柱融合临床的安全性。