Click Chemistry for Immobilized Bone Morphogenetic Protein

固定化骨形态发生蛋白的点击化学

• 批准号: 7570694
• 负责人: Shrikumar Ambujakshan Nair
• 金额: $ 113.51万
• 依托单位: AFFINERGY ,INC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7570694
• 关键词: Address; Affinity; Allografting; Amino Acids; Animal Model; Autologous Transplantation; Binding; Biocompatible Materials; Biological; Biological Assay; Biology; Bone Morphogenetic Proteins; Bone Regeneration; Bone Transplantation; Caring; Chemistry; Collagen; Coupling; Data; Defect; Dose; Frequencies; Generations; Goals; Growth Factor; Harvest; Hydroxyapatites; Implant; Laboratories; Lateral; Length; Libraries; Liquid substance; Mediating; Medical; Medical Device; Methods; Operative Surgical Procedures; Oryctolagus cuniculus; Osteogenesis; Outcome; Pain; Patients; Peptide Synthesis; Peptides; Phase; Phase I Clinical Trials; Porifera; Procedures; Recombinant Growth Factor; Recombinant Proteins; Recombinants; S Phase; Services; Side; Signaling Molecule; Solid; Specificity; Spinal Fusion; Sterilization for infection control; System; Techniques; Technology; Testing; Therapeutic; Therapeutic Effect; Tissues; Transplanted tissue; base; biomaterial compatibility; bone; bone healing; bone morphogenetic protein 2; combinatorial; commercialization; cost; cycloaddition; design; dosage; extracellular; high throughput screening; implant material; improved; in vitro activity; in vivo; interfacial; medical implant; novel therapeutic intervention; programs; protein aminoacid sequence; prototype; tricalcium phosphate

DESCRIPTION (provided by applicant): Growth factors are potent signaling molecules, initiating essential cellular programs for differentiation, proliferation and survival. Only recently have large molecules like growth factors, been employed to enhance the efficacy and specificity of medical implant therapies. In particular, procedures that require native tissues to interact with an implanted material stand to benefit from inclusion of growth factors. A successful merger at the interface between technology and biology is generally predictive of subsequent therapeutic outcome. Affinergy Inc., has developed bifunctional peptide linkers, called interfacial biomaterials (IFBMs) that help promote biology at the critical interface between a synthetic and a biologic. Attaching one peptide designed to bind a growth factor, to another peptide designed to bind a medical device, offers a simple and target-specific therapeutic strategy. In addition, our modular approach allows interchangeability of peptide halves , to produce a combinatorial array of potential bifunctional IFBMs. Currently we chemically synthesize our peptides as one continuous sequence. This approach presents significant challenges, as coupling efficiency of solid-phase peptide synthesis decreases dramatically as chain length approaches 30 residues. We proposed a Phase I study, exploring the use of [3 + 2] cycloaddition or click chemistry to prepare IFBMs. This method takes advantage of our modular approach and allows for higher total yields through the coupling of shorter peptides (<25 mers). Additionally, selective coupling in the presence of unprotected amino acid side chains enables high-throughput screening capabilities of completed IFBM libraries. We have generated two IFBMs which bind a resorbable collagen sponge and a bone morphogenetic protein (BMP); one using click chemistry and one using traditional solid-phase synthesis. In our Phase I studies, we found nearly identical biostability and in vitro activity of IFBMs made with both synthesis techniques. Successful completion of these aims has encouraged us to expand our IFBM technology to other growth factors and bone graft materials. Our goal in Phase II is to optimize click chemistry for IFBM manufacturing, examine the biocompatibility, storage, and sterilization of prototype IFBMs, and test their efficacy in vivo. Affinergy's IFBM technology is designed to improve growth factor therapy in three potential ways: 1) promoting the sustained release of BMP from existing carriers; 2) reducing the supraphysiological amounts of recombinant growth factor required to provide the desired therapeutic effect and 2) capturing and concentrating endogenous molecules from the extracellular milieu, potential decreasing or eliminating the requirement for recombinant protein.Project Narrative Bone grafts currently take one of three forms, which include autograft (typically harvested from the patient's iliac crest) allograft (cadaveric bone) and synthetics (helistat sponge, hydroxyapatite or tricalcium phosphate). Autografts harbor all the endogenous biological capacity for bone regeneration, but represent a painful additional surgical step. Allograft and synthetics require no such secondary procedure, but have limited or no osteoinductive capabilities. Our goal is to therefore merge the benefits of both grafts, by adding a growth factor binding peptide coating to collagen-based bone grafts. We envision this technology as a means of reducing the dosage of expensive growth factors, while removing the pain and potential complications associated with bone harvesting. This technology is likely most applicable to intervertebral and posterior lateral spinal fusion, procedures growing in frequency and known to benefit from osteoinductive growth factors. With over 45,000 spinal fusion surgeries performed each year, the demand for improved technique, care and cost is unlikely to be soon assuaged.

描述（由申请人提供）：生长因子是有效的信号分子，启动了分化，增殖和生存的基本细胞程序。直到最近才有大分子（例如生长因子）来增强医疗植入物疗法的功效和特异性。特别是，需要天然组织与植入物质架相互作用的程序受益于生长因子的包含。技术与生物学之间的界面成功合并通常可以预测随后的治疗结果。 Affinergy Inc.开发了双功能肽接头，称为界面生物材料（IFBMS），可在合成和生物学之间的关键接口上促进生物学。将一种旨在结合生长因子结合的肽连接到旨在结合医疗装置的另一个肽上，提供了一种简单而特定的治疗策略。此外，我们的模块化方法允许肽一半的互换性产生潜在的双功能IFBM的组合阵列。目前，我们将肽化学合成为一个连续序列。这种方法提出了重大挑战，因为随着链长接近30个残基，固相肽合成的耦合效率会急剧下降。我们提出了一项I期研究，探讨了[3 + 2]环加成的使用或单击化学准备IFBM。该方法利用了我们的模块化方法，并通过较短的肽（<25 mers）的耦合来允许更高的总产率。此外，在没有保护的氨基酸侧链存在下选择性耦合可以使完整的IFBM库的高通量筛选能力。我们已经产生了两个结合可吸收胶原海绵和骨形态发生蛋白（BMP）的IFBM。一种使用点击化学，一种使用传统的固相合成。在我们的第一阶段研究中，我们发现了使用这两种合成技术制成的IFBM的生物稳定性和体外活性。这些目标的成功完成鼓励我们将IFBM技术扩展到其他生长因素和骨移植材料。我们在第二阶段中的目标是优化IFBM制造的点击化学，检查原型IFBM的生物相容性，存储和灭菌，并在体内测试其功效。 Affinergy的IFBM技术旨在通过三种潜在的方式改善生长因素疗法：1）促进BMP从现有载体中持续释放； 2）减少提供所需治疗效果所需的重组生长因子的超生理量，2）从细胞外环境中捕获和浓缩内源分子，潜在的降低或消除重组蛋白质的要求。 目前，骨移植物采用三种形式之一，其中包括自体移植（通常是从患者的iac rest收获）同种异体移植物（尸体骨）和合成（螺旋海绵，羟基磷灰石或磷酸三氯）。自体移植具有内源性生物学能力的骨再生能力，但代表了痛苦的额外手术步骤。同种异体移植物和合成剂不需要这种次要程序，但具有有限或没有骨诱导能力。因此，我们的目标是通过在基于胶原蛋白的骨移植物中添加生长因子结合肽涂层来合并两个移植物的益处。我们设想这项技术是减少昂贵生长因子剂量的一种手段，同时消除了与骨骼收获相关的疼痛和潜在并发症。该技术可能最适用于椎间盘和后侧脊柱融合，频率生长的过程，并已知可从骨诱导生长因子中受益。每年进行超过45,000次脊柱融合手术，对技术，护理和成本的需求不太可能很快得到缓解。