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Histone targeted non-viral gene delivery to enhance bone repair

组蛋白靶向非病毒基因传递以增强骨修复

基本信息

批准号：
9229553
负责人：
Millicent O Sullivan
金额：
$ 34.98万
依托单位：
UNIVERSITY OF DELAWARE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9229553
关键词：
Address Area BMP2 gene Binding Biocompatible Materials Biology Bone Injury Bone Regeneration Bone Transplantation Cations Cell Differentiation process Cells Chemistry Chromatin Clinical Clinical Research Complex Coupled DNA DNA Binding Defect Development Exhibits Fostering Fracture Gene Delivery Gene Expression Gene Targeting Gene Transfer Genes Genetic Transcription Goals Growth Factor Growth Factor Gene Health Heterotopic Ossification Histones Image Image Analysis Implant In Situ In Vitro Individual Knowledge Letters Link Mediating Mediation Mesenchymal Differentiation Mesenchymal Stem Cells Methods Modeling Monitor Mus Mutagenesis Natural regeneration Nature Nuclear Operative Surgical Procedures Orthopedics Osteogenesis Outcome Pathway interactions Peptides Physiologic Ossification Post-Translational Protein Processing Process Production Productivity Proteins Publishing Rattus Regulator Genes Reporting Role Safety Speed Structure System Tail Testing Therapeutic Tissue Engineering Transfection Translations Viral Viral Genes base biomaterial compatibility bone bone healing bone morphogenetic protein 2 clinical efficacy combinatorial controlled release cost design economic cost gene delivery system gene product gene therapy healing imaging potential immunogenicity improved in vivo insight interest mimetics nanoGold nanoparticle new technology non-viral gene delivery novel osteogenic plasmid DNA public health relevance release factor repaired scaffold self assembly spatiotemporal success tissue repair trafficking uptake viral gene delivery

项目摘要

DESCRIPTION (provided by applicant): Large segmental bone defects are a persistent clinical challenge that poses significant economic costs as well as costs to individual health and societal productivity. Limitations in bone grafting emphasize the need for alternative strategies. Accordingly, a myriad of therapeutic approaches have been explored to address this health problem, including the direct delivery of growth factors and delivery of viral growth factor gene therapies. While these approaches have improved healing outcomes, they have not been widely employed clinically, owing at least in part to limited protein stability (direct delivery) and safey concerns (viral gene therapies). Non-viral strategies to induce efficient, cell-mediated production of growth factors would offer a provocative approach to overcome these difficulties. We propose to address these challenges through the development of new, histone-targeted gene transfer scaffolds with tunable DNA binding and controllable gene delivery. The display of histone motifs on nanoparticle scaffolds (e.g. nanogold) will capitalize on our preliminary studies proving that post-translationally modified histone tails promote nuclear accumulation, DNA release, transcription, and enhanced transfection by non-viral vehicles. Additionally, our approach builds on established advantages of nanogold, including imaging potential, biocompatibility, functionalizability, and cell entry capacity. The novel presentation of histone tails on nanogold should mimic the native, multifaceted display and functionality of these sequences on the histone octamer. Hence, these new scaffolds should provide additional important, yet unexplored, benefits for controlling and understanding gene packaging, trafficking, and release through enhanced utilization of native gene transfer and trafficking pathways. Accordingly, the goal of this proposal is to create and optimize multifunctional "designer" histones to induce efficient gene transfer, and ultimately, enable improved tissue repair for orthopedics and other applications. We will produce nanogold-plasmid DNA (pDNA) assemblies, and will determine whether the multivalent presentation of pDNA-binding residues and histone peptides enhances pDNA-binding stability and improves transfection. We will capitalize on traditional as well as nanogold-specific imaging analyses to elucidate key steps in non-viral gene transfer, and will clearly link enhanced gene transfer efficiency to improved osteogenic potential of growth factors such as bone morphogenetic protein-2 (BMP-2). Finally, we will use murine and rat orthopedic models to test the ability of the BMP-2 gene product to enhance bone formation and increase the speed and efficacy of defect repair. Our approaches will not only elucidate mechanistic details about the trafficking of histone-associated genes, but will also ultimately will be useful as a general biomaterials platform applicable to bone repair, implant functionalization, and tissue engineering.

描述（由申请人提供）：大节段性骨缺损是一个持续的临床挑战，它带来了巨大的经济成本，以及对个人健康和社会生产力的成本。骨移植的局限性强调了对替代策略的需求。因此，已经探索了无数的治疗方法来解决这一健康问题，包括直接递送生长因子和递送病毒生长因子基因疗法。虽然这些方法改善了愈合效果，但它们尚未在临床上广泛应用，至少部分原因是蛋白质稳定性有限（直接递送）和安全性问题（病毒基因疗法）。非病毒策略诱导高效，细胞介导生产