International Research Fellowship Program: Systematic Design and Evaluation of Synthetic Virus-like Particles for Gene Delivery: Overcoming Barriers for In Vitro

国际研究奖学金计划：用于基因传递的合成病毒样颗粒的系统设计和评估：克服体外障碍

• 批准号: 0401542
• 负责人: Ayesha Ahmad
• 金额: $ 8.4万
• 依托单位: Ahmad, Ayesha
• 依托单位国家: 美国
• 项目类别: Fellowship Award
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0401542&HistoricalAwards=false
• 关键词: International; Research; Fellowship; Program; Systematic

0401542AhmadThe International Research Fellowship Program enables U.S. scientists and engineers to conduct three to twenty-four months of research abroad. The program's awards provide opportunities for joint research, and the use of unique or complementary facilities, expertise and experimental conditions abroad.This award will support a twenty-two-month research fellowship by Dr. Ayesha Ahmad to work with Dr. Andrew Miller at Imperial College in London, United Kingdom.Gene Therapy refers to the process of curing inherited and acquired diseases by adding, replacing, or correcting genes through the introduction of foreign DNA. A viable vector has to be able to, among other things, package the DNA, deliver the DNA to the cell, and release the DNA into the nucleus thereby allowing the cell to use its machinery to express the therapeutic protein. Biological methods, chemical methods, and physical methods, are all currently being used, with their various advantages and disadvantages, in the development of this field. This proposal focuses on using chemical or synthetic methods, which have attracted considerable attention due to their inherent advantages including ease of production, lack of immunogenic response, and variable preparation. Despite their advantages over viral-based gene delivery systems, synthetic gene delivery systems have met with limited success. Although there is an abundance of and variation in synthetic vectors, a full characterization and understanding of the interactions and processes that occur at the many different steps of the gene delivery course is lacking. Several biological barriers have been identified that impede the path of non-viral vectors at several steps in the gene delivery process. The key to improving non-viral delivery systems is to identify the interactions that occur between the synthetic DNA complexes and the cells at these various barriers. This allows directed alteration and optimization of vector structure and complex formulations to overcome the various biological impediments and barriers the complex encounters. At the Imperial College Genetics Therapy Centre, researchers have developed a synthetic non-viral vector platform system known as liposome:mu:DNA (LMD). The LMD system is a ternary LD system built around the ? (mu) peptide associated with the condensed core complex of the adenovirus. LMD systems are not considered an end in themselves but represent a firm platform on which to build clinically viable synthetic non-viral vector systems in the future. LMD represents a well-characterized, well-understood transfection vehicle constructed from a primary tool-kit of well-defined chemical components. Given this firm foundation, the next generation of LMD systems, LMDII, will now be developed in a sequential and logical fashion for clinical readiness by making modular adaptations to this primary vehicle using new secondary tool-kits comprised of supplementary sets of chemical components. The proposed research program is considered the only systematic way to reach a clinically viable non-viral gene therapy vector. The need to merge physicochemical - cellular biology - pharmaceutical characterization of the novel virus-like nanoparticles, is critical in terms of developing non-viral gene therapy vectors, therefore offering clinically viable alternatives to the effective, yet precarious, viral vectors predominantly employed in clinical trials today.

0401542艾哈迈德国际研究奖学金计划使美国科学家和工程师能够在国外进行三到二十四个月的研究。 该计划的奖项提供了联合研究的机会，以及使用国外独特或互补的设施，专业知识和实验条件。该奖项将支持Ayesha Ahmad博士与英国伦敦帝国理工学院的Andrew米勒博士合作进行为期22个月的研究奖学金。基因治疗是指通过添加，替换，或通过引入外源DNA来纠正基因。 一个有活力的载体必须能够包装DNA，将DNA递送到细胞中，并将DNA释放到细胞核中，从而允许细胞使用其机制来表达治疗性蛋白。生物学方法、化学方法和物理方法都是目前正在使用的方法，它们具有各种优点和缺点，在该领域的发展中。该提案侧重于使用化学或合成方法，由于其固有的优点，包括易于生产，缺乏免疫原性反应和可变的制备，这些方法引起了相当大的关注。尽管它们优于基于病毒的基因递送系统，但合成基因递送系统取得了有限的成功。尽管合成载体的种类繁多，但缺乏对基因传递过程中许多不同步骤中发生的相互作用和过程的全面表征和理解。已经确定了在基因递送过程的几个步骤中阻碍非病毒载体路径的几种生物屏障。改进非病毒递送系统的关键是鉴定合成DNA复合物和细胞之间在这些不同屏障处发生的相互作用。这允许载体结构和复合物制剂的定向改变和优化，以克服复合物遇到的各种生物学障碍和屏障。 在帝国理工学院遗传治疗中心，研究人员开发了一种合成的非病毒载体平台系统，称为脂质体：μ：DNA（LMD）。该LMD系统是一个三元LD系统围绕？(mu)与腺病毒的浓缩核心复合物相关的肽。LMD系统本身并不被认为是目的，但代表了一个坚实的平台，在此基础上建立临床可行的合成非病毒载体系统在未来。LMD代表了一种充分表征、充分理解的转染载体，其由明确定义的化学组分的主要工具包构建。 鉴于这一坚实的基础，下一代LMD系统，LMDII，现在将开发一个顺序和逻辑的方式，临床准备，使模块化的适应这一主要车辆使用新的辅助工具包组成的补充套化学成分。 拟议的研究计划被认为是唯一系统的方法，以达到临床可行的非病毒基因治疗载体。需要合并新型病毒样纳米颗粒的物理化学-细胞生物学-药物表征，这在开发非病毒基因治疗载体方面是至关重要的，因此为当今临床试验中主要采用的有效但不稳定的病毒载体提供了临床可行的替代方案。