SBIR Phase I: Development Of An Orally Administered Gene Delivery Platform For Induced Protein Secretion Via The Gastrointestinal Tract

SBIR 第一阶段：开发口服基因传递平台，用于通过胃肠道诱导蛋白质分泌

• 批准号: 1846078
• 负责人: Timothy Day
• 金额: $ 22.47万
• 依托单位: DNALITE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1846078&HistoricalAwards=false
• 关键词: SBIR; Phase; Development; Orally; Administered

This SBIR Phase I project will further the development of an orally administered gene delivery vehicle called the Crypt-Reaching Particle (CRP) that is able to overcome the physical barriers of the mucus to deliver DNA-based drugs to the cells of the gastrointestinal tract. The therapeutic agent will then be expressed as a protein locally in the gastrointestinal tract or be secreted into the bloodstream to treat the full body. Development of this vehicle will lead to novel scientific insights on DNA delivery that will benefit and educate the field of fundamental science and engineering. Successful commercialization would benefit pharmaceutical companies by providing an oral drug delivery platform for approved and novel drugs, U.S. patients by reducing the need for injectable drugs and thereby increasing compliance and quality of life, and payers by reducing costs associated with injectable drugs and improving outcomes by increasing patient compliance via oral administration. The drug-agnostic feature provides broad and diverse market opportunities within the rapidly expanding market for biologics, among other therapeutic agents leading to substantial job creation. As an example, a potential addressable market in four areas (i.e., delivering TNF inhibitors, protein replacement, peptide hormones, and blood factors) exceeds $90 billion per year.This project is designed to prepare a stable oral formulation of the Crypt-Reaching Particle (CRP), a novel drug-agnostic drug delivery vehicle, and demonstrate that it can deliver a functional DNA cargo for expression and secretion in intestinal epithelial cells in vitro and in vivo. This project focuses on the technical challenges associated with preserving the functionality of a DNA cargo as an example of a challenging drug delivery scenario that is difficult to replicate. The innovation is the design of the vehicle to penetrate through the mucus and transfect underlying epithelial cells by mimicking the enteric poliovirus. This will lay the foundation for the first oral gene therapy. Briefly, the project will address three objectives. First, preparation of a formulation for the CRP for oral administration via lyophilization with analyses to assess formulation and DNA stability as a function of time, temperature, and pH. Second, testing the ability of the orally formulated CRP to deliver a functional DNA plasmid encoding Gaussia luciferase to Caco-2 intestinal epithelial cells in vitro by measuring both cellular and secreted expression. Finally, testing the ability of the orally formulated and administered CRP to deliver a functional Gaussia luciferase plasmid to intestinal epithelial cells in vivo in Fischer 344 rats to assess expression and secretion.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该 SBIR 第一阶段项目将进一步开发一种名为隐窝颗粒 (CRP) 的口服基因递送载体，该载体能够克服粘液的物理障碍，将基于 DNA 的药物递送至胃肠道细胞。然后治疗剂将在胃肠道中局部表达为蛋白质或分泌到血流中以治疗全身。这种载体的开发将带来关于 DNA 传递的新颖的科学见解，这将有利于基础科学和工程领域并对其进行教育。成功的商业化将为制药公司带来好处，为已批准的新药提供口服给药平台，使美国患者受益，减少对注射药物的需求，从而提高依从性和生活质量，使付款人受益，减少与注射药物相关的成本，并通过以下方式改善结果：通过口服给药提高患者的依从性。与药物无关的特征在快速扩张的生物制剂市场以及其他治疗药物市场中提供了广泛且多样化的市场机会，从而创造了大量就业机会。例如，四个领域（即肿瘤坏死因子抑制剂、蛋白质替代品、肽激素和血液因子）的潜在潜在市场每年超过 900 亿美元。该项目旨在制备一种稳定的到达隐窝颗粒的口服制剂(CRP)，一种新型的药物不可知药物递送载体，并证明它可以递送功能性 DNA 货物，以便在体外和体内肠上皮细胞中表达和分泌。该项目重点关注与保留 DNA 货物功能相关的技术挑战，作为难以复制的具有挑战性的药物输送场景的示例。这项创新是通过模拟肠道脊髓灰质炎病毒来穿透粘液并转染下面的上皮细胞的载体设计。这将为第一个口服基因疗法奠定基础。简而言之，该项目将实现三个目标。首先，通过冻干制备用于口服给药的 CRP 制剂，并进行分析以评估制剂和 DNA 稳定性随时间、温度和 pH 的变化。其次，通过测量细胞和分泌的表达，测试口服配制的 CRP 在体外将编码 Gaussia 荧光素酶的功能性 DNA 质粒递送至 Caco-2 肠上皮细胞的能力。最后，在 Fischer 344 大鼠体内测试口服配制和施用的 CRP 将功能性 Gaussia 荧光素酶质粒递送至肠上皮细胞的能力，以评估表达和分泌。该奖项反映了 NSF 的法定使命，并通过评估认为值得支持利用基金会的智力优势和更广泛的影响审查标准。