Reconstituted High Density Lipoprotein Particles as siRNA Carriers

重组高密度脂蛋白颗粒作为 siRNA 载体

• 批准号: 9347763
• 负责人: Dev Kumar Chatterjee
• 金额: $ 32.46万
• 依托单位: FANNIN PARTNERS, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9347763
• 关键词: Adoption; Animal Cancer Model; Animal Model; Antineoplastic Agents; Apoptosis; Blood Circulation; Bolus Infusion; Cell Proliferation; Characteristics; Chemistry; Clinical; Data; Development; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Excretory function; Foundations; Funding; Gene Targeting; Genes; Genetic Materials; Grant; Growth; Half-Life; High Density Lipoproteins; Innovative Therapy; Kinetics; Legal patent; Lipoproteins; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Metabolism; Methodology; Modeling; Mus; Neoplasm Metastasis; Nobel Prize; Oncogenes; Pathway interactions; Peer Review; Pharmaceutical Preparations; Phase; Physiological; Process; Production; Publications; Publishing; RNA Interference; Request for Proposals; Research; Route; Scientist; Small Interfering RNA; Technology; Therapeutic; Time; Tissues; Toxic effect; Toxicology; Tumor Burden; absorption; cancer cell; cancer therapy; clinical application; clinical development; commercialization; drug development; expectation; experimental study; falls; gene therapy; immunogenicity; improved; in vivo; innovation; meetings; novel; novel therapeutics; overexpression; particle; preclinical development; receptor; reconstitution; residence; survival outcome; targeted treatment; therapeutic siRNA; tool; tumor; tumor growth; tumorigenesis; uptake

Project Summary Since the discovery of the Nobel prize-winning mechanism of RNA interference (RNAi) ten years ago, it has become a promising drug target for the treatment of multiple diseases, including cancer. However, significant barriers still exist on the road to clinical applications of siRNA drugs, including poor cellular uptake, instability under physiological conditions, off-target effects and possible immunogenicity. The successful application of siRNA for cancer therapy requires the development of clinically suitable, safe and effective drug delivery systems. We are developing a novel therapeutic strategy for this cancer by harnessing the power of the body’s natural lipoproteins to deliver siRNA specifically to cancer cells that inhibits tumor growth. These siRNA interfere with processes critical to tumorigenesis and metastasis, and offer the potential to reverse poor survival outcomes. Further, inhibition of this gene results in increased tumor apoptosis, which could be leveraged to reduce tumor burden. Here, we present a novel mechanism to deliver the therapeutic siRNA to cancer cells using a reconstituted version of the body’s natural high density lipoprotein (rHDL). This lipoprotein has a long circulating half-life and targets the SR-B1 receptor, which is over-expressed in most types of ovarian cancer cells. Our in vivo experiments demonstrate siRNA/rHDL targets ovarian cancer through the SR-B1 receptor. It also reduces the tumor burden in orthotopic animal models of cancer. The technology has been granted a patent, as well as published in a top-tier peer-reviewed publication. Fannin Partners is a privately held early stage biomedical commercialization company dedicated to the advancement of innovative therapies in early pre-clinical development. The current innovation is the direct result of ground-breaking research conducted by the scientific team of Dr. Andres Lacko and Dr. Anil Sood. Both the original inventors will be directly involved in the development of the drug. The focus of this proposal is to accomplish key milestones that will further transition this cancer therapy technology to commercialization by optimizing manufacturing parameters, measuring distribution to other tissues, metabolism, and elimination, and also give a better understanding of potential toxicities.

项目摘要 自从十年前发现了获得诺贝尔奖的RNA干扰机制以来， 成为治疗包括癌症在内的多种疾病的有前途的药物靶点。然而，重要的 在siRNA药物的临床应用道路上仍然存在障碍，包括细胞摄取差，不稳定性， 在生理条件下，脱靶效应和可能的免疫原性。的成功应用 用于癌症治疗的siRNA需要开发临床上合适的、安全的和有效的药物递送 系统. 我们正在为这种癌症开发一种新的治疗策略，通过利用身体的自然力量， 脂蛋白，将siRNA特异性地递送到癌细胞，抑制肿瘤生长。这些siRNA干扰 这些过程对肿瘤发生和转移至关重要，并提供了逆转不良生存结局的潜力。 此外，该基因的抑制导致肿瘤细胞凋亡增加，这可以用来减少肿瘤细胞凋亡。 负担 在这里，我们提出了一种新的机制，使用重组的siRNA将治疗性siRNA递送到癌细胞， 高密度脂蛋白（HDL）是人体的天然高密度脂蛋白（rHDL）。这种脂蛋白具有较长的循环半衰期， 靶向SR-B1受体，该受体在大多数类型的卵巢癌细胞中过度表达。我们的体内 实验证明siRNA/rHDL通过SR-B1受体靶向卵巢癌。也会减少 原位癌症动物模型中的肿瘤负荷。该技术已获得专利， 发表在顶级同行评审刊物上 Fannin Partners是一家私人控股的早期生物医学商业化公司，致力于 在早期临床前开发中推进创新疗法。目前的创新是直接的 Andres拉科博士和Anil Sood博士的科学团队进行的突破性研究的结果。 这两位原发明者都将直接参与药物的开发。 该提案的重点是实现进一步转变这种癌症治疗的关键里程碑 通过优化制造参数，测量分布到其他 组织、代谢和消除，并更好地了解潜在的毒性。