Targeted nanoparticle gene therapy for lung cancer

肺癌靶向纳米颗粒基因治疗

• 批准号: 8374329
• 负责人: Taneli Jouhikainen
• 金额: $ 19.04万
• 依托单位: SAVARA, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8374329
• 关键词: Acute; Adverse effects; Angiotensin II; Animals; Apoptosis Promoter; Attenuated; Biological Models; Bolus Infusion; Calcium; Cancer Cell Growth; Cancer Model; Cancer cell line; Cell Culture Techniques; Cell Death; Cells; Cellular Membrane; Chronic; DNA; Data; Dosage Forms; Drug Formulations; Epithelial Cells; Fibroblasts; Foundations; Future; Gene Expression; Gene Mutation; Genes; Genome; Gold; Growth; Histologic; Human; Immune response; Inflammation; Intravenous; K-ras Gene; Kansas; Lewis Lung Carcinoma; Licensing; Lung; Lung Adenocarcinoma; Lung diseases; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Monitor; Morbidity - disease rate; Mus; Non-Small-Cell Lung Carcinoma; Normal tissue morphology; Nucleic Acids; Oncogenes; Outcome; Particle Size; Peptides; Pharmacologic Substance; Phase; Population; Powder dose form; Production; RNA; Receptor Gene; Research; Route; Safety; Serum; Side; Small Interfering RNA; Solid; Stem cells; Suspension substance; Suspensions; System; TNF-related apoptosis-inducing ligand; Technology; Therapeutic; Tissues; Tobacco-Associated Carcinogen; Toxic effect; Transfection; Translational Research; Translations; Tumor Burden; Tumor Suppressor Genes; Tumor Tissue; Type 2 Angiotensin II Receptor; Universities; Viral Genes; Viral Vector; attenuation; base; cancer cell; cancer stem cell; cancer therapy; commercialization; cytotoxicity; design; dosage; drug development; gene delivery system; gene therapy; in vivo; innovation; intravenous administration; intravenous injection; lung Carcinoma; mortality; mouse model; nanoparticle; novel; particle; programs; public health relevance; reconstitution; research study; safety study; success; therapeutic gene; translational study; treatment effect; treatment strategy; tumor; tumor growth; vector

DESCRIPTION (provided by applicant): Project Summary A transformational NanoNucleic delivery technology is being investigated by Savara Inc. as a promising first-in-class gene therapy candidate for lung cancer. A potent lung cancer therapy with fewer side effects is urgently needed due to the exceptionally high rates of morbidity and mortality of this particular cancer. Gene therapy, while promising, remains clinically unsuccessful, mainly due to insufficient therapeutic gene expression in cancer tissues, and adverse effects of the delivery vectors. Recently, a novel nanoparticle technology for nucleic acid delivery ("NanoNucleic" technology) was developed at the University of Kansas, and licensed exclusively to Savara Inc, a drug development company specializing in the treatment of lung diseases. The NanoNucleic technology comprises a cationic peptide bundled with DNA (or RNA for siRNA delivery), and condensed by calcium into small nanoparticles (75-100 nm). Using the NanoNucleic technology, high local expression of endogenous apoptosis inducer genes (TRAIL and angiotensin II type 2 receptor (AT2R)) was achieved in the lungs of mice. Over-expression of either gene induced marked cell death in several human lung cancer cell lines in culture, but the effect on normal lung epithelial cells or fibroblasts was minimal. AT2R over-expression also induced significant cell death in lung cancer progenitor cells in culture. After administering an intratracheal spray o AT2R or TRAIL genes as NanoNucleic formulations to LLC mice, gene expression lasted at least two weeks. Observations of the treated lungs revealed a remarkable reduction in tumor burden, without any signs of toxicity toward the native tissue, nor signs of inflammation. Unlike viral vector-based gene therapy, NanoNucleic gene therapy is expected to generate minimal host immune response and none of the viral gene- associated drawbacks such as gene mutations or the production of oncogenes via random insertion into the genome. The aim of the proposed research is to provide therapeutic proof-of- concept of an optimized form of NanoNucleic gene therapy approach using two different therapeutic gene candidates (AT2R, and TRAIL) in two different in vivo lung cancer models. NanoNucleic formulations will be administered intratracheally, with or without complementary intravenous administration. The strong preliminary data in the mouse LLC model suggest a high likelihood of success in this proposed Phase I research. Successful completion of the Phase I will enable advancement of the program into efficacy studies using K-ras gene mutation- and tobacco carcinogen-induced lung cancer models, as well as chronic safety studies in larger animals, and thereby build a solid foundation for eventual translational research.

描述（由申请人提供）：项目总结Savara Inc.正在研究一种变革性的NanoNucleic递送技术。作为一个有前途的一流的肺癌基因治疗候选人。由于肺癌的发病率和死亡率非常高，因此迫切需要一种副作用较少的有效肺癌治疗方法。基因治疗虽然有希望，但在临床上仍然不成功，主要是由于癌症组织中治疗性基因表达不足以及递送载体的不良作用。最近，堪萨斯大学开发了一种用于核酸递送的新型纳米颗粒技术（“NanoNucleic”技术），并独家授权给Savara Inc，一家专门治疗肺部疾病的药物开发公司。NanoNucleic技术包括与DNA（或用于siRNA递送的RNA）捆绑的阳离子肽，并通过钙凝聚成小纳米颗粒（75-100 nm）。使用NanoNucleic技术，在小鼠肺中实现内源性凋亡诱导基因（TRAIL和血管紧张素II 2型受体（AT 2 R））的高局部表达。在培养的几种人肺癌细胞系中，两种基因的过度表达都诱导了显著的细胞死亡，但对正常肺上皮细胞或成纤维细胞的影响很小。AT 2 R过表达也诱导培养的肺癌祖细胞中显著的细胞死亡。在向LLC小鼠施用作为NanoNucleic制剂的AT 2 R或TRAIL基因的气管内喷雾后，基因表达持续至少两周。经处理的肺的观察结果显示肿瘤负荷显著降低，对天然组织没有任何毒性迹象，也没有炎症迹象。与基于病毒载体的基因治疗不同，NanoNucleic基因治疗预计将产生最小的宿主免疫应答，并且不会产生病毒基因相关的缺点，例如基因突变或通过随机插入基因组产生致癌基因。这项研究的目的是提供一种优化形式的NanoNucleic基因治疗方法的治疗概念验证，该方法在两种不同的体内肺癌模型中使用两种不同的候选治疗基因（AT 2 R和TRAIL）。NanoNucleic制剂将在有或没有补充静脉内给药的情况下进行血管内给药。小鼠LLC模型中强有力的初步数据表明，这项拟议的I期研究成功的可能性很高。第一阶段的成功完成将使该项目能够推进到使用K-ras基因突变和烟草致癌物诱导的肺癌模型的疗效研究，以及大型动物的慢性安全性研究，从而为最终的转化研究奠定坚实的基础。