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Novel bioengineered microRNA therapeutics for lung cancer

新型生物工程 microRNA 疗法治疗肺癌

基本信息

批准号：
10304850
负责人：
Aiming Yu
金额：
$ 34.28万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304850
关键词：
Accounting Adverse effects Biologic Development Biological Biological Models Biomedical Engineering Blood Blood Chemical Analysis Cancer Etiology Cancer cell line Cancerous Cell Proliferation Cell physiology Cells Cessation of life Chemical Engineering Development Disease Drug Kinetics Effectiveness Encapsulated Endotoxins Engineering Escherichia coli Excretory function Exhibits Foundations Gene Expression Goals Human Hybrids Immune response Immunocompetent Kidney Liposomes Malignant Neoplasms Malignant neoplasm of lung Metabolic Methods MicroRNAs Modification Molecular Mus Non-Small-Cell Lung Carcinoma Nonmetastatic Oligoribonucleotides Oncogenic Peripheral Blood Mononuclear Cell Pharmacologic Actions Phase I Clinical Trials Polynucleotides Prodrugs Production Property Proteins Proteome RNA Regulation Research Ribonucleases STAT3 gene Safety Serious Adverse Event Serum Solid Structure of parenchyma of lung Techniques Technology Testing Therapeutic Transfer RNA United States Untranslated RNA Woman Xenograft procedure antagonist base body system chemical synthesis combat cost effective cytokine cytokine release syndrome high risk immunogenicity improved in vivo innovation insight interest large scale production lung cancer cell men microRNA replacement therapy milligram mouse model nanotherapeutic new technology novel novel strategies novel therapeutic intervention novel therapeutics overexpression patient derived xenograft model polypeptide pre-miRNA research and development restoration stemness success tRNA Precursor therapeutic RNA therapeutic miRNA therapeutically effective therapy outcome transcriptome translational potential tumor tumor growth tumor progression tumor xenograft

项目摘要

Lung cancer remains a leading cause of cancer death in both women and men in the United States. There is a clear need for developing new and more effective therapeutics for the treatment of lung cancer, especially the most common subtype non-small cell lung cancer (NSCLC). As master regulators of transcriptome and proteome dynamics, microRNAs (miRNAs or miRs) govern many critical cancer cellular processes including proliferation, invasion and stemness. Therefore, restoration of tumor suppressive miRNAs (e.g., miR-34a and miR-124) lost in NSCLC cells represents a new therapeutic strategy. However, current miRNA mimics for research and development are made by chemical synthesis and decorated with various and extensive artificial modifications. This is in sharp contrast to miRNA molecules produced in living cells that do not carry any modifications or just a few necessary posttranscriptional modifications. Indeed it has been well documented that chemically-engineered/synthesized oligoribonucleotides (e.g., miRNA mimics) are readily recognized as foreign RNA molecules and thus cause immunogenicity. To break this barrier, we have made large efforts to develop novel approach for large-scale production of biologic miRNA agents (BERAs) in living cells. Our identification of hybrid tRNA/pre-miRNA molecules stably expressed in E. coli opens up a new avenue for RNA bioengineering. Furthermore, we have demonstrated that target miRNAs (e.g., miR-34a) are selectively released from BERA “prodrugs” in human cells, and consequently regulate target gene expression, inhibit NSCLC cell proliferation, and suppress xenograft tumor growth while they do not induce severe immune responses. In addition, our studies have found that liposome-polyethylenimine (LPP) nanocomplex increases BERA stability in serum and improves delivery efficiency to lung tissues. Given these exciting preliminary findings, we hypothesize that BERAs can be engineered at higher levels and on large scale; and fully-humanized BERA/miR-34a and BERA/miR-124 may be delivered by LPP as novel therapeutics for the treatment of NSCLC. To test the hypothesis, we proposed to establish more stable ncRNA carriers and produce a set of full-humanized ready-to-use BERAs (Aim 1), delineate the molecular pharmacological actions of BERAs in the control of human NSCLC cellular processes critical for therapeutic outcomes (Aim 2), and define the effectiveness and safety profiles of LPP-loaded BERA/miR-34a and miR-124 in metastatic NSCLC xenograft and patient-derived xenograft (PDX) mouse models (Aim 3). The proposed research will establish a novel technology for the production of fully-humanized biologic miRNA agents and open up new directions for the development of biologic RNA therapeutics.

肺癌仍然是美国男性和女性癌症死亡的主要原因。有