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：
10530617
负责人：
Aiming Yu
金额：
$ 33.91万
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 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10530617
关键词：
Accounting Adverse effects Biologic Development Biological 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 Genetic Transcription Genomics Goals Human Hybrids Immune response Immunocompetent Invaded Kidney Liposomes Malignant Neoplasms Malignant neoplasm of lung Metabolic Methods MicroRNAs Modeling Modification Molecular Mus Non-Small-Cell Lung Carcinoma Oligoribonucleotides Oncogenic Peripheral Blood Mononuclear Cell Pharmacologic Actions Phase I Clinical Trials Polynucleotides Prodrugs Production Proliferating Property Proteins Proteome RNA Regulation Replacement Therapy 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 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 milligram mouse model nanocomplexes nanotherapeutic new technology novel novel strategies novel therapeutic intervention novel therapeutics overexpression patient derived xenograft model polypeptide posttranscriptional research and development restoration stemness success 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.

肺癌仍然是美国女性和男性癌症死亡的主要原因。显然需要开发新的、更有效的疗法来治疗肺癌，特别是最常见的非小细胞肺癌（NSCLC）亚型作为转录组的主要调节因子。蛋白质组动力学、microRNA（miRNA 或 miR）控制许多关键的癌细胞过程，包括因此，肿瘤抑制性 miRNA（例如 miR-34a）的恢复。和 miR-124）在 NSCLC 细胞中丢失代表了一种新的治疗策略，然而，目前的 miRNA 模仿。用于研究和开发的产品通过化学合成制成，并装饰有各种广泛的这与活细胞中产生的 miRNA 分子形成鲜明对比。携带任何修饰或仅进行一些必要的转录后修饰。据记载，化学工程/合成的寡核糖核苷酸（例如 miRNA 模拟物）很容易被识别为外来 RNA 分子，从而产生免疫原性。为了打破这一障碍，我们有努力开发大规模生产生物miRNA制剂的新方法 (BERA) 在活细胞中的鉴定，在大肠杆菌中稳定表达的杂合 tRNA/pre-miRNA 分子。为 RNA 生物工程开辟了一条新途径，此外，我们还证明了靶向 miRNA。（例如，miR-34a）从人类细胞中的 BERA“前药”选择性释放，从而调节靶向基因表达，抑制 NSCLC 细胞增殖，并抑制异种移植肿瘤生长此外，我们的研究发现，脂质体-聚乙烯亚胺不会引起严重的免疫反应。 (LPP) 纳米复合物可提高血清中 BERA 的稳定性并提高肺组织的输送效率。鉴于这些令人兴奋的初步发现，我们追求 BERA 可以在更高水平上进行设计并且大规模地；并且完全人源化的 BERA/miR-34a 和 BERA/miR-124 可以通过 LPP 递送为了检验这一假设，我们建议建立更稳定的治疗非小细胞肺癌的新疗法。 ncRNA 载体并产生一套全人源化即用型 BERA（目标 1），描绘分子 BERA 在控制对治疗至关重要的人类 NSCLC 细胞过程中的药理作用结果（目标 2），并定义加载 LPP 的 BERA/miR-34a 和的有效性和安全性概况转移性 NSCLC 异种移植和患者来源的异种移植 (PDX) 小鼠模型中的 miR-124（目标 3）。拟议的研究将建立一种生产全人源化生物 miRNA 的新技术并为生物RNA疗法的发展开辟新方向。