A Chemopreventive Strategy Based on Edible MicroRNAs Produced in Plants

基于植物中产生的可食用 MicroRNA 的化学预防策略

• 批准号: 8916654
• 负责人: VICKI VANCE
• 金额: $ 7.33万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916654
• 关键词: Achievement; Address; Affect; American Cancer Society; Animal Model; ApcMin/+ mice; Arabidopsis; Basic Science; Biogenesis; Biological Assay; Biological Models; Biological Process; Biology; Biomedical Engineering; Cancer Etiology; Canned Foods; Cell Culture System; Cell Proliferation; Cessation of life; Characteristics; Chemopreventive Agent; Colon; Colon Carcinoma; Colorectal Cancer; Custom; Development; Devices; Diagnosis; Diet; Disease; Eating; Edible Plants; Effectiveness; Engineering; Feasibility Studies; Gastrointestinal tract structure; Gene Targeting; Genetic Engineering; Genetic Models; Genetically Modified Plants; Human; Human Genome; Ingestion; Laboratories; Legal patent; Malignant Neoplasms; Mammals; Metabolism; Methods; Methylation; MicroRNAs; Modeling; Mouse-ear Cress; Mus; Nutraceutical; Operative Surgical Procedures; Oral Administration; Outcome; Pathway interactions; Patients; Pharmacologic Substance; Pilot Projects; Plant RNA; Plants; Positioning Attribute; Preventive; Production; Public Health; RNA; Recurrence; Regimen; Replacement Therapy; Research; Research Design; Research Personnel; Role; Small Intestines; Small RNA; Source; Staging; System; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Transgenic Plants; Translations; Treatment Protocols; Tumor Burden; Tumor Suppressor Proteins; Work; anticancer research; base; cancer diagnosis; cancer therapy; carcinogenesis; clinical application; cost effective; effective therapy; experience; feeding; human disease; large scale production; mouse model; novel; plant genetics; prevent; public health relevance; research study; restoration; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the third most commonly diagnosed cancer and a leading cause of cancer deaths in the US. The primary treatment is surgery, which can be curative especially in early stages of CRC. However, recurrence of the disease is a major problem, and is often fatal. Thus, development of new chemopreventive strategies for CRC remains a high priority. MicroRNAs (miRNAs) are an emerging class of therapeutic agents with significant translational potential for the treatment of cancer. Many different forms of cancer, including CRC, are associated with loss or reduced accumulation of one or more miRNAs that function as tumor suppressors. In animal models, restoration of the missing tumor suppressor miRNA prevents the initiation, progression and/or spread of the disease, suggesting a promising therapeutic role for these small RNAs. However, the current absence of an efficient method for systemic delivery of therapeutic miRNAs is a critical barrier to their use in cancer therapies. The proposed pilot project will test a novel chemopreventive strategy for miRNA replacement therapy based on ingestion of plants that have been bioengineered to produce therapeutic miRNAs. The work builds on our promising preliminary results showing that oral administration of plant RNA spiked with a cocktail of three tumor-suppressor miRNAs (miR-34a, -143, and -145), synthesized with the 3'-methylation characteristic of plant miRNAs, has significant chemopreventive activity in the ApcMin/+ mouse model of CRC. In Aim 1 of the proposed feasibility study, we will determine the combination of the three miRNAs that is most effective in suppressing tumorigenesis when delivered orally to ApcMin/+ mice. The research design is to feed plant RNA spiked with various combinations of synthesized tumor suppressor miRNAs to the mice either before or after tumors have developed (preventive and therapeutic regimens, respectively) and determine the impact of the treatment by assaying tumor burden, level of administered therapeutic miRNAs and expression of select miRNA target genes in treatment versus control tissues. Although the commercially synthesized miRNAs used in our pilot study and in Aim 1 allow rapid testing of specific miRNA replacement strategies, they are prohibitively expensive for translation to humans. Therefore, in Aim 2, we will establish transgenic plant line(s) producing high levels of the most effective combination(s) of tumor suppressor miRNAs as determined in Aim 1, and assay their impact when fed to ApcMin/+ mice via a custom diet. The concept of producing therapeutic miRNAs in edible plants has significant potential in basic, translational and clinical applications and provides a cost-effective alternative to currently available synthetic RNA production methods. Our group is uniquely positioned to undertake this project based on complementary expertise of the investigators. Dr. Vance is a pioneer in small RNA biology in plants and is primary co-inventor on patented technology for the use of genetically engineered miRNAs produced in plants, and Dr. Pena has many years of experience and a strong record of achievement in CRC research using mouse model systems.

描述（由申请人提供）：结直肠癌 (CRC) 是美国第三大最常诊断的癌症，也是癌症死亡的主要原因。主要治疗方法是手术，尤其是在结直肠癌的早期阶段，手术可以治愈。然而，该疾病的复发是一个主要问题，并且常常是致命的。因此，开发新的结直肠癌化学预防策略仍然是重中之重。 MicroRNA (miRNA) 是一类新兴的治疗药物，在癌症治疗方面具有巨大的转化潜力。许多不同形式的癌症，包括结直肠癌，都与一种或多种充当肿瘤抑制因子的 miRNA 的丢失或积累减少有关。在动物模型中，缺失的肿瘤抑制 miRNA 的恢复可以防止疾病的发生、进展和/或扩散，这表明这些小 RNA 具有潜在的治疗作用。然而，目前缺乏系统性递送治疗性 miRNA 的有效方法是实现这一目标的关键障碍。 它们在癌症治疗中的用途。拟议的试点项目将测试一种新的 miRNA 替代疗法化学预防策略，该策略基于摄入经过生物工程改造以产生治疗性 miRNA 的植物。这项工作建立在我们有希望的初步结果的基础上，该结果表明，口服掺有三种肿瘤抑制 miRNA（miR-34a、-143 和 -145）混合物的植物 RNA（用植物 miRNA 的 3'-甲基化特征合成）在 CRC 的 ApcMin/+ 小鼠模型中具有显着的化学预防活性。在拟议可行性研究的目标 1 中，我们将确定三种 miRNA 的组合，当口服给 ApcMin/+ 小鼠时，这三种 miRNA 能够最有效地抑制肿瘤发生。研究设计是在肿瘤形成之前或之后（分别是预防方案和治疗方案），向小鼠喂食掺有各种合成抑癌 miRNA 组合的植物 RNA，并通过分析肿瘤负荷、治疗性 miRNA 的施用水平以及治疗组织与对照组织中选定 miRNA 靶基因的表达来确定治疗的影响。尽管我们的初步研究和目标 1 中使用的商业合成的 miRNA 可以快速测试特定的 miRNA 替换策略，但将它们转化为人类的成本却非常昂贵。因此，在目标 2 中，我们将建立转基因植物系，产生目标 1 中确定的高水平最有效的肿瘤抑制 miRNA 组合，并通过定制饮食喂养 ApcMin/+ 小鼠时测定其影响。在可食用植物中生产治疗性 miRNA 的概念在基础、转化和临床应用中具有巨大潜力，并为目前可用的合成 RNA 生产方法提供了一种经济高效的替代方案。我们的团队处于独特的地位，可以根据研究人员的互补专业知识来开展该项目。 Vance 博士是植物小 RNA 生物学领域的先驱，也是使用植物中产生的基因工程 miRNA 的专利技术的主要共同发明人，Pena 博士在使用小鼠模型系统进行 CRC 研究方面拥有多年的经验和良好的成就记录。