Non-viral gene therapy for cancer pain

癌症疼痛的非病毒基因疗法

• 批准号: 9284436
• 负责人: Brian L Schmidt
• 金额: $ 40.16万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9284436
• 关键词: Adenovirus Vector; Adverse effects; Alpha Cell; Analgesics; Anatomy; Attenuated; Cancer Model; Cancer Patient; Cardiac; Carrying Capacities; Cations; Cell Line; Clinic; Clinical; Clinical Trials; Cysteine; DNA; Data; Deglutition; Development; Drug usage; Eating; Environment; Epigenetic Process; Gene Delivery; Gene Transfer; Genes; Genetic Recombination; Genetic Transcription; Goals; HIV-1; Hepatic; Histidine; Histologic; Human; Hybrids; Immune response; Immunocompetent; In Vitro; Intramuscular Injections; Kidney; Lipids; Malignant Epithelial Cell; Malignant Neoplasms; Medicine; Methods; Morbidity - disease rate; Mus; Nociception; Non-Viral Vector; Normal Cell; Normal tissue morphology; Opioid; Opioid Receptor; Oral; Pain; Pain management; Patients; Peptides; Permeability; Pharmaceutical Preparations; Phase I Clinical Trials; Polymers; Publishing; Quality of life; Reporting; Research; Safety; Serum; Signal Transduction; Specificity; Techniques; Testing; Tongue; Toxic effect; Transfection; Viral; Viral Vector; Work; animal mortality; attenuation; base; cancer cell; cancer pain; cancer site; cancer therapy; cancer type; cell type; chemical carcinogen; cost; cytokine; cytotoxicity; design; effective therapy; functional restoration; gene therapy; in vivo; innovation; malignant mouth neoplasm; malignant tongue neoplasm; mouse model; mouth squamous cell carcinoma; non-viral gene delivery; non-viral gene therapy; novel; orofacial; preclinical study; protein aminoacid sequence; restoration; safety study; transgene expression; translational impact; tumor microenvironment; vector; viral gene delivery

Project Summary/Abstract The intensity of oral cancer pain is higher than other cancers. Quality of life for oral cancer patients is the lowest of all cancer patients because uncontrolled pain interferes with necessary oral functions including eating, talking and swallowing. Exogenous opioids are minimally effective for this type of pain and have significant side effects. Our long-term goal is to develop an effective and safe treatment for oral cancer pain. We recently demonstrated that OPRM1 (the gene for the µ-opioid receptor) is methylated and down regulated in oral cancer compared to matched normal tissues in the same patients; these patients reported pain at the site of cancer. We further demonstrated that OPRM1 re-expression with viral transduction significantly reduced cancer pain in a mouse model. Expression of the µ-opioid receptor on the cancer led to the secretion of opioids into the cancer microenvironment. Drawbacks of a viral transduction approach are that viral gene delivery has safety concerns and limited carrying capacity. To overcome these barriers we developed two non-viral hybrid vectors. The first is composed of a cell-permeable peptide (HIV-1 Tat peptide sequence modified with histidine and cysteine residues) combined with a cationic lipid. The second vector substitutes cationic polymer for the lipid. The vectors have excellent transfection efficiency with minimal cytotoxicity in vitro and in vivo. Moreover, the non-viral vectors preferentially transfects oral cancer cells compared to normal cells. Based on our preliminary work we hypothesize that re-expression of the OPRM1 gene within oral cancer using our non-viral vectors will attenuate cancer pain and restore orofacial function without excessive toxicity. In Specific Aim 1 we will d etermine the efficacy of ex vivo OPRM1 gene transfer with non-viral vectors to attenuate cancer-induced pain. Our goal is to move our method of non-viral transfection to the clinic. We foresee clinicians directly inoculating our non-viral vector into an oral cancer. Therefore, in Specific Aim 2 we will determine the feasibility and efficacy of in vivo OPRM1 gene transfer (i.e., directly into the tongue cancer) with non-viral vectors for attenuation of cancer-induced pain. Because our prerequisites for a clinical trial are toxicity and safety studies in Specific Aim 3 we will analyze toxicity and immune response in the cancer mice treated with non-viral OPRM1 gene delivery. The proposed research is significant because we will use a local delivery technique directly into the cancer to reduce the potential side effects of systemic drugs. Our approach is innovative because we will transduce the cancer cells for the treatment of cancer pain. facilitate the development of an effective therapy to treat cancer pain. Ultimately, these studies might

项目摘要/摘要 口腔癌疼痛的强度高于其他癌症。口腔癌患者的生活质量是 在所有癌症患者中最低，因为不受控制的疼痛干扰了必要的口服功能，包括进食 说话和吞咽。外源阿片类药物对这种类型的疼痛至少有效，并且具有明显的一面 效果。我们的长期目标是为口腔癌疼痛开发有效且安全的治疗方法。我们最近 证明OPRM1（µ阿片受体的基因）是甲基化的，并在口腔中调节 癌症与同一患者的正常时间相比；这些患者报告了该部位的疼痛 癌症。我们进一步证明，OPRM1重新表达了病毒转导的表达可显着降低 小鼠模型中的癌症疼痛。 μ阿片受体在癌症上的表达导致卵虫类药物的分泌 进入癌症微环境。 病毒转移方法的缺点是病毒基因递送 安全问题和有限的承载能力。为了克服这些障碍，我们开发了两个非病毒杂种 向量。第一个由可渗透肽（用组氨酸修饰的HIV-1 TAT肽序列组成）组成 和半胱氨酸保留）与阳离子脂质结合。第二个载体取代阳离子聚合物 脂质。载体在体外和体内具有极佳的转化效率，具有最小的细胞毒性。 而且， 与正常细胞相比，非病毒载体优选地翻译了口腔癌细胞。基于我们 初步工作，我们假设使用非病毒的OPRM1基因重新表达了OPRM1基因 载体将减轻癌症疼痛并恢复口面功能，而不会过多毒性。 在特定的目标1中我们 会d 可怕的 疼痛。我们的目标是将非病毒转化方法移至诊所。我们直接预见了临床医生 将我们的非病毒载体接种到口腔癌中。因此，在特定目标2中，我们将确定可行性 与非病毒载体的体内OPRM1基因转移（即直接进入舌癌）的效率和效率 癌症引起的疼痛的衰减。因为我们进行临床试验的先决条件是毒性和安全研究 在特定目标3中，我们将分析用非病毒治疗的癌症小鼠的毒性和免疫反应 OPRM1基因递送。拟议的研究很重要，因为我们将使用本地交付技术 直接进入癌症，以减少全身药物的潜在副作用。我们的方法是创新的 因为我们将转导癌细胞治疗癌症疼痛。 促进开发有效治疗癌症疼痛的疗法。 最终，这些研究可能