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

项目总结/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 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腔功能，包括进食， 说话和吞咽外源性阿片类药物对这种类型的疼痛效果最低， 方面的影响.我们的长期目标是开发一种有效和安全的口腔癌疼痛治疗方法。我们最近 表明OPRM 1（μ-阿片受体基因）在口服给药中甲基化并下调。 癌症与相同患者的匹配正常组织相比;这些患者报告了 癌我们进一步证明，OPRM 1的再表达与病毒转导显著减少， 癌症疼痛的小鼠模型。肿瘤上μ-阿片受体的表达导致阿片类物质的分泌 进入癌症微环境。 病毒转导方法的缺点是病毒基因递送具有以下缺点： 安全问题和有限的承载能力。为了克服这些障碍，我们开发了两种非病毒杂交 向量。第一种是由一种细胞渗透性肽（用组氨酸修饰的HIV-1达特肽序列）组成 和半胱氨酸残基）与阳离子脂质组合。第二载体用阳离子聚合物代替 脂质该载体具有优异的转染效率，在体外和体内具有最小的细胞毒性。 此外，委员会认为， 与正常细胞相比，非病毒载体优先感染口腔癌细胞。基于我们 初步工作中，我们假设使用我们的非病毒表达， 载体将减轻癌症疼痛并恢复口面功能而没有过度毒性。 具体目标1， 将D 确定用非病毒载体进行离体OPRM 1基因转移以减弱癌症诱导的肿瘤细胞增殖的功效。 痛苦我们的目标是将我们的非病毒转染方法应用于临床。我们预见临床医生直接 将我们的非病毒载体植入口腔癌。因此，在具体目标2中，我们将确定 和体内OPRM 1基因转移的功效（即，直接进入舌癌）与非病毒载体， 减轻癌症引起的疼痛。因为我们进行临床试验的先决条件是毒性和安全性研究 在具体目标3中，我们将分析用非病毒治疗的癌症小鼠的毒性和免疫应答， OPRM 1基因递送。拟议的研究是有意义的，因为我们将使用一个本地交付技术 以减少全身性药物的潜在副作用。我们的方法是创新的 因为我们会将癌细胞移植到癌症疼痛的治疗中。 促进开发治疗癌症疼痛的有效疗法。 最终，这些研究可能