Non-viral gene therapy for cancer pain.

用于癌症疼痛的非病毒基因疗法。

• 批准号: 9090715
• 负责人: Brian L Schmidt
• 金额: $ 39.63万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9090715
• 关键词: Adenovirus Vector; Adverse effects; Analgesics; Attenuated; Cancer Model; Cancer Patient; Cardiac; Carrying Capacities; Cell Line; Cells; Clinic; Clinical; Clinical Trials; DNA; Data; Deglutition; Development; Eating; Environment; Epigenetic Process; Gene Delivery; Gene Transfer; Genes; Genetic Recombination; Goals; Health; Hepatic; 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; Patients; Peptides; Pharmaceutical Preparations; Phase I Clinical Trials; Polymers; Publishing; Quality of life; Relative (related person); Reporting; Research; Research Design; Safety; Serum; Signal Transduction; Specificity; Staging; Techniques; Testing; Tongue; Toxic effect; Transfection; Viral; Viral Vector; Work; animal mortality; attenuation; base; cancer cell; cancer pain; cancer site; chemical carcinogen; cost; cytotoxicity; effective therapy; functional restoration; gene therapy; improved; 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; restoration; safety study; transgene expression; tumor microenvironment; vector; viral gene delivery

 DESCRIPTION: 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 o 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 novel non-viral hybrid vectors: a cell-permeable peptide combined with either a cationic lipid or a cationic polymer. The vectors have excellent transfection efficiency with minimal cytotoxicity in vitro and in vivo. Moreover, the non viral vectors preferentially transfected 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 determine 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 and our non-viral vector more efficiently targets oral cance cells relative to normal cells. Ultimately, these studies might facilitate the development of an effective therapy to treat cancer pain.

 描述：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的，因为不受控制的疼痛会干扰患者的生活。 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甚微，并且具有显着的副作用，我们最近证明了 OPRM1（与相同患者的匹配正常组织相比，口腔癌中的μ-阿片受体基因被甲基化并下调；我们进一步证明，病毒转导后 OPRM1 重新表达显着。癌症上μ-阿片受体的表达导致阿片类药物分泌到癌症微环境中，从而减轻了小鼠模型中的癌症疼痛。病毒转导方法的缺点是病毒基因传递存在安全性问题和有限的携带能力。我们开发了两种新型非病毒杂合载体：与阳离子脂质或阳离子聚合物组合的细胞渗透性肽，这些载体具有优异的转染效率，并且在体外和体内的细胞毒性最小。此外，与正常细胞相比，非病毒载体优先转染口腔癌细胞。根据我们的初步工作，我们发现使用我们的非病毒载体在口腔癌中重新表达 OPRM1 基因将减轻癌症疼痛并恢复口面部功能。在具体目标 1 中，我们将确定使用非病毒载体进行离体 OPRM1 基因转移以减轻癌症引起的疼痛的功效。我们预计将我们的非病毒载体直接接种到口腔癌中，因此，在具体目标 2 中，我们将确定用非病毒进行体内 OPRM1 基因转移（即直接转移到舌癌中）的可行性和功效。由于我们临床试验的先决条件是特定目标 3 中的毒性和安全性研究，因此我们将分析接受非病毒治疗的癌症小鼠的毒性和免疫反应。 OPRM1 基因递送非常重要，因为我们将使用局部递送技术直接进入癌症，以减少全身药物的潜在副作用，因为我们将转导癌细胞来治疗癌症疼痛和我们的治疗。相对于正常细胞，非病毒载体更有效地靶向口腔癌细胞，最终，这些研究可能有助于开发治疗癌痛的有效疗法。