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干扰 必要的口服功能，包括饮食，说话和吞咽。外源性OIOID对这种类型的疼痛至少有效，并且具有明显的副作用。我们的长期目标是o为口腔癌疼痛开发有效且安全的治疗方法。我们最近证明，与同一患者中匹配的正常时间相比，OPRM1（µ-阿片受体的基因）是甲基化的，并且在口腔癌中调节。这些患者报告了癌症部位的疼痛。我们进一步证明，在小鼠模型中，OPRM1对病毒转导的重新表达可显着减轻癌症疼痛。 μ阿片受体在癌症上的表达导致阿片类药物分泌到癌症微环境中。病毒转导方法的缺点是病毒基因输送具有安全性和有限的承载能力。为了克服这些障碍，我们开发了两个新型的非病毒杂化载体：一种可渗透的肽与阳离子脂质或阳离子聚合物结合。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。此外，与正常细胞相比，非病毒载体优先翻译了口腔癌细胞。基于我们的初步工作，我们假设使用非病毒载体在口腔癌中重新表达OPRM1基因将减轻癌症的疼痛并恢复过多的毒性，而不会过多毒性。在特定目标1中，我们将确定用非病毒载体转移离体OPRM1基因转移的有效性，以减轻癌症诱发的疼痛。我们的目标是将非病毒转移方法移至诊所。我们预测，临床医生将非病毒载体直接接种到口腔癌中。因此，在特定的目标2中，我们将用非病毒载体来确定体内OPRM1基因转移（即直接进入舌癌）的可行性和效率，以衰减癌症诱发的疼痛。由于我们进行临床试验的先决条件是特定目的3中的毒性和安全研究，因此我们将分析用非病毒OPRM1基因递送治疗的癌症小鼠的毒性和免疫反应。拟议的研究很重要，因为我们将直接使用局部递送技术来减少全身药物的潜在副作用。我们的方法具有创新性，因为我们将转化癌细胞治疗癌症疼痛，而非病毒载体则更有效地靶向口腔癌细胞相对于正常细胞。最终，这些研究可能支持开发有效治疗癌症疼痛的疗法。