hAAT-engineered Mesenchymal Stem Cells for the Treatment of Chronic Pain

hAAT 工程改造的间充质干细胞用于治疗慢性疼痛

• 批准号: 10292900
• 负责人: Hongjun Wang
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292900
• 关键词: Acute Pain; Anti-Inflammatory Agents; Atrophic; Blood; Cell Culture System; Cells; Classification; Coculture Techniques; Cytometry; Data; Development; Disease; Disease Progression; Disease remission; Drug usage; Engineering; Excision; Fibrosis; Flow Cytometry; Functional disorder; Genes; Harvest; Health; Healthcare; Human; Human Engineering; Hypersensitivity; Immune; Immune Cell Suppression; In Vitro; Inflammation; Inflammatory; Infusion procedures; Ion Channel Protein; Lentivirus; Measures; Mediating; Medicine; Mesenchymal Stem Cells; Mission; Modeling; Mononuclear; Neurons; Nociception; Nociceptors; Pain; Pain Measurement; Pain management; Painless; Pancreas; Pancreatic Diseases; Patients; Peripheral; Phenotype; Population; Post-Concussion Syndrome; Post-Traumatic Stress Disorders; Preclinical Testing; Reporting; Rodent Model; Role; Sampling; Source; Sulfonic Acids; Syndrome; System; Telemetry; Therapeutic; Therapeutic Effect; Translating; Trinitrobenzenes; Veterans; Visceral; alpha 1-Antitrypsin; base; chronic pain; chronic pain management; chronic painful condition; chronic pancreatitis; court; disability; effective therapy; experimental study; falls; immune activation; improved; insight; migration; military veteran; mouse model; novel strategies; novel therapeutics; overexpression; pain behavior; pain inhibition; pain reduction; pain relief; painful neuropathy; peripheral blood; pre-clinical; protein expression; side effect; stem cell function; stem cell therapy; stemness; tool; translation to humans; transmission process; vector

Chronic pain is one of the most frequently reported conditions in Veterans and is now ruled by the court as a VA disability. There is a significant interaction between chronic pain, post-traumatic stress disorder (PTSD), and persistent post-concussive syndromes common to the veteran population. Therefore, the VA healthcare mission to explore novel strategies to reduce chronic pain is vital. Chronic pain falls into two most common classifications including nociceptive and neuropathic pains. The majority of chronic pain disorders start off with a nociceptive source, although it is not uncommon for someone to have multiple pain conditions . Chronic pancreatitis (CP) is an inflammatory disease of the pancreas characterized by irreversible fibrosis, pancreas atrophy, and exocrine dysfunction. Pain suffered by CP patients is among the worst encountered in medicine. Chronic pain in the VA population and patients with CP share common underlying mechanisms, which are inflammation and altered nociceptor transmission in peripheral neurons. CP pain therefore provides a useful model for the understanding and treatment of pain syndromes with an identifiable nociceptive source in general. Although current therapy provides relief to acute pain, drugs used for treatment of chronic pain are typically less efficacious and limited by many side effects. The use of mesenchymal stem cells (MSCs) and other anti-inflammatory agent such as human alpha-1 antitrypsin (AAT), as therapeutic tools are novel therapies to treat chronic pain. In our previous studies we found that MSC infusion or treatment with hAAT reduced pain and mitigated pancreas inflammation and disease progression in mouse models of CP. To enhance the functionality of MSCs and to effectively deliver AAT locally into the pancreas in a sustainable fashion, we engineered human AAT (hAAT) overexpressing MSCs by transfecting MSCs with a lentivirus encoding the hAAT gene. hAAT-MSCs showed better migration ability, increased stemness and secretion of AAT and other factors critical for MSC function compared to vector-treated control MSCs. Based on these data, we hypothesize that hAAT-MSC infusion is an effective therapy for the treatment of CP and its associated pain by inhibition of immune cell activation and suppression of nociceptor activation. The overall objective of this study is to determine, in a pre-clinical rodent model of painful CP, the therapeutic and mechanistic impact of hAAT-MSCs in inflammation reduction and pain relief and explore their potential translation to human therapy using samples collected from patients with painful CP.

慢性疼痛是退伍军人中最常报告的状况之一，现在由法院统治为 VA残疾。慢性疼痛，创伤后应激障碍（PTSD）， 以及退伍军人人口共有的持续脑震荡综合征。因此，VA医疗保健 探索减轻慢性疼痛的新型策略的使命至关重要。慢性疼痛落入两个最常见的 分类包括伤害性和神经性疼痛。大多数慢性疼痛障碍始于 一种伤害性的来源，尽管某人患有多种疼痛状况并不少见。慢性的 胰腺炎（CP）是一种炎症性疾病 以不可逆的纤维化，胰腺为特征的胰腺 萎缩和外分泌功能障碍。 CP患者遭受的疼痛是医学中最严重的疼痛之一。 VA人群的慢性疼痛和CP患者具有共同的潜在机制， 周围神经元中的炎症和伤害感受器的传播。因此，CP疼痛提供了有用的 了解和治疗具有可识别伤害源的疼痛综合征的模型 一般的。尽管目前的疗法可以缓解急性疼痛，但用于治疗慢性疼痛的药物是 通常不太有效，受许多副作用的限制。间充质干细胞（MSC）的使用和 其他抗炎剂，例如人α-1抗胰蛋白酶（AAT），因为治疗工具是新颖的 治疗慢性疼痛的疗法。在我们先前的研究中，我们发现MSC输注或使用HAAT治疗 CP小鼠模型中的疼痛减轻和缓解胰腺炎症和疾病进展。到 增强MSC的功能，并在可持续性中有效地将AAT当地运送到胰腺 时尚，我们通过用慢病毒将MSC转染MSC设计了人类AAT（HAAT）过表达MSC 编码HAAT基因。 HAAT-MSC显示出更好的迁移能力，增加的茎和分泌 与矢量处理的对照MSC相比，AAT和其他对MSC功能至关重要的因素。基于这些 数据，我们假设HAAT-MSC输注是治疗CP及其相关的有效疗法 通过抑制免疫细胞激活和伤害感受器激活的抑制来疼痛。总体目标 这项研究是在疼痛的CP的临床前啮齿动物模型中确定治疗和机械影响 HAAT-MSC在减轻炎症和缓解疼痛方面的影响，并探索其潜在的翻译为人类 使用从疼痛CP患者中收集的样品的治疗。