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

慢性疼痛是退伍军人中最常报告的疾病之一，现在被法院裁定为 退伍军人事务部残疾慢性疼痛，创伤后应激障碍（PTSD）， 以及退伍军人常见的持续性脑震荡后综合征。因此，VA医疗保健 使命是探索新的策略，以减少慢性疼痛是至关重要的。慢性疼痛福尔斯分为两种最常见的 分类包括伤害性疼痛和神经性疼痛。大多数慢性疼痛疾病开始于 一个伤害性的来源，虽然它并不罕见的人有多种疼痛条件。慢性 胰腺炎（CP）是一种炎症性疾病， 胰腺以不可逆纤维化为特征，胰腺 萎缩和外分泌功能障碍。CP患者所遭受的疼痛是医学上遇到的最严重的疼痛之一。 VA人群和CP患者的慢性疼痛具有共同的潜在机制， 炎症和外周神经元中改变的伤害感受器传递。因此，CP疼痛提供了一个有用的 模型的理解和治疗疼痛综合征与可识别的伤害性来源， 将军尽管目前的疗法提供了对急性疼痛的缓解，但是用于治疗慢性疼痛的药物是不安全的。 通常效果较差并受到许多副作用的限制。间充质干细胞（MSC）的用途和 作为治疗工具的其它抗炎剂如人α-1抗胰蛋白酶（AAT）是新的 治疗慢性疼痛的方法。在我们以前的研究中，我们发现MSC输注或用hAAT治疗， 在CP小鼠模型中减少疼痛并减轻胰腺炎症和疾病进展。到 增强MSC的功能，并以可持续的方式有效地将AAT局部递送到胰腺中。 我们以慢病毒介导的骨髓间充质干细胞转染方法，构建了过表达人AAT（hAAT 编码hAAT基因。hAAT-MSCs表现出更好的迁移能力，增加了干细胞和分泌细胞因子。 与载体处理的对照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及其相关疾病的有效疗法。 通过抑制免疫细胞活化和抑制伤害感受器活化来减轻疼痛。的总体目标 本研究旨在确定在临床前啮齿动物疼痛性CP模型中， hAAT-MSCs在炎症减轻和疼痛缓解中的作用，并探索其向人类转化的潜力。 使用从疼痛性CP患者中收集的样本进行治疗。

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.