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

慢性疼痛是退伍军人中最常见的疾病之一，现在被法院裁定为 退伍军人病残。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，退伍军人医疗保健 探索减少慢性疼痛的新策略的使命至关重要。慢性疼痛分为两种最常见的 分类包括伤害性和神经性疼痛。大多数慢性疼痛障碍都是从 这是一种伤害性来源，尽管对一个人来说有多种疼痛状况并不少见。慢性 胰腺炎(CP)是一种炎症性疾病 以不可逆转的纤维化为特征的胰腺 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。 退伍军人人群和CP患者的慢性疼痛具有共同的潜在机制，即 炎症和周围神经元伤害性感受器传递的改变。因此CP疼痛提供了一种有用的 具有可识别伤害感受源的疼痛综合征的理解和治疗模型 将军。虽然目前的治疗方法可以缓解急性疼痛，但用于治疗慢性疼痛的药物有 通常效果较差，并受到许多副作用的限制。间充质干细胞(MSCs)和 作为治疗工具的其他抗炎药，如人α-1抗胰蛋白酶(AAT)也是新的 治疗慢性疼痛的疗法。在我们以前的研究中，我们发现MSC输注或与HAAT一起治疗 减轻慢性胰腺炎小鼠模型的疼痛，减轻胰腺炎症和疾病进展。至 增强MSCs的功能，并以可持续的方式将AAT局部有效地输送到胰腺 时尚，我们通过用慢病毒转染MSCs来改造人AAT(Haat)过表达MSCs 编码Haat基因。HAAT-MSCs具有更好的迁移能力，增加了干细胞的干性和分泌 与载体处理的对照MSCs相比，AAT和其他对MSC功能至关重要的因素。基于这些 数据，我们假设输注HAAT-MSC是治疗CP及其相关疾病的有效方法。 疼痛通过抑制免疫细胞的激活和抑制伤害性感受器的激活来实现。总的目标是 这项研究是为了在临床前的痛性脑性瘫痪啮齿动物模型中确定治疗和机制的影响 HAAT-MSCs抗炎止痛作用的研究及其移植到人类的可能性 使用从痛性脑瘫患者采集的样本进行治疗。

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.