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

点击翻译按钮获取中文摘要

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.