In situ production of analgesic peptides for the treatment of joint pain

骨性关节炎是最常见的、使人虚弱的关节炎形式。目前治疗骨性关节炎的方法不足以控制疼痛，因此需要新的治疗方法来治疗慢性关节疼痛。实验和临床证据表明，骨关节炎疼痛是通过持续的外周伤害性输入来驱动和维持的。该项目旨在通过利用基因疗法在关节内局部产生重组止痛肽来阻止正在进行的伤害性输入。研究人员Tony Lim博士将在Ewan Smith博士的指导下，在剑桥大学药理系进行一项临床前概念验证研究，并将：1)产生一个基于AAV的载体，驱动滑膜细胞分泌功能性重组ProToxin-II(一种蜘蛛毒肽，阻断电压门控钠通道1.7，具有镇痛特性)；2)在体外关节炎疼痛模型中，确定ProToxin-II分泌细胞是否抑制感觉神经元活性；以及3)评估ProToxin-II基因治疗在关节炎疼痛临床前模型中的有效性和安全性。作为这项研究的一部分，研究人员还将在Paul Heppenstall教授的监督下访问国际高级研究中心Avanzati，以帮助生成病毒工具。这项工作有可能启动一种治疗关节疼痛的新的基因疗法。

Osteoarthritis is the most common, debilitating form of arthritis. Current treatments for osteoarthritis provide inadequate pain control, and there is a need for new therapies for chronic joint pain. Experimental and clinical evidence suggests that osteoarthritic pain is driven and maintained through ongoing peripheral nociceptive input. This project aims to block the ongoing nociceptive input by utilizing gene therapy to locally produce recombinant analgesic peptides within the joint. The researcher, Dr. Tony Lim, will carry out a preclinical proof-of-concept study in the Department of Pharmacology at the University of Cambridge under the supervision of Dr. Ewan Smith and will: 1) Generate an AAV-based vector that drives secretion of functional recombinant ProToxin-II (a spider venom peptide that blocks voltage-gated sodium channel 1.7 and possesses analgesic properties) in synoviocytes, 2) determine whether ProToxin-II secreting synoviocytes inhibit sensory neuron activity in an in vitro arthritic pain model, and 3) evaluate the effectiveness and safety of ProToxin-II gene therapy in preclinical models of arthritic pain. As part of this research, the researcher will also visit the Scuola Internazionale Superiore di Studi Avanzati under the supervision of Prof. Paul Heppenstall to assist in the generation of viral tools. This work has the potential to kickstart a novel gene therapy for the treatment of joint pain.