Molecular Therapy - Methods & Clinical Development ( IF 4.7 ) Pub Date : 2020-06-25 , DOI: 10.1016/j.omtm.2020.06.018 Daewook Kim 1 , Kyung-Ran Kim 1 , Yejin Kwon 1 , Minjung Kim 1 , Min-Ju Kim 1 , Yeomoon Sim 1 , Hyelin Ji 1 , Jang-Joon Park 1 , Jong-Ho Cho 1 , Heonsik Choi 1 , Sujeong Kim 1
Neuropathic pain is a chronic pain state characterized by nerve damage, inflammation, and nociceptive neuron hyperactivity. As the underlying pathophysiology is complex, a more effective therapy for neuropathic pain would be one that targets multiple elements. Here, we generated recombinant adeno-associated viruses (AAVs) encoding three therapeutic genes, namely, glutamate decarboxylase 65, glial cell-derived neurotrophic factor, and interleukin-10, with various combinations. The efficacy for pain relief was evaluated in a rat spared nerve injury model of neuropathic pain. The maximal analgesic effect was achieved when the AAVs expressing all three genes were administered to rats with neuropathic pain. The combination of two virus constructs expressing the three genes was named KLS-2031 and evaluated as a potential novel therapeutic for neuropathic pain. Single transforaminal epidural injections of KLS-2031 into the intervertebral foramen to target the appropriate dorsal root ganglion produced notable long-term analgesic effects in female and male rats. Furthermore, KLS-2031 mitigated the neuroinflammation, neuronal cell death, and dorsal root ganglion hyperexcitability induced by the spared nerve injury. These results suggest that KLS-2031 represents a promising therapeutic option for refractory neuropathic pain.
中文翻译:
AAV介导的神经性疼痛联合基因疗法:GAD65,GDNF和IL-10。
神经性疼痛是一种慢性疼痛状态,其特征在于神经损伤,炎症和伤害性神经元活动亢进。由于潜在的病理生理学很复杂,因此针对神经性疼痛的更有效疗法将是针对多种因素的疗法。在这里,我们生成了编码三种治疗基因的重组腺相关病毒(AAV),这三种基因分别是谷氨酸脱羧酶65,神经胶质细胞源性神经营养因子和白介素10,具有各种组合。在大鼠备用的神经性疼痛神经损伤模型中评估了缓解疼痛的功效。当将表达所有三个基因的AAVs给予患有神经性疼痛的大鼠时,可获得最大的镇痛作用。表达这三个基因的两种病毒构建体的组合称为KLS-2031,并被评估为潜在的新型神经痛疗法。单次经椎间孔硬膜外注射KLS-2031到椎间孔以靶向适当的背根神经节对雌性和雄性大鼠产生了明显的长期镇痛作用。此外,KLS-2031可以减轻因神经损伤而引起的神经炎症,神经元细胞死亡和背根神经节过度兴奋。