Kurek J B, Radford A J, Crump D E, Bower J J, Feeney S J, Austin L, Byrne E
AMRAD Corporation Ltd, Melbourne, Australia.
J Neurol Sci. 1998 Oct;160 Suppl 1:S106-13. doi: 10.1016/s0022-510x(98)00208-1.
Growth factors are theoretically promising agents for ALS therapy, but have been disappointing in subcutaneous delivery due to either toxicity or lack of major efficacy. Leukaemia inhibitory factor (LIF), was named after its effect on haemopoietic cells, and belongs to a group of cytokines which includes CNTF, IL-6, CT-1, OM and IL-11. All group members use the gp130 signal transducing subunit for intracellular signalling, but show differences in biological effect. In vitro and in vivo studies on axotomy and nerve crush models demonstrate a powerful effect of LIF in the survival of both motor and sensory neurones, while reducing denervation induced muscle atrophy. Its effects in muscle also include stimulating myoblast proliferation in vitro, and up-regulation after muscle injury. LIF will also stimulate muscle regeneration in vivo when applied exogenously after injury. In published studies of both axotomy induced neuronal death and in the Wobbler mouse models LIF is active at doses of 10 microg/kg delivered systemically, well below the expected maximum tolerated dose suggested by primate safety studies. LIF is expressed in low levels by spinal cord neurones with significant up-regulation when the neurones are damaged by BOAA toxin, an excitatory amino acid associated with a form of ALS. This augments other evidence suggesting LIF is a trauma factor playing a role in the injury response of adult neuronal tissue, and may be more effective than related growth factors. Taken together, the data suggests LIF is a physiologically relevant trophic factor with implications in clinical medicine as a therapy for ALS, and a human recombinant form (AM424), entered human clinical trials during 1998.
生长因子在理论上是治疗肌萎缩侧索硬化症（ALS）的有前景的药物，但由于毒性或缺乏主要疗效，皮下给药效果令人失望。白血病抑制因子（LIF），因其对造血细胞的作用而得名，属于一组细胞因子，其中包括睫状神经营养因子（CNTF）、白细胞介素 - 6（IL - 6）、心肌营养素 - 1（CT - 1）、鄂托蛋白（OM）和白细胞介素 - 11（IL - 11）。所有该组成员都使用gp130信号转导亚基进行细胞内信号传导，但在生物学效应上存在差异。对轴突切断和神经挤压模型的体外和体内研究表明，LIF对运动神经元和感觉神经元的存活具有强大作用，同时可减少去神经支配引起的肌肉萎缩。它在肌肉中的作用还包括在体外刺激成肌细胞增殖，以及在肌肉损伤后上调。损伤后外源性应用LIF也会在体内刺激肌肉再生。在已发表的关于轴突切断诱导的神经元死亡和摇摆小鼠模型的研究中，全身给药剂量为10微克/千克时LIF具有活性，远低于灵长类动物安全性研究所建议的预期最大耐受剂量。脊髓神经元低水平表达LIF，当神经元被与一种ALS形式相关的兴奋性氨基酸BOAA毒素损伤时，LIF会显著上调。这进一步证明了LIF是一种在成年神经元组织损伤反应中起作用的创伤因子，并且可能比相关生长因子更有效。综上所述，数据表明LIF是一种生理相关的营养因子，在临床医学中作为ALS的治疗方法具有潜在意义，并且一种重组人形式（AM424）于1998年进入人体临床试验。
