Saenger S, Goeldner C, Frey J R, Ozmen L, Ostrowitzki S, Spooren W, Ballard T M, Prinssen E, Borroni E, Metzger F
F. Hoffmann-La Roche Ltd., CNS Pharma Research & Early Development, Basel, Switzerland.
Growth Horm IGF Res. 2011 Oct;21(5):292-303. doi: 10.1016/j.ghir.2011.07.006. Epub 2011 Aug 23.
Due to its potent neurotrophic activity, insulin-like growth factor I (IGF-I) has been proposed many times for therapeutic application in disorders of the central nervous system (CNS). However, insufficient brain delivery to yield beneficial central without peripheral side effects have prevented clinical development in most instances.
We recently reported the generation of a polyethylene-glycol modified IGF-I variant (PEG-IGF-I) with prolonged half-life and less acute side effects, but with fully maintained slow anabolic activity. Here we investigated if these beneficial properties result in improved brain availability of the drug, thereby reaching therapeutically relevant steady-state concentrations to elicit beneficial effects on neuronal function.
After a single subcutaneous injection, PEG-IGF-I reached much higher steady-state levels in brain tissue and cerebrospinal fluid compared with IGF-I. Two weeks treatment with PEG-IGF-I was sufficient to modulate brain plasticity processes, as judged by changes in synaptic proteins and related animal behavior. Furthermore, chronic treatment of a mouse model of brain amyloidosis with PEG-IGF-I reverted deficits in insulin/IGF-I signaling, synaptic proteins and cognitive performance.
Our data generate the therapeutic potential for PEG-IGF-I to treat CNS disorders by systemic drug application, and in addition scientifically support its application in disorders of synaptic function and neuronal development.
由于胰岛素样生长因子I（IGF-I）具有强大的神经营养活性，其多次被提议用于中枢神经系统（CNS）疾病的治疗。然而，在大多数情况下，由于无法有效将其输送至脑部以产生有益的中枢作用而不产生外周副作用，阻碍了其临床开发。
我们最近报道了一种聚乙二醇修饰的IGF-I变体（PEG-IGF-I）的产生，其半衰期延长且急性副作用较少，但仍完全保持缓慢的合成代谢活性。在此，我们研究了这些有益特性是否会提高药物在脑内的可用性，从而达到治疗相关的稳态浓度以对神经元功能产生有益影响。
与IGF-I相比，单次皮下注射后，PEG-IGF-I在脑组织和脑脊液中达到了更高的稳态水平。通过突触蛋白和相关动物行为的变化判断，PEG-IGF-I治疗两周足以调节脑可塑性过程。此外，用PEG-IGF-I对脑淀粉样变性小鼠模型进行长期治疗可逆转胰岛素/IGF-I信号传导、突触蛋白和认知能力方面的缺陷。
我们的数据表明PEG-IGF-I通过全身给药治疗CNS疾病具有治疗潜力，此外还从科学上支持其在突触功能和神经元发育障碍中的应用。
