Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA.
Mol Ther. 2010 Dec;18(12):2075-84. doi: 10.1038/mt.2010.206. Epub 2010 Sep 21.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron cell death in the cortex, brainstem, and spinal cord. Extensive efforts have been made to develop trophic factor-based therapies to enhance motor neuron survival; however, achievement of adequate therapeutic delivery to all regions of the corticospinal tract has remained a significant challenge. Here, we show that adeno-associated virus serotype 4 (AAV4)-mediated expression of insulin-like growth factor-1 (IGF-1) or vascular endothelial growth factor (VEGF)-165 in the cellular components of the ventricular system including the ependymal cell layer, choroid plexus [the primary cerebrospinal fluid (CSF)-producing cells of the central nervous system (CNS)] and spinal cord central canal leads to trophic factor delivery throughout the CNS, delayed motor decline and a significant extension of survival in SOD1(G93A) transgenic mice. Interestingly, when IGF-1- and VEGF-165-expressing AAV4 vectors were given in combination, no additional benefit in efficacy was observed suggesting that these trophic factors are acting on similar signaling pathways to modestly slow disease progression. Consistent with these findings, experiments conducted in a recently described in vitro cell culture model of ALS led to a similar result, with both IGF-1 and VEGF-165 providing significant motor neuron protection but in a nonadditive fashion. These findings support the continued investigation of trophic factor-based therapies that target the CNS as a potential treatment of ALS.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是大脑皮层、脑干和脊髓中的运动神经元细胞死亡。人们已经做出了大量努力来开发基于营养因子的治疗方法，以增强运动神经元的存活；然而，要实现向皮质脊髓束的所有区域都有足够的治疗输送，仍然是一个重大挑战。在这里，我们表明，腺相关病毒血清型 4（AAV4）介导的胰岛素样生长因子-1（IGF-1）或血管内皮生长因子-165（VEGF-165）在脑室系统的细胞成分中的表达，包括室管膜细胞层、脉络丛[中枢神经系统（CNS）的主要脑脊液（CSF）产生细胞]和脊髓中央管，导致营养因子在整个中枢神经系统中的输送、运动功能下降的延迟和 SOD1（G93A）转基因小鼠的存活时间显著延长。有趣的是，当给予表达 IGF-1 和 VEGF-165 的 AAV4 载体的组合时，没有观察到疗效的额外益处，这表明这些营养因子作用于相似的信号通路，以适度减缓疾病进展。与这些发现一致，在最近描述的 ALS 体外细胞培养模型中进行的实验也得出了类似的结果，IGF-1 和 VEGF-165 都为运动神经元提供了显著的保护，但不是累加的方式。这些发现支持对靶向中枢神经系统的营养因子治疗方法的进一步研究，作为肌萎缩侧索硬化症的潜在治疗方法。
