Haase G, Pettmann B, Bordet T, Villa P, Vigne E, Schmalbruch H, Kahn A
INSERM U129, Institut Cochin de Génétique Moléculaire, Paris, France.
Ann Neurol. 1999 Mar;45(3):296-304.
Ciliary neurotrophic factor (CNTF) has demonstrated therapeutic effects in several mouse mutants with motoneuronal degeneration. However, the poor bioavailability and toxic side effects of recombinant CNTF protein have complicated its use in patients with amyotrophic lateral sclerosis. CNTF gene transfer strategies were developed but faced the question of whether CNTF should be delivered to motoneuron cell bodies or to their axons or muscle targets. To address this issue, we have used an adenoviral vector (AdCNTF) coding for a secretable form of CNTF and compared different routes of its administration in the mouse mutant progressive motor neuronopathy (pmn). Intramuscular, intravenous, and intracerebroventricular injections of AdCNTF or the control vector AdlacZ resulted in transgene expression in skeletal muscle fibers, hepatocytes, and ependymal cells, respectively, as determined by histochemistry and reverse transcription-polymerase chain reaction. AdCNTF intramuscularly treated and intravenously treated pmn mice showed a 25% increase in mean life span and a reduced degeneration of phrenic myelinated nerve fibers, which correlated with elevated CNTF serum bioactivities. In contrast, intracerebroventricular AdCNTF administration did not affect the mean life span or motor axonal degeneration of pmn mice. The differential efficacy of peripheral and central CNTF vector administrations might be of interest for future studies in human motor neuron diseases.
睫状神经营养因子（CNTF）已在几种运动神经元变性的小鼠突变体中显示出治疗效果。然而，重组CNTF蛋白的生物利用度低和毒副作用使其在肌萎缩侧索硬化症患者中的应用变得复杂。虽然开发了CNTF基因转移策略，但面临着CNTF应递送至运动神经元细胞体还是其轴突或肌肉靶点的问题。为了解决这个问题，我们使用了一种编码可分泌形式CNTF的腺病毒载体（AdCNTF），并比较了其在小鼠突变体进行性运动神经元病（pmn）中的不同给药途径。通过组织化学和逆转录-聚合酶链反应确定，肌肉内、静脉内和脑室内注射AdCNTF或对照载体AdlacZ分别导致骨骼肌纤维、肝细胞和室管膜细胞中的转基因表达。肌肉内和静脉内给予AdCNTF治疗的pmn小鼠平均寿命增加了25%，膈神经有髓神经纤维的变性减少，这与CNTF血清生物活性升高相关。相比之下，脑室内给予AdCNTF对pmn小鼠的平均寿命或运动轴突变性没有影响。外周和中枢给予CNTF载体的不同疗效可能对未来人类运动神经元疾病的研究具有重要意义。
