Therapeutic benefits of intrathecal protein therapy in a mouse model of amyotrophic lateral sclerosis
Therapeutic benefits of intrathecal protein therapy in a mouse model of amyotrophic lateral sclerosis
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DOI：
10.1002/jnr.21747
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发表时间：
2008-10-01
影响因子：
4.2
通讯作者：
Abe, Koji
中科院分区：
文献类型：
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作者：
Ohta, Yasuyuki;Kamiya, Tatsushi;Abe, Koji
当与来自人类免疫缺陷病毒Tat蛋白的蛋白转导结构域(PTD)融合时，蛋白质可以穿过血脑屏障和细胞膜，转移到包括大脑在内的几个组织中，使蛋白质治疗各种神经疾病成为可能。我们构建了抗细胞凋亡基因修饰的BclX-L蛋白(最初由BclX-L构建而成)与TAT衍生的PTD融合，并在家族性肌萎缩侧索硬化症(ALS)小鼠模型上验证了其临床疗效。我们证明了鞘内注射TAT融合蛋白可以有效地转移到脊髓神经元，包括运动神经元，并且鞘内注射TAT修饰的BclX-L延缓了疾病的发生，延长了生存时间，并改善了运动能力。组织学研究显示，经TAT修饰的BCL-X-L处理的G93A小鼠腰髓运动神经元丢失减轻，caspase9、caspase3和末端脱氧核苷酸转移酶介导的dUTP缺口末端标记(TUNEL)阳性细胞数量减少。我们的结果表明，使用TAT融合蛋白的鞘内蛋白治疗ALS是一种有效的临床工具。(C)2008年Wiley-Liss，Inc.
When fused with the protein transduction domain (PTD) derived from the human immunodeficiency virus TAT protein, proteins can cross the blood-brain barrier and cell membrane and transfer into several tissues, including the brain, making protein therapy feasible for various neurological disorders. We have constructed a powerful antiapoptotic modified Bcl-X-L protein (originally constructed from Bcl-X-L) fused with PTD derived from TAT (TAT-modified Bcl-X-L), and, to examine its clinical effectiveness in a mouse model of familial amyotrophic lateral sclerosis (ALS), transgenic mice expressing human Cu/Zn superoxide dismutase (SOD1) bearing a G93A mutation were treated by intrathecal infusion of TAT-modified Bcl-X-L. We demonstrate that intrathecally infused TAT-fused protein was effectively transferred into spinal cord neurons, including motor neurons, and that intrathecal infusion of TAT-modified Bcl-X-L delayed disease onset, prolonged survival, and improved motor performance. Histological studies show an attenuation of motor neuron loss and a decrease in the number of cleaved caspase 9-, cleaved caspase 3-, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells in the lumbar cords of TAT-modified BCl-X-L-treated G93A mice. Our results indicate that intrathecal protein therapy using a TAT-fused protein is an effective clinical tool for the treatment of ALS. (C) 2008 Wiley-Liss, Inc.