AAV1.NT-3 Gene Therapy for Charcot-Marie-Tooth Neuropathy
AAV1.NT-3 Gene Therapy for Charcot-Marie-Tooth Neuropathy
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DOI：
10.1038/mt.2013.250
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发表时间：
2014-03-01
影响因子：
12.4
通讯作者：
Mendell, Jerry R.
中科院分区：
文献类型：
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作者：
Sahenk, Zarife;Galloway, Gloria;Mendell, Jerry R.
夏-玛丽-图斯（CMT）神经病是一种异质的周围神经疾病，影响2500人中有1人。其中一种变体，CMT1A，是一种原发性雪旺细胞（SC）疾病，代表了最常见的单一变体。在之前的研究中，我们发现神经营养因子-3 （NT-3）改善了-tremblerJ （Tr-J）小鼠，对CMT1A患者也有疗效。由于NT-3半衰期短和缺乏可用性，长期治疗NT-3是不可能的。这导致考虑通过腺相关病毒（AAV）递送到肌肉的NT-3基因治疗，作为分泌器官广泛分布这种神经营养剂。在脱髓鞘CMT的TrJ模型中，rAAV1。NT-3治疗导致血液中可测量的NT-3分泌水平足以改善周围神经的运动功能、组织病理学和电生理。此外，我们发现复合肌肉动作电位振幅可以作为功能改善的替代指标，并确定了治疗剂量和肌肉特异性启动子以达到持续的NT-3水平。这些研究是关于rAAV1肌内（i.m）递送的。NT-3可作为未来CMT1A临床试验的模板，有可能将治疗扩展到其他神经再生受损的神经疾病。
Charcot-Marie-Tooth (CMT) neuropathies represent a heterogeneous group of peripheral nerve disorders affecting 1 in 2,500 persons. One variant, CMT1A, is a primary Schwann cell (SC) disorder, and represents the single most common variant. In previous studies, we showed that neurotrophin-3 (NT-3) improved the -tremblerJ (Tr-J) mouse and also showed efficacy in CMT1A patients. Long-term treatment with NT-3 was not -possible related to its short half-life and lack of availability. This led to considerations of NT-3 gene therapy via -adenoassociated virus (AAV) delivery to muscle, acting as secretory organ for widespread distribution of this neurotrophic agent. In the TrJ model of demyelinating CMT, rAAV1. NT-3 therapy resulted in measurable NT-3 secretion levels in blood sufficient to provide improvement in motor function, histopathology, and electrophysiology of peripheral nerves. Furthermore, we showed that the compound muscle action potential amplitude can be used as surrogate for functional improvement and established the therapeutic dose and a preferential muscle- specific promoter to achieve sustained NT-3 levels. These studies of intramuscular (i.m.) delivery of rAAV1. NT-3 serve as a template for future CMT1A clinical trials with a potential to extend treatment to other nerve diseases with impaired nerve regeneration.