Long-term replacement of a mutated nonfunctional CNS gene: Reversal of hypothalamic diabetes insipidus using an EIAV-based lentiviral vector expressing arginine vasopressin
Long-term replacement of a mutated nonfunctional CNS gene: Reversal of hypothalamic diabetes insipidus using an EIAV-based lentiviral vector expressing arginine vasopressin
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DOI：
10.1016/s1525-0016(03)00069-8
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发表时间：
2003-05-01
影响因子：
12.4
通讯作者：
Uney, JB
中科院分区：
文献类型：
--
作者：
Bienemann, AS;Martin-Rendon, E;Uney, JB
由于大脑功能的复杂性和监测神经元基因表达变化的困难，慢病毒基因治疗载体治疗中枢神经系统疾病的潜力很难完全评估。在这项研究中，我们评估了第三代马传染性贫血病毒 (EIAV) 在布拉特尔伯勒大鼠尿崩症模型中的效用，其中精氨酸加压素 (AVP) 基因的突变导致产生无功能的突变 AVP 前体蛋白。重要的是，通过使用该模型，可以通过非侵入性测定来监测基因治疗的成功。将 EIAV-CMV-AVP 载体注射到下丘脑视上核中导致大细胞神经元中功能性 AVP 肽的表达。与此同时，通过持续 1 年测量期的每日饮水量、尿液产生量和尿液渗透压评估，水稳态恢复 100%。这些数据表明，导致神经系统疾病的单基因缺陷可以通过基于慢病毒的策略来纠正。这项研究强调了使用病毒基因疗法长期治疗中枢神经系统疾病的潜力。
Due to the complexity of brain function and the difficulty in monitoring alterations in neuronal gene expression, the potential of lentiviral gene therapy vectors to treat disorders of the CNS has been difficult to fully assess. In this study, we have assessed the utility of a third-generation equine infectious anemia virus (EIAV) in the Brattleboro rat model of diabetes insipidus, in which a mutation in the arginine vasopressin (AVP) gene results in the production of nonfunctional mutant AVP precursor protein. Importantly, by using this model it is possible to monitor the success of the gene therapy treatment by noninvasive assays. Injection of an EIAV-CMV-AVP vector into the supraoptic nuclei of the hypothalamus resulted in expression of functional AVP peptide in magnocellular neurons. This was accompanied by a 100% recovery in water homeostasis as assessed by daily water intake, urine production, and urine osmolality lasting for a 1-year measurement period. These data show that a single gene defect leading to a neurological disorder can be corrected with a lentiviral-based strategy. This study highlights the potential of using viral gene therapy for the long-term treatment of disorders of the CNS.