Neurturin Delivery for Huntington's Disease

描述（由申请人提供）：亨廷顿病（HD）是一种严重衰弱的遗传性神经退行性疾病，目前尚无治疗方法。因为有一个基因测试可用于HD，干预之前，疾病发作将是可能的，如果有效的治疗是可用的。已经显示，当将生长因子neurturin（NTN）递送至脑时，其有效地改善HD啮齿动物模型中的神经变性。 然而，作为一种蛋白质生长因子，NTN在全身给药后将不容易到达脑靶点。使用病毒载体的基因转移是将生长因子递送至脑的特定区域的有前景的方法，并且基于腺相关病毒（AAV）的载体在许多方面是最适合于该应用的载体。作为开发用于治疗HD的AAV递送的NTN（AAV-NTN）的第一步，我们将在两种不同的HD啮齿动物模型中测试AAV-NTN的功效：刘易斯大鼠中的3-硝基丙酸（3 NP）损伤和N171- 82 Q转基因小鼠。将评估AAV-NTN在3 NP损伤大鼠中预防神经变性和运动缺陷，并在N171- 82 Q转基因小鼠中减少神经元核内包涵体的积累以及运动和认知缺陷的能力。 这些研究的成功结果将导致在大鼠中进行安全性研究，在非人灵长类动物中进行安全性和有效性研究，如果有指征，还将提交IND和在HD患者中进行临床试验。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a severely debilitating heritable neurodegenerative condition for which there currently is no treatment. Because there is a genetic test available for HD, intervention prior to disease onset would be possible if an effective treatment were available. The growth factor neurturin (NTN) has been shown to effectively ameliorate neural degeneration in rodent models of HD when delivered to the brain. However, as a protein growth factor, NTN will not readily access brain targets following systemic administration. Gene transfer using a viral vector is a promising method for delivering growth factors to specific regions of the brain, and the adeno-associated virus (AAV) based vector is in many ways the best-suited vector for this application. As a first step towards developing AAV-delivered NTN (AAV-NTN) for the treatment of HD, we will test the efficacy of AAV-NTN in two distinct rodent models of HD: the 3-nitroproprionic acid (3NP) lesion in Lewis rats, and N171-82Q transgenic mice. The ability of AAV-NTN to prevent neurodegeneration and motor deficits in 3NP lesioned rats, and reduce accumulation of neuronal intranuclear inclusions, and motor and cognitive deficits in N171-82Q transgenic mice will be assessed. Successful results from these studies will lead to safety studies in rats, safety and efficacy studies in non-human primates, and if indicated, the filing of an IND and clinical trials in HD patients.