Neurturin Delivery for Huntington's Disease

描述(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，目前还没有治疗方法。因为HD有一种基因测试，如果有有效的治疗方法，在疾病发作之前进行干预是可能的。生长因子神经肽(NTN)被证明能有效地改善HD啮齿动物模型的神经退行性变。然而，作为一种蛋白质生长因子，NTN在全身给药后不会轻易进入大脑靶点。利用病毒载体进行基因转移是一种将生长因子转移到大脑特定区域的有前景的方法，而基于腺相关病毒(AAV)的载体在许多方面都是最适合这一应用的载体。作为开发AAV传递的NTN(AAV-NTN)治疗HD的第一步，我们将在两种不同的HD啮齿动物模型上测试AAV-NTN的疗效：Lewis大鼠的3-硝酸(3NP)损伤和N171-82Q转基因小鼠。将评估AAV-NTN预防3NP损伤大鼠神经退行性变和运动障碍的能力，以及减少N171-82Q转基因小鼠神经元核内包涵体积累以及运动和认知障碍的能力。这些研究的成功结果将导致在大鼠身上进行安全性研究，在非人类灵长类动物上进行安全性和有效性研究，如果有指示，还将提交IND和HD患者的临床试验。

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.