Preclinical development of a gene therapy for Niemann-Pick disease, type A

描述(申请人提供)：该项目的广泛目标是开发一种有效的方法，将一种基因疗法输送到人脑，以改善A型尼曼-皮克病(NPD)所遇到的神经缺陷。有了小鼠疗效数据，我们相信编码人类酸性鞘磷脂酶(HASM)的AAV载体很可能在治疗人类疾病方面有效。然而，一个主要的挑战是，为了实现人类临床上的显著改善，可能需要广泛表达hASM。基因敲除小鼠的疗效数据虽然令人鼓舞，但并没有真正解决我们在更大的人脑中面临的技术问题。临床疗效将在很大程度上取决于将基因治疗载体输送到脑干等敏感和高度有问题的区域的技术的发展。最近，我们开发了一种在MRI上可视化输液导管放置的方法，实际上可以实时跟踪注射标记有Gd的脂质体，称为实时对流输送(RCD)。在初步实验中，我们发现这些脂质体的分布非常像AAV1。我们假设，含有hASM基因和GDL的AAV1的混合物将允许实时跟踪AAV介导的基因治疗。我们计划将MRI引导下的AAV1-hASM应用于Niemann-Pick病的治疗。我们建议在这一应用中进行实验，我们相信这些实验将形成总体上大脑基因治疗的重大改进的基础，更具体地说，将在LSD的神经方面的治疗中形成基础。

DESCRIPTION (provided by applicant): The broad aim of this project is to develop an efficient means to deliver to the human brain a genetic therapy to ameliorate the neurological deficits encountered in Type A Niemann-Pick disease (NPD). Armed with mouse efficacy data, we are confident that an AAV vector that encodes human acidic sphingomyelinase (hASM) is likely to be effective in treating the disease in humans. A major challenge, however, is that widespread expression of hASM will probably be required in order to achieve significant clinical improvement in humans. Efficacy data in knockout mice, although encouraging, does not really address the technical issues that we face in the very much larger human brain. Clinical efficacy will rely considerably upon the development of techniques to deliver gene therapy vectors to such sensitive and highly problematic regions as brainstem. Recently, we have developed a method of visualizing placement of infusion cannulas on MRI, and can actually follow infusion of liposomes tagged with Gadolinium in real-time, termed Real-time Convective Delivery (RCD). In preliminary experiments, we found that these liposomes distribute very like AAV1. We hypothesize that a mixture of AAV1 containing the hASM cDNA and GDL will permit real-time tracking of AAV-mediated gene therapy. We plan to use MRI-guided delivery of AAV1-hASM in the development of a therapy for Niemann-Pick disease. We propose experiments in this application that we believe will form the basis of a major improvement in brain gene therapy in general, and more specifically in the treatment of neurological aspects of LSD's.