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

描述（由申请人提供）：该项目的主要目的是开发一种有效的方法，向人脑提供基因治疗，以改善A型尼曼-皮克病（NPD）中遇到的神经功能缺损。根据小鼠疗效数据，我们确信编码人酸性鞘磷脂酶（hASM）的AAV载体可能有效治疗人类疾病。然而，一个主要的挑战是，为了在人类中实现显著的临床改善，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类大脑中面临的技术问题。临床疗效将在很大程度上依赖于技术的发展，以提供基因治疗载体的敏感和高度成问题的地区，如脑干。最近，我们开发了一种在MRI上可视化输注插管放置的方法，并且实际上可以实时跟踪用钆标记的脂质体的输注，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AAV 1。我们假设含有hASM cDNA和GDL的AAV 1的混合物将允许实时跟踪AAV介导的基因治疗。我们计划使用MRI引导的AAV 1-hASM递送来开发尼曼-匹克病的疗法。我们建议在这个应用程序中的实验，我们相信将形成一个重大的改善大脑基因治疗的基础一般，更具体地说，在神经方面的LSD的治疗。

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.