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

描述（由申请人提供）：本项目的主要目标是开发一种有效的方法，将基因疗法传递到人类大脑，以改善a型尼曼-皮克病（NPD）中所遭遇的神经功能缺陷。根据小鼠疗效数据，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，为了在人类中取得显著的临床改善，可能需要hASM的广泛表达。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取决于技术的发展，将基因治疗载体输送到脑干等敏感和高度问题的区域。最近，我们已经开发了一种在MRI上可视化输液套管放置的方法，并且可以实时跟踪注射带有钆标记的脂质体，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与AAV1非常相似。我们假设含有hASM cDNA和GDL的AAV1的混合物将允许实时跟踪aav介导的基因治疗。我们计划在Niemann-Pick病的治疗开发中使用mri引导的AAV1-hASM。我们在这个应用中提出的实验，我们相信将构成大脑基因治疗总体上的重大改进的基础，更具体地说，是LSD的神经学方面的治疗。

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.