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

A 型尼曼-匹克病基因疗法的临床前开发

基本信息

批准号：
7315710
负责人：
Krystof S Bankiewicz
金额：
$ 56.03万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7315710
关键词：
Achievement Address Animals Appendix Ataxia Behavioral Brain Brain Stem Brain region Cannulas Cells Cerebellum Characteristics Classical Niemann-Pick Disease Clinic Clinical Collaborations Complementary DNA Condition Corpus striatum structure Data Development Disease Dose Ensure Enzymes Face Gadolinium Gene Transduction Agent Goals Health Human Infusion procedures Investigation Knockout Mice Knowledge Letters Liposomes Magnetic Resonance Imaging Mediating Methods Monitor Monkeys Mus Neurologic Niemann-Pick Diseases Placement Primates Principal Investigator Program Development Range Rattus Reflux Research Personnel Structure Surveys Symptoms System Techniques Thalamic structure Therapeutic Effect Thinking Time Tissues Toxic effect Upper arm acidic sphingomyelinase adeno-associated viral vector base brain tissue clinical efficacy cohort experience gene therapy gray matter hemiparesis improved pre-clinical programs putamen research study technique development vector white matter

项目摘要

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.

描述（由申请人提供）：该项目的总体目标是开发一种有效的方法，向人脑提供基因疗法，以改善 A 型尼曼-匹克病 (NPD) 中遇到的神经缺陷。有了小鼠功效数据，我们相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，一个主要挑战是，为了在人类中实现显着的临床改善，可能需要 hASM 的广泛表达。基因敲除小鼠的功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将基因治疗载体递送至脑干等敏感且高度问题的区域的技术的发展。最近，我们开发了一种在 MRI 上可视化输注插管放置的方法，并且实际上可以实时跟踪标记有钆的脂质体的输注，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与AAV1非常相似。我们假设含有 hASM cDNA 和 GDL 的 AAV1 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 AAV1-hASM 递送来开发尼曼-匹克病的治疗方法。我们在此应用中提出实验，我们相信这些实验将构成脑基因治疗总体重大改进的基础，更具体地说是LSD神经系统方面的治疗。