Global AAV gene therapy of Tay-Sachs disease in sheep.

绵羊泰萨克斯病的全球 AAV 基因治疗。

基本信息

项目摘要

PROJECT SUMMARY Lysosomal storage diseases (LSDs) consist of >40 distinct disorders, with a cumulative prevalence of 1 in 7,700 live births, similar in frequency to cystic fibrosis and hemophilia. Each LSD has an underlying defect in lysosomal function that leads to widespread storage of undegraded substrates in all tissues. Many lysosomal storage diseases have some level of neurologic involvement, with several previously thought peripheral tissue only subtypes now categorized as neuropathic. Though effective treatments have been developed for peripheral manifestations of some lysosomal diseases, those with neurological components have been virtually untreatable. Tay-Sachs (TSD) and Sandhoff disease (SD) are each caused by a subunit deficiency in the enzyme Hexosaminidase (Hex), and are almost clinically indistinguishable. Intracranial injection of adeno associated viral (AAV) vectors has led to > 4-fold increases in life span and vastly improved quality of life in mice and cats with Sandhoff disease. The newly discovered Tay-Sachs sheep is the only relevant animal model of Tay-Sachs disease (TSD) and may inform on challenges associated with TSD not experienced in the Sandhoff cat and mouse. Additionally, testing therapy in an authentic model of TSD with brain and body size on the same order of magnitude as children, will provide invaluable data on vector safety, biodistribution and efficacy. Sheep with Tay-Sachs experience heterogeneous clinical signs which are representative of the highly variable age of onset and clinical signs experienced by human juvenile patients. The first aim of this proposal is to identify, characterize and validate biomarkers of sheep Tay-Sachs and understand their relationship to disease progression. This project will make use of ultra-high field (7 Tesla) magnetic resonance imaging, combined functional MRI–electroencephalography, MR spectroscopy, diffusion tensor imaging as well as metabolomics and electrodiagnostic testing; and these techniques will be used to evaluate therapeutic success in Aim 2. Preliminary studies have shown that simultaneous delivery of both Hex subunits is ideal for normal ratios of Hex isozymes, but enzymatic levels were below normal. Therefore, we plan to test a novel bicistronic vector that expresses both Hex subunits in a single construct with superior enzymatic expression using a novel AAV capsid that transduces the brain with greater efficiency than the industry standard AAV9 (Aim 2). To bypass the invasiveness of parenchymal brain injections, we will administer this new AAV by intravenous injection and compare side by side with the “the gold standard” routes of Thalamic+CSF delivery. Conclusions from this project will ultimately inform future human clinical trials for GM2 gangliosidosis as well as other AAV trials for LSDs.
项目摘要 溶酶体贮积病(LSD)由>40种不同的疾病组成,累积患病率为1/10。 7,700例活产,与囊性纤维化和血友病的发生频率相似。每种迷幻药都有一个潜在的缺陷, 溶酶体功能,导致未降解底物在所有组织中广泛储存。许多溶酶体 胆积症有一定程度的神经系统受累,有几种以前认为的外周组织受累 只有亚型现在被归类为神经性的。虽然已经开发出有效的治疗方法, 一些溶酶体疾病的外周表现,那些具有神经成分的几乎已经被 无法治愈泰-萨二氏病(TSD)和山德霍夫病(SD)各自由免疫球蛋白中的亚单位缺乏引起。 酶己糖胺酶(Hex),并且几乎在临床上无法区分。颅内腺注射 相关病毒(AAV)载体已经导致寿命增加> 4倍,并极大地改善了人类的生活质量。 患山德霍夫病的老鼠和猫。新发现的泰-萨克斯羊是唯一相关的动物 Tay-Sachs病(TSD)的模型,并可能告知与TSD相关的挑战,而不是在 桑德霍夫猫和老鼠。此外,在具有大脑和身体尺寸的TSD真实模型中测试治疗 将提供关于病媒安全、生物分布和 功效患有泰-萨二氏病的绵羊经历异质性临床体征,这些体征代表了 人类青少年患者的发病年龄和临床体征各不相同。这项建议的第一个目的是 识别、表征和验证绵羊泰-萨二氏病的生物标志物,并了解它们与 疾病进展。该项目将利用超高场(7特斯拉)磁共振成像, 结合功能MRI-脑电图、MR波谱、扩散张量成像以及 代谢组学和电诊断测试;这些技术将用于评估治疗成功率 目标2初步研究表明,同时递送两种Hex亚基对于正常人是理想的。 Hex同工酶的比率,但酶水平低于正常。因此,我们计划测试一种新的双顺反子 载体,其在单一构建体中表达两种Hex亚基,并使用新的酶促表达方法进行上级酶促表达。 AAV衣壳,其以比工业标准AAV 9更高的效率转导脑(Aim 2)。到 绕过脑实质注射的侵入性,我们将通过静脉内注射这种新的AAV, 注射,并与“黄金标准”的丘脑+CSF递送途径并排比较。结论 最终将为未来的GM 2神经节苷脂沉积症以及其他AAV的人类临床试验提供信息。 迷幻药的试验

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Natural history of Tay-Sachs disease in sheep.
  • DOI:
    10.1016/j.ymgme.2021.08.009
  • 发表时间:
    2021-09
  • 期刊:
  • 影响因子:
    3.8
  • 作者:
    Story B;Taghian T;Gallagher J;Koehler J;Taylor A;Randle A;Nielsen K;Gross A;Maguire A;Carl S;Johnson S;Fernau D;Diffie E;Cuddon P;Corado C;Chandra S;Sena-Esteves M;Kolodny E;Jiang X;Martin D;Gray-Edwards H
  • 通讯作者:
    Gray-Edwards H
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Heather L Gray-Edwards其他文献

Cardiovascular manifestations of feline Sandhoff disease after intravenous AAV gene therapy
  • DOI:
    10.1016/j.ymgme.2016.11.090
  • 发表时间:
    2017-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Lauren E Ellis;Randolph Winter;Heather L Gray-Edwards;Stacy Maitland;Ashley E Randle;Robert Edwards;Miguel Sena-Esteves;Douglas R Martin;Raymond Y Wang
  • 通讯作者:
    Raymond Y Wang

Heather L Gray-Edwards的其他文献

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{{ truncateString('Heather L Gray-Edwards', 18)}}的其他基金

Generation of a Large Animal Model of Sialidosis to Enable Future Translation of Novel Therapeutics
生成唾液酸贮积症的大型动物模型,以实现新疗法的未来转化
  • 批准号:
    10578286
  • 财政年份:
    2023
  • 资助金额:
    $ 18.94万
  • 项目类别:
Global AAV gene therapy of Tay-Sachs disease in sheep.
绵羊泰萨克斯病的全球 AAV 基因治疗。
  • 批准号:
    9243030
  • 财政年份:
    2016
  • 资助金额:
    $ 18.94万
  • 项目类别:
In vivo magnetic resonance-based analysis of inherited neurologic disease after g
基于体内磁共振的遗传性神经系统疾病分析
  • 批准号:
    8527241
  • 财政年份:
    2013
  • 资助金额:
    $ 18.94万
  • 项目类别:
In vivo magnetic resonance-based analysis of inherited neurologic disease after g
基于体内磁共振的遗传性神经系统疾病分析
  • 批准号:
    8657391
  • 财政年份:
    2013
  • 资助金额:
    $ 18.94万
  • 项目类别:
In vivo magnetic resonance-based analysis of inherited neurologic disease after g
基于体内磁共振的遗传性神经系统疾病分析
  • 批准号:
    8837710
  • 财政年份:
    2013
  • 资助金额:
    $ 18.94万
  • 项目类别:

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童年积极影响和愤怒是青少年危险行为的预测因素
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州大麻政策会影响青少年大麻和酒精的使用吗?
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