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
- 批准号:9243030
- 负责人:
- 金额:$ 16.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-01 至 2021-11-30
- 项目状态:已结题
- 来源:
- 关键词:5 year oldAdolescentAffectAge of OnsetAnimal ModelAnimalsBiochemicalBiodistributionBiological MarkersBloodBlood - brain barrier anatomyBody SizeBrainBypassCapsidChildClinicalClinical TrialsConsultCystic FibrosisDataDefectDevelopmentDiffusion Magnetic Resonance ImagingDiseaseDisease ProgressionElectroencephalographyEnsureEnzymesExhibitsFelis catusFrequenciesFunctional Magnetic Resonance ImagingFutureG(M2) GangliosideGangliosidoses GM2Gastric Feeding TubesGene DeliveryGenerationsGlycosphingolipidsGoalsGoldHemophilia AHumanIndustry StandardInjection of therapeutic agentInstructionIntravenousIsoenzymesK-Series Research Career ProgramsKnockout MiceLive BirthLongevityLysosomal Storage DiseasesMagnetic Resonance ImagingMagnetic Resonance SpectroscopyMentorsMethodsModalityModelingMonitorMusNatural HistoryNerve DegenerationNervous system structureNeurodegenerative DisordersNeurologicNeuropathyNeurosciencesOnset of illnessPalliative CarePatientsPeripheralPrevalenceProductionQuality of lifeReportingResearchResearch PersonnelResidual stateRouteSafetySandhoff DiseaseScientistSheepSideSymptomsTay-Sachs DiseaseTechniquesTestingThalamic structureTherapeuticTissuesTrainingUnited States National Institutes of HealthValidationVegetative StatesViralViral GenesViral VectorWorkadeno-associated viral vectorbeta-n-acetylhexosaminidasebiomarker identificationbrain sizecellular transductionclinical effectdisease heterogeneityeffective therapyexperienceexperimental studygene therapygene transfer vectorimprovedinfancyintravenous injectionmetabolomicsmouse modelnovelsuccesstranslational neurosciencevectorvirtual
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.
项目概要
溶酶体贮积病 (LSD) 由超过 40 种不同的疾病组成,累积患病率为 1%
7,700 名活产婴儿,其发生率与囊性纤维化和血友病相似。每种 LSD 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。
贮积病有一定程度的神经系统受累,以前认为有几种与周围组织有关
尽管已经开发出有效的治疗方法,但目前仅将其归类为神经病亚型。
一些溶酶体疾病的外周表现,那些具有神经系统成分的疾病实际上已被
泰-萨克斯病 (TSD) 和桑德霍夫病 (SD) 都是由基因中的亚基缺陷引起的。
酶己糖胺酶(Hex),与颅内注射的腺苷几乎无法区分。
相关病毒 (AAV) 载体使人类的寿命延长了 4 倍以上,并大大提高了生活质量
患有桑霍夫病的小鼠和猫新发现的泰萨克斯羊是唯一相关的动物。
泰-萨克斯病 (TSD) 模型,并可能揭示与 TSD 相关的挑战,而这些挑战在
此外,桑霍夫猫和老鼠还在真实的 TSD 模型中测试了大脑和身体尺寸的治疗方法。
与儿童处于同一数量级,将提供有关病媒安全、生物分布和
患有泰萨克斯病的绵羊经历了异质的临床症状,这些症状代表了高度的症状。
人类青少年患者的发病年龄和临床症状各异。该提案的首要目标是。
识别、表征和验证泰萨克斯羊的生物标志物,并了解它们与
该项目将利用超高场(7特斯拉)磁共振成像,
结合功能性 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与否
目标 2。初步研究表明,同时递送两个 Hex 亚基对于正常情况来说是理想的。
六同工酶的比率,但酶水平低于正常水平,因此,我们计划测试一种新型双顺反子。
使用新颖的方法在单个构建体中表达两个六角亚基的载体,具有优异的酶表达
AAV 衣壳比行业标准 AAV9 更高效地转导大脑(目标 2)。
绕过脑实质注射的侵入性,我们将通过静脉注射这种新的 AAV
注射并与丘脑+脑脊液输送的“黄金标准”途径进行比较。
该项目最终将为 GM2 神经节苷脂沉积症以及其他 AAV 的未来人体临床试验提供信息
LSD 试验。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Heather L Gray-Edwards其他文献
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:
$ 16.91万 - 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:
10063918 - 财政年份:2016
- 资助金额:
$ 16.91万 - 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:
$ 16.91万 - 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:
$ 16.91万 - 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:
$ 16.91万 - 项目类别:
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