Expression System with Adeno-Associated Viral Vectors
具有腺相关病毒载体的表达系统
基本信息
- 批准号:7216729
- 负责人:
- 金额:$ 30.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:Pseudomonas aeruginosaadeno associated virus groupapoptosiscell linechloride channelscystic fibrosiscytokinedisease /disorder modelgene expressiongene therapygenetically modified animalsglycosylationhistopathologyhuman tissueinflammationlaboratory mousemucosal immunitypatient oriented researchprotease inhibitorrespiratory epitheliumterminal nick end labelingtoxicologytransfection /expression vectortumor antigens
项目摘要
The complexity of the CF lung disease phenotype has, up to now, defied precise explanation. Primary aberrations within the airways of CF patients include deficiency of cAMP-activated chloride conductance, sodium hyperabsorption, and a marked propensity for infection with Pseudomonas aeruginosa resulting in purulent inflammation and an imbalance of protease activity over antiprotease activity. These effects ultimately result in partial or complete
obstruction of the airway lumen, cytotoxicity, and destruction of the extracellular matrix. The exact mechanisms underlying the propensity to inflammatory airways disease are unknown, but may relate to an alteration in the glycosylation pattern of surface glycoproteins, increased binding of Pseudomonas aeruginosa, and an exaggerated pro-inflammatory cytokine response that might relate to the presence of a cell stress response. Recent microarray studies have indicated that the complex phenotype of CF lung disease is reflected by a complex pattern of altered gene regulation, both at baseline and in response to Pseudomonas exposure. While it remains axiomatic that wild-type CFTR gene transfer itself will be the ultimate primary prevention for CF lung disease, there may yet be many individuals with existing CF lung disease for whom a secondary amelioration strategy may be more feasible. The primary hypotheses to be tested in this proposal are the following: Aberrant down-regulation of certain anti-protease, anti-inflammatory, and gly?osylation-related genes contribute to CF lung disease, and augmentation of these substances will ameliorate the CF lung disease phenotype. There is also a secondary hypothesis related to the observation that two of the anti-proteases that are down-regulated in CF, squamous cell carcinoma antigen-1 (SCCA-1) and SCCA-2 appear to be primarily intracellular anti-proteases that are up-regulated in malignant lung tumors and
down-regulated in CF. This might lead one to speculate as to whether these intracellular anti-proteases could also be anti-apoptotic (perhaps through caspase inhibition), thus contributing to the immortalization of tumor cells, and conversely to epithelial cell death in CF. The latter hypothesis will also be studied in the context of CF lung disease models. Four aims are proposed: (1) The down-regulation of anti-proteases, anti-inflammatory cytokines and
glycosylation enzymes will be examined in CF cell lines, the CFTR knock-out mouse, and clinical samples of CF lung tissue; (2) The effects of exogenous vector-mediated expression of a number of anti-proteases will be evaluated in the Pseudomonas-infected CFTR knock-out mouse model; (2a) Depending on the results of Aim 1, the potential value of augmenting other gene products, such as anti-inflammatory cytokines and glycosylation enzymes, will be evaluated;
(3) The in vivo dynamic range of transcriptionally-regulated vector cassettes will be assessed; and (4) The anti-protease-rAAV constructs determined to biologically active and safe in the infected lung models outlined in Aim 2 will undergo formal preclinical toxicology testing will be performed as a prelude to clinical trials in CF patients. We anticipate that whether or not gene augmentation of these specific molecules becomes practical, that lessons learned in these models might serve as target validation for these molecules or for agents with similar mechanisms of action.
迄今为止,CF 肺病表型的复杂性尚无法准确解释。 CF患者气道内的主要异常包括cAMP激活的氯离子电导不足、钠吸收过度以及明显的铜绿假单胞菌感染倾向,导致化脓性炎症和蛋白酶活性与抗蛋白酶活性失衡。这些影响最终导致部分或全部
气道腔阻塞、细胞毒性和细胞外基质破坏。炎症性气道疾病倾向的确切机制尚不清楚,但可能与表面糖蛋白糖基化模式的改变、铜绿假单胞菌结合增加以及可能与细胞存在有关的过度促炎细胞因子反应有关应激反应。最近的微阵列研究表明,CF 肺病的复杂表型反映在基线和对假单胞菌暴露的反应中基因调控改变的复杂模式。虽然野生型 CFTR 基因转移本身将是 CF 肺病的最终一级预防仍然是不言而喻的,但对于许多患有 CF 肺病的个体来说,二级改善策略可能更可行。本提案要测试的主要假设如下:某些抗蛋白酶、抗炎和糖基化相关基因的异常下调会导致 CF 肺病,而增加这些物质将改善 CF 肺病疾病表型。还有一个与观察结果相关的次要假设,即 CF 中下调的两种抗蛋白酶、鳞状细胞癌抗原 1 (SCCA-1) 和 SCCA-2 似乎主要是细胞内抗蛋白酶,它们在恶性肺部肿瘤中上调
CF 中下调。这可能会导致人们推测这些细胞内抗蛋白酶是否也可以抗凋亡(可能通过半胱天冬酶抑制),从而有助于肿瘤细胞的永生化,并反过来促进 CF 中的上皮细胞死亡。后一种假设也将在 CF 肺部疾病模型的背景下进行研究。提出了四个目标:(1)抗蛋白酶、抗炎细胞因子和
将在 CF 细胞系、CFTR 敲除小鼠和 CF 肺组织临床样本中检查糖基化酶; (2) 将在假单胞菌感染的CFTR敲除小鼠模型中评估外源载体介导的多种抗蛋白酶表达的效果; (2a) 根据目标 1 的结果,将评估增强其他基因产物(例如抗炎细胞因子和糖基化酶)的潜在价值;
(3) 评估转录调控载体盒的体内动态范围; (4) 目标 2 中概述的被确定在受感染肺部模型中具有生物活性和安全性的抗蛋白酶-rAAV 构建体将接受正式的临床前毒理学测试,作为 CF 患者临床试验的前奏。我们预计,无论这些特定分子的基因增强是否变得实用,在这些模型中学到的经验教训都可以作为这些分子或具有类似作用机制的药物的目标验证。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Terence R. Flotte其他文献
Swinging for the fences: persistent and efficient liver-directed gene therapy for hemophilia A
摇摆不定:针对血友病 A 的持续有效的肝脏定向基因治疗
- DOI:
- 发表时间:
2004 - 期刊:
- 影响因子:0
- 作者:
Terence R. Flotte - 通讯作者:
Terence R. Flotte
Why Human Gene Therapy Scientists Should Care About Model Organisms.
为什么人类基因治疗科学家应该关心模型生物。
- DOI:
- 发表时间:
2016 - 期刊:
- 影响因子:4.2
- 作者:
Terence R. Flotte - 通讯作者:
Terence R. Flotte
Immunity to adeno-associated virus serotype 2 delivered transgenes imparted by genetic predisposition to autoimmunity
对腺相关病毒血清型 2 传递的转基因的免疫力是由自身免疫遗传倾向赋予的
- DOI:
- 发表时间:
2004 - 期刊:
- 影响因子:5.1
- 作者:
Ying Zhang;Matthew Powers;C. Wasserfall;T. Brusko;Sihong Song;Terence R. Flotte;Richard O. Snyder;Mark Potter;Marda Scott;M. Campbell;James M. Crawford;Harry S. Nick;A. Agarwal;T. Ellis;Mark A. Atkinson - 通讯作者:
Mark A. Atkinson
Intrathecal gene therapy for neurologic disease in humans.
用于人类神经系统疾病的鞘内基因治疗。
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:12.4
- 作者:
Terence R. Flotte - 通讯作者:
Terence R. Flotte
Adeno-associated virus vectors for gene therapy of cystic fibrosis.
用于囊性纤维化基因治疗的腺相关病毒载体。
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:0
- 作者:
Terence R. Flotte;Barrie J. Carter - 通讯作者:
Barrie J. Carter
Terence R. Flotte的其他文献
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{{ truncateString('Terence R. Flotte', 18)}}的其他基金
Models and Gene Therapies for AAT Deficiency
AAT 缺乏症的模型和基因疗法
- 批准号:
10463802 - 财政年份:2021
- 资助金额:
$ 30.45万 - 项目类别:
Models and Gene Therapies for AAT Deficiency
AAT 缺乏症的模型和基因疗法
- 批准号:
10270089 - 财政年份:2021
- 资助金额:
$ 30.45万 - 项目类别:
Models and Gene Therapies for AAT Deficiency
AAT 缺乏症的模型和基因疗法
- 批准号:
10463803 - 财政年份:2021
- 资助金额:
$ 30.45万 - 项目类别:
Optimized Gene Replacement for AAT deficiency and Modeling of Clinical Outcomes in small and large animal models
针对 AAT 缺陷的优化基因替换以及小型和大型动物模型中的临床结果建模
- 批准号:
10674943 - 财政年份:2021
- 资助金额:
$ 30.45万 - 项目类别:
Optimized Gene Replacement for AAT deficiency and Modeling of Clinical Outcomes in small and large animal models
针对 AAT 缺陷的优化基因替换以及小型和大型动物模型中的临床结果建模
- 批准号:
10463807 - 财政年份:2021
- 资助金额:
$ 30.45万 - 项目类别:
Models and Gene Therapies for AAT Deficiency
AAT 缺乏症的模型和基因疗法
- 批准号:
10674935 - 财政年份:2021
- 资助金额:
$ 30.45万 - 项目类别:
Models and Gene Therapies for AAT Deficiency
AAT 缺乏症的模型和基因疗法
- 批准号:
10674934 - 财政年份:2021
- 资助金额:
$ 30.45万 - 项目类别:
Models and Gene Therapies for AAT Deficiency
AAT 缺乏症的模型和基因疗法
- 批准号:
10270088 - 财政年份:2021
- 资助金额:
$ 30.45万 - 项目类别:
Optimized Gene Replacement for AAT deficiency and Modeling of Clinical Outcomes in small and large animal models
针对 AAT 缺陷的优化基因替换以及小型和大型动物模型中的临床结果建模
- 批准号:
10270092 - 财政年份:2021
- 资助金额:
$ 30.45万 - 项目类别:
New Approaches to Gene Therapy for Alpha-1 Antitrypsin Deficiency
治疗 Alpha-1 抗胰蛋白酶缺乏症的基因治疗新方法
- 批准号:
9322543 - 财政年份:2016
- 资助金额:
$ 30.45万 - 项目类别:
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基于 PDL1 的 rAAV 介导的小鼠 T1D 基因治疗
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