Models and Gene Therapies for AAT Deficiency

AAT 缺乏症的模型和基因疗法

基本信息

项目摘要

Project Summary (OVERALL) Alpha-1 antitrypsin deficiency (AATD) is caused by mutations in the SERPINA1 gene. The E342K (PI*Z) mutant allele is very common among those of European ancestry, and E342K homozygotes encode a protein with impaired secretion, resulting in deficient AAT serum levels. Since AAT normally protects elastin in the lung from degradation, loss of effective AAT triggers lung inflammation, airways obstruction and emphysema, which is the primary life-limiting manifestation of AATD. The projects within this proposal seek to pursue numerous parallel strategies to develop a gene therapy for AATD. Most of these strategies revolve around the use of recombinant adeno-associated virus (rAAV)-based vectors, a platform technology that has been very successful for other genetic diseases. In Project 1, optimized rAAV vectors will be studied in genetically defined animal models (including mice and ferrets) in comparison with transgenic reconstitution studies using a regulated conditional transgenic system to compare two relevant potential target replacement levels (11µM and 25µM) and clinically relevant endpoints will be studied. In Project 2, novel CRISPR variants will be used for gene editing, base editing and prime editing strategies to treat AATD. In Project 3, we will screen naturally occurring AAV capsid libraries obtained from remote populations in Western China to identify capsids with enhanced efficacy and safety for AATD gene therapy. Finally, in project 4, we will use novel Treg and CAR-Treg strategies to selectively modulate anti-vector immune responses. There will also be two cores. Core A will provide each project with important Vector Immunology assays, which can identify limitations due to host immune responses to AAV capsids, the AAT transgene or to Cas9-derived proteins. Core B will provide animal models and physiologic measurements in the animal models for testing of optimized rAAV vectors, gene editing tools and immune modulation approaches. Program investigators have a track record of interactions and collaborations that we anticipate will continue in future years.
项目总结(总体)

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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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
Asymptomatic Chlamydia trachomatis infections among sexually active men.
性活跃男性中的无症状沙眼衣原体感染。
  • DOI:
    10.1093/infdis/154.5.900
  • 发表时间:
    1986
  • 期刊:
  • 影响因子:
    0
  • 作者:
    George H. Karam;David H. Martin;Terence R. Flotte;Frank O. Bonnarens;John R. Joseph;Tomasz F. Mroczkowski;William D. Johnson
  • 通讯作者:
    William D. Johnson
Real time laryngoscopy with olfactory challenge for diagnosis of psychogenic stridor
实时喉镜嗅觉激发诊断心因性喘鸣
  • DOI:
  • 发表时间:
    1993
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    S. Tomares;Terence R. Flotte;D. Tunkel;M. Pao;G. Loughlin
  • 通讯作者:
    G. Loughlin
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
498. AAV Δ264CFTR Enhances Maturation of ΔF508CFTR and wt CFTR Expression
  • DOI:
    10.1016/j.ymthe.2006.08.568
  • 发表时间:
    2006-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Liudmila Cebotaru;Terence R. Flotte;William B. Guggino
  • 通讯作者:
    William B. Guggino

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:
    10270089
  • 财政年份:
    2021
  • 资助金额:
    $ 267.67万
  • 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:
    $ 267.67万
  • 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:
    $ 267.67万
  • 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:
    $ 267.67万
  • 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:
    $ 267.67万
  • 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:
    $ 267.67万
  • 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:
    $ 267.67万
  • 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:
    $ 267.67万
  • 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:
    $ 267.67万
  • 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:
    9071187
  • 财政年份:
    2016
  • 资助金额:
    $ 267.67万
  • 项目类别:

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腺嘌呤核苷酸转位酶在慢性阻塞性肺病(COPD)线粒体功能相关衰老中的作用
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心脏缺血中琥珀酸积累和腺嘌呤核苷酸消耗的途径
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    10534031
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    2022
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Development of nobel assay methods for miRNA and adenine methyltransferase using FRET
使用 FRET 开发 miRNA 和腺嘌呤甲基转移酶的诺贝尔检测方法
  • 批准号:
    21K05120
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    2021
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    $ 267.67万
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健康老龄化和阿尔茨海默病脑细胞 DNA 腺嘌呤甲基化的批判性评估
  • 批准号:
    10365337
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    2021
  • 资助金额:
    $ 267.67万
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DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
  • 批准号:
    10033546
  • 财政年份:
    2020
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    $ 267.67万
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DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
  • 批准号:
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DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
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    10226235
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    2020
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    $ 267.67万
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DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
  • 批准号:
    10396102
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DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
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    10705982
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