Models and Gene Therapies for AAT Deficiency
AAT 缺乏症的模型和基因疗法
基本信息
- 批准号:10270088
- 负责人:
- 金额:$ 278.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-09 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdenineAffinityAllelesAnimal ModelAntibody ResponseAntigen ReceptorsBiodiversityBiological AssayBiological MarkersCRISPR/Cas technologyCapsidChinaChronic Obstructive Airway DiseaseClinicalClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsComplexCryoelectron MicroscopyDeaminaseDensitometryDiseaseDisease modelDoctor of PhilosophyElastinEnvironmentEnzymesEuropeanExhibitsFacultyFerretsFutureGene SilencingGene Transduction AgentGenesGeneticGenetic DiseasesHomozygoteHumanHuman GeneticsHybridsImmune EvasionImmune responseImmunologyImpairmentInterferon Type IILaboratoriesLeadLibrariesLifeLiverLungLung CAT ScanLung InflammationLung diseasesMeasurementMeasuresMechanicsMediatingModelingMolecularMusMuscleMutationOther GeneticsOutcomePharmaceutical PreparationsPhenotypePhysiologicalPhysiologyPopulationPropertyProteinsPulmonary EmphysemaRNA-Directed DNA PolymeraseRecombinant adeno-associated virus (rAAV)Regulatory T-LymphocyteResearch PersonnelRoleSafetySerotypingSerumSiteStructure-Activity RelationshipSystemTechnologyTestingTimeTransducersTransgenesTransgenic AnimalsTransgenic OrganismsVariantVeterinary MedicineVeterinary SchoolsWild Type Mouseadeno-associated viral vectorairway obstructionalpha 1-Antitrypsinalpha 1-Antitrypsin Deficiencybasecell mediated immune responseclinically relevantcollaborative environmentcomparative efficacydesignenzyme activityenzyme linked immunospot assaygene delivery systemgene replacementgene therapyimmunogenicimmunoregulationimprovedinnovationmouse modelmutantneutralizing antibodyneutralizing monoclonal antibodiesnew technologynext generationnonhuman primatenovelprogramsreconstitutionresponsescreeningsuccesstoolvector
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.
项目概要(总体)
Alpha-1 抗胰蛋白酶缺乏症 (AATD) 是由 SERPINA1 基因突变引起的。这
E342K (PI*Z) 突变等位基因在欧洲血统中非常常见,并且 E342K
纯合子编码的蛋白质分泌受损,导致 AAT 血清水平不足。
由于 AAT 通常会保护肺部的弹性蛋白免遭降解,因此有效 AAT 触发因素的丧失
肺部炎症、气道阻塞和肺气肿是限制生命的主要因素
AATD 的表现。本提案中的项目力求追求众多并行
开发 AATD 基因疗法的策略。大多数这些策略都围绕着使用
基于重组腺相关病毒 (rAAV) 的载体,这是一种平台技术,
在治疗其他遗传病方面也取得了非常成功的成果。在项目1中,优化的rAAV载体将是
在基因定义的动物模型(包括小鼠和雪貂)中进行研究,并与
使用受监管的条件转基因系统进行转基因重建研究以进行比较
两个相关的潜在目标替代水平(11μM 和 25μM)且具有临床相关性
将研究终点。在项目 2 中,新的 CRISPR 变体将用于基因编辑,
治疗 AATD 的碱基编辑和主要编辑策略。在项目3中,我们将自然筛选
从中国西部偏远人群中获得的 AAV 衣壳文库用于鉴定
衣壳增强了 AATD 基因治疗的功效和安全性。最后,在项目 4 中,我们将
使用新型 Treg 和 CAR-Treg 策略选择性调节抗载体免疫反应。
还将有两个核心。 Core A会为每个项目提供重要的Vector
免疫学检测,可以识别宿主对 AAV 免疫反应造成的限制
衣壳、AAT 转基因或 Cas9 衍生蛋白。核心B将提供动物模型和
动物模型中的生理测量,用于测试优化的 rAAV 载体、基因
编辑工具和免疫调节方法。计划调查员有以下记录
我们预计未来几年将继续进行互动和合作。
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:
10463802 - 财政年份:2021
- 资助金额:
$ 278.91万 - 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:
$ 278.91万 - 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:
$ 278.91万 - 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:
$ 278.91万 - 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:
$ 278.91万 - 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:
$ 278.91万 - 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:
$ 278.91万 - 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:
$ 278.91万 - 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:
$ 278.91万 - 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:
$ 278.91万 - 项目类别:
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