Human Hepatocyte and Discovery Core
人类肝细胞和发现核心
基本信息
- 批准号:10560532
- 负责人:
- 金额:$ 40.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-05 至 2027-01-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAnimalsBiologyBlood Coagulation FactorBreedingCRISPR/Cas technologyCellsChimerismClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsCryopreservationEngraftmentF8 geneFetal LiverGene TransferGenesGenetic EngineeringHarvestHematopoietic stem cellsHemophilia AHepaticHepatocyteHepatocyte transplantationHepatotoxicityHumanImmuneImmune responseImmune systemImmunobiologyImmunocompetentImmunologic Deficiency SyndromesIn VitroInstitutionInvestigationKnock-outKupffer CellsLentivirus VectorLiverModelingMolecularMusNatural Killer CellsPlasmaProcessRNA analysisRag1 MouseResearch PersonnelSafetyServicesSystemTherapeuticTissuesTransgenic OrganismsTransplantationViralViral GenesViral VectorcDNA Libraryexperienceexperimental studyfetalgene therapygenetic manipulationhumanized mouseimmune activationin vivoliver injurymaleoverexpressionpreservationprogramsresponseretransplantationsingle-cell RNA sequencingtwo-dimensionalvector
项目摘要
PROJECT SUMMARY/ABSTRACT
Gene therapy for hemophilia A holds promise to accomplish a lasting cure. Adeno-associated viral (AAV) gene
transfer of clotting factor FVIII to the livers of males can achieve therapeutic correction but this is not sustained.
The reasons for hepatotoxicity and the decline in FVIII expression in clinical trials are unclear. The AAV therapies
currently under investigation target hepatocytes in the liver. There is, however, a limited understanding of the
interactions between the vector and hepatocytes as well as effect of FVIII expression and immune responses.
Core B will provide primary human hepatocyte models to address these basic and mechanistic questions related
to the biology of AAV and FVIII. The central hypothesis of this proposal is that multiple interconnected features
of AAV and FVIII biology limit durability of therapeutic expression and pose serious safety concerns. The
objectives of Core B, the Human Hepatocyte and Discovery Core, is to provide three primary human hepatocytes
models to study AAV vector and FVIII biology. The first model is primary hepatocyte cultures that retain stable
hepatocyte functions in 2-dimensional format. These will be used for in vitro studies. The second model is
chimeric mice whose livers are highly repopulated with primary human hepatocytes. These will be used for in
vivo AAV studies. And the third model is mice doubly engrafted with hematopoietic stem cells and livers for in
vivo studies of human immune cells in the liver. Core B will provide these services to investigators to address
major unanswered questions in FVIII biology, gene therapy for hemophilia, liver-directed gene transfer, and
molecular and immunobiology of AAV vectors.
项目概要/摘要
A 型血友病的基因疗法有望实现持久治愈。腺相关病毒(AAV)基因
将凝血因子 FVIII 转移至男性肝脏可以实现治疗纠正,但这并不能持续。
临床试验中肝毒性和 FVIII 表达下降的原因尚不清楚。 AAV疗法
目前正在研究肝脏中的目标肝细胞。但人们对此的了解还很有限
载体和肝细胞之间的相互作用以及 FVIII 表达和免疫反应的影响。
核心 B 将提供初级人类肝细胞模型来解决这些相关的基本和机制问题
AAV 和 FVIII 的生物学。该提案的中心假设是多个相互关联的特征
AAV 和 FVIII 生物学特性限制了治疗表达的持久性并造成严重的安全问题。这
核心 B(人类肝细胞和发现核心)的目标是提供三种原代人类肝细胞
研究 AAV 载体和 FVIII 生物学的模型。第一个模型是原代肝细胞培养物,保持稳定
肝细胞以二维形式发挥功能。这些将用于体外研究。第二个模型是
嵌合小鼠的肝脏高度重新填充了原代人类肝细胞。这些将用于
体内 AAV 研究。第三种模型是对小鼠进行造血干细胞和肝脏双重移植,以进行短期治疗。
肝脏中人体免疫细胞的体内研究。核心 B 将向调查人员提供这些服务来解决
FVIII 生物学、血友病基因治疗、肝脏定向基因转移和
AAV 载体的分子和免疫生物学。
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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Ype Peter De Jong其他文献
Ype Peter De Jong的其他文献
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{{ truncateString('Ype Peter De Jong', 18)}}的其他基金
Enhancing immune regulation in gene therapy for hemophilia
增强血友病基因治疗中的免疫调节
- 批准号:
9721569 - 财政年份:2018
- 资助金额:
$ 40.06万 - 项目类别:
Enhancing immune regulation in gene therapy for hemophilia
增强血友病基因治疗中的免疫调节
- 批准号:
9756452 - 财政年份:2018
- 资助金额:
$ 40.06万 - 项目类别:
Enhancing immune regulation in gene therapy for hemophilia
增强血友病基因治疗中的免疫调节
- 批准号:
10615731 - 财政年份:2016
- 资助金额:
$ 40.06万 - 项目类别:
Enhancing immune regulation in gene therapy for hemophilia
增强血友病基因治疗中的免疫调节
- 批准号:
10401846 - 财政年份:2016
- 资助金额:
$ 40.06万 - 项目类别:
Enhancing immune regulation in gene therapy for hemophilia
增强血友病基因治疗中的免疫调节
- 批准号:
9278274 - 财政年份:2016
- 资助金额:
$ 40.06万 - 项目类别:
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