Liver Cancer Risk with rAAV Gene Therapy
rAAV 基因治疗的肝癌风险
基本信息
- 批准号:9233058
- 负责人:
- 金额:$ 58.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-04-01 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAlcoholsAnimal ModelCRISPR/Cas technologyCellsChromosomes, Human, Pair 12ChronicClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsDataDevelopmentDoseEnhancersEventExperimental ModelsEye diseasesFatty acid glycerol estersFemaleFrequenciesFutureGene TargetingGene Transduction AgentGene therapy trialGenomeHemophilia AHepatocyteHereditary DiseaseHumanInjectableInjection of therapeutic agentInsertional MutagenesisIntravenousLeadLiverLongitudinal StudiesMacaca mulattaMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of liverMicroRNAsModelingMonitorMonkeysMusNewborn InfantOutcomePatientsPrimary carcinoma of the liver cellsRecombinant adeno-associated virus (rAAV)ReportingResistanceRiskRisk FactorsSmall Nucleolar RNASystemTechnologyTestingTransplantationVirus Diseasesage effectcancer riskclinical effectclinical practiceclinically relevantcohortdesignexperimental studyfollow-upgene therapyhomologous recombinationhuman diseasein vivolipoprotein lipaseliver cell proliferationliver injurymaleneonatenonhuman primatenucleaseoverexpressionpredictive modelingpromoterpublic health relevancesuccesstumorvector
项目摘要
DESCRIPTION (provided by applicant):
Gene therapy based on recombinant adeno-associated virus (rAAV) vectors is showing great clinical promise. Previously, we showed that an intravenous rAAV injection could cause hepatocellular carcinoma (HCC) in newborn mice due to vector integration into and activation of a specific locus on chromosome 12 which we call the AAV-HCC locus in this proposal. Even a single integration event was sufficient to cause HCC in mice. Given that this locus is highly conserved and overexpressed in a subclass of human HCC, these mouse studies raise significant concerns about a possible risk of HCC induction in human gene therapy trials. In order to advance the promising field of liver-directed rAAV therapy, it is important to establish whether rAAV is likely to cause HCC in humans. In this proposal we systematically explore the risk of HCC caused by vector integration at the AAV-HCC locus, using three different animal models to establish the effects of clinically relevant risk factors, as well as vector design on HC induction. In addition, we will assess the risk conferred by random integration of rAAV gene therapy vectors in the liver. Our results will have a significant impact on the clinical practice o liver-directed gene therapy, not only for rAAV vectors, but also for any integrating vector, and may lead to new experimental models of human HCC.
描述(由申请人提供):
基于重组腺相关病毒(rAAV)载体的基因治疗显示出巨大的临床前景。以前,我们表明,静脉注射rAAV可能会导致新生小鼠肝细胞癌(HCC),由于载体整合和激活染色体12上的一个特定位点,我们称之为AAV-HCC位点在这个建议。即使是单一整合事件也足以在小鼠中引起HCC。鉴于该基因座在人类HCC的一个亚类中高度保守和过表达,这些小鼠研究引起了对人类基因治疗试验中HCC诱导的可能风险的重大关注。为了推进肝脏靶向rAAV治疗的前景,重要的是要确定rAAV是否可能在人类中引起HCC。在该提案中,我们系统地探索了由AAV-HCC位点处的载体整合引起的HCC的风险,使用三种不同的动物模型来建立临床相关风险因素以及载体设计对HC诱导的影响。此外,我们将评估rAAV基因治疗载体在肝脏中随机整合所带来的风险。我们的研究结果将对肝脏定向基因治疗的临床实践产生重大影响,不仅对于rAAV载体,而且对于任何整合载体,并可能导致新的人类HCC实验模型。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Markus Grompe其他文献
Markus Grompe的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Markus Grompe', 18)}}的其他基金
In vivo targeting of diabetes-relevant human cell types with rAAV vectors
rAAV 载体体内靶向糖尿病相关人类细胞类型
- 批准号:
8812513 - 财政年份:2014
- 资助金额:
$ 58.59万 - 项目类别:
相似海外基金
Collaborative Research: Overlooked Oxidation of Aqueous Alcohols: Kinetics, Mechanism, and Relevance to Water Reuse
合作研究:被忽视的水醇氧化:动力学、机制以及与水回用的相关性
- 批准号:
2304861 - 财政年份:2023
- 资助金额:
$ 58.59万 - 项目类别:
Continuing Grant
STTR Phase I: Development of Modular Reactors to Convert Methane to Alcohols at Low Temperatures
STTR 第一阶段:开发在低温下将甲烷转化为醇的模块化反应器
- 批准号:
2151256 - 财政年份:2023
- 资助金额:
$ 58.59万 - 项目类别:
Standard Grant
Development of amine-dehydrogenase and lyase biocatalysts for the sustainable manufacturing of unnatural chiral amino acids and amino alcohols
开发胺脱氢酶和裂解酶生物催化剂,用于可持续生产非天然手性氨基酸和氨基醇
- 批准号:
2870226 - 财政年份:2023
- 资助金额:
$ 58.59万 - 项目类别:
Studentship
Collaborative Research: Overlooked Oxidation of Aqueous Alcohols: Kinetics, Mechanism, and Relevance to Water Reuse
合作研究:被忽视的水醇氧化:动力学、机制以及与水回用的相关性
- 批准号:
2304860 - 财政年份:2023
- 资助金额:
$ 58.59万 - 项目类别:
Continuing Grant
Postdoctoral Fellowship: MPS-Ascend: Development of Selective Reaction Schemes for Photoactivation of Alcohols
博士后奖学金:MPS-Ascend:醇光活化选择性反应方案的开发
- 批准号:
2316541 - 财政年份:2023
- 资助金额:
$ 58.59万 - 项目类别:
Fellowship Award
Development of phosphorylation of alcohols in protein based on the structural modification of phosphoenolpyruvate
基于磷酸烯醇丙酮酸结构修饰的蛋白质醇磷酸化研究进展
- 批准号:
22KJ1152 - 财政年份:2023
- 资助金额:
$ 58.59万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Nickel Cross-Coupling Cascades with α-Heteroatom Radicals to Prepare Sterically Hindered Alcohols and Amines
镍与α-杂原子自由基交叉偶联级联制备位阻醇和胺
- 批准号:
10604535 - 财政年份:2023
- 资助金额:
$ 58.59万 - 项目类别:
Towards a better understanding of the effect of the pentafluorosulfanyl group on the lipophilicity and acid/base properties of alcohols and amines
更好地了解五氟硫基对醇和胺的亲脂性和酸/碱性质的影响
- 批准号:
571856-2021 - 财政年份:2022
- 资助金额:
$ 58.59万 - 项目类别:
Alliance Grants
Pd-Catalyzed C(sp3)-H Functionalizations Directed by Free Alcohols and Boc-Protected Amines
由游离醇和 Boc 保护的胺引导的 Pd 催化 C(sp3)-H 官能化
- 批准号:
10606508 - 财政年份:2022
- 资助金额:
$ 58.59万 - 项目类别:
MPS-Ascend: Nickel/Photoredox-Catalyzed C(sp3)–C(sp3) Cross-Coupling Between Alkyl Halides and Activated Alcohols
MPS-Ascend:镍/光氧化还原催化的 C(sp3)→C(sp3) 烷基卤化物和活化醇之间的交叉偶联
- 批准号:
2213210 - 财政年份:2022
- 资助金额:
$ 58.59万 - 项目类别:
Fellowship Award