Endonuclease-mediated disruption of latent HSV as curative therapy
核酸内切酶介导的潜伏 HSV 破坏作为治疗方法
基本信息
- 批准号:10405036
- 负责人:
- 金额:$ 43.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-06-12 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAfferent NeuronsAnimal ModelAnimalsAntiviral TherapyAreaAutonomic ganglionCRISPR/Cas technologyCell DeathCellsChronicClinicClinicalDNADNA IntegrationDataDependovirusDevelopmentDiseaseEnzymesEvaluationExcisionFrequenciesGangliaGene DeliveryGenesGenomeGenomicsGoalsHIVHealth behaviorHepatitis B VirusHerpesvirus Type 3HomingHuman GenomeHuman PapillomavirusImmunochemistryIndividualInfiltrationInflammatoryInjectionsKineticsLaboratoriesLatent virus infection phaseLeadMeasuresMediatingMorbidity - disease rateMusMutagenesisMutateMutationNeuronsPathway interactionsPhenotypePrimary InfectionProcessRecurrenceRecurrent diseaseReporterReproducibilityRouteSafetySamplingSensory GangliaSerotypingShockSimplexvirusSiteSourceStaphylococcus aureusSystemTechnologyTestingTherapeuticTherapeutic EffectTimeTreatment EfficacyVaccinesVibrissaeViralViral GenomeViral Load resultViral PathogenesisViral reservoirVirusVirus DiseasesVirus IntegrationVirus LatencyVirus ReplicationWorkclinical applicationclinical developmentcurative treatmentsdelivery vehicleendonucleasegenome-wide analysisgenotoxicityimprovedin vivoinnovationinsertion/deletion mutationmouse genomemouse modelnext generation sequencingnovel therapeutic interventionnucleasepreclinical developmentpromoterreactivation from latencyscreeningtargeted nucleasestherapeutic developmenttransgene deliverytransgene expressiontransmission processviral DNAvirology
项目摘要
Project Summary
Herpes simplex virus (HSV) infections remain a common, serious problem associated with significant
morbidity. After primary infection, HSV establishes latency, which is not eliminated by current antiviral therapy.
Latent virus is the source for viral reactivation and the recurrence of clinical disease. Despite much effort, a
vaccine remains elusive. Therefore, there is a need for a novel therapeutic approach that would cure
latent HSV infection. We have been developing a new curative strategy to latent HSV infection, in which an
HSV-targeted endonuclease induces mutagenesis of essential HSV genes, disabling viral genomes and
rendering the virus incapable of replication or reactivation from latency. Our hypothesis is that recent advances
in the field of gene-editing technologies and in vivo gene delivery offer the opportunity to improve our current
anti-viral approach and reach therapeutic efficacy. Here, we propose to evaluate Staphylococcus aureus
(Sa)CRIPSR/Cas9 and homing endonucleases (HEs) for their ability to disable HSV in latently infected
neurons by targeted viral genome disruption, thus eliminating the source of viral pathogenesis in an animal
model of HSV infection. The goal of this project is to maximize the efficacy and safety of our approach to
eliminate latent HSV infection in vivo, using a murine model of HSV latent infection. Our results will also be
applicable in efforts to cure varicella zoster virus, another alphaherpesvirus that like HSV establishes latency in
sensory neurons. Furthermore, the data generated will be highly relevant to the development of cures for other
chronic or latent viral infections such as hepatitis B virus, HIV, or human papillomavirus.
In SA1: Address the remaining barriers to effective in vivo HSV gene editing, we will compare 1) new
AAV serotypes to our current AAV serotypes for transgene delivery after administration via different routes,
and 2) the gene editing abilities of CRISPR/Cas9 vs. HEs. In SA2: Optimize the efficacy of in vivo gene
editing and determine the impact on viral pathogenesis, we will evaluate whether the simultaneous
targeting of two HSV sites provides superior efficacy over targeting a single site, and the efficacy of gene
editing necessary to impact viral pathogenesis. In SA3: Evaluate the safety of in vivo gene editing in our
mouse model, we will use our mouse model of latent HSV infection to evaluate tolerability, safety, and
genotoxicity of nuclease exposure.
This project is expected to demonstrate the feasibility of our therapeutic approach directed towards the
elimination of HSV pathogenesis in vivo, and to provide critical information for the development of a larger
scale animal study necessary to bring this new therapeutic approach to the clinic.
项目摘要
单纯疱疹病毒(HSV)感染仍然是一个常见的,严重的问题
发病率。原发性感染后,HSV建立了潜伏期,目前的抗病毒治疗不会消除。
潜伏病毒是病毒重新激活和临床疾病复发的来源。尽管付出了很多努力,但
疫苗仍然难以捉摸。因此,需要一种新颖的治疗方法可以治愈
潜在的HSV感染。我们一直在开发一种新的治愈策略来潜在的HSV感染,其中
靶向HSV的核酸内切酶诱导基本HSV基因的诱变,使病毒基因组和
使该病毒无法复制或重新激活潜伏期。我们的假设是最近的进步
在基因编辑技术和体内基因传递的领域中,有机会改善我们的当前
抗病毒方法并达到治疗功效。在这里,我们建议评估金黄色葡萄球菌
(SA)CRIPSR/CAS9和HOUSING核酸内切酶(HES),因为它们在潜在受感染中禁用HSV的能力
通过靶向病毒基因组破坏神经元,从而消除了动物中病毒发病的来源
HSV感染的模型。该项目的目的是最大化我们方法的功效和安全性
使用HSV潜在感染的鼠模型消除体内潜在的HSV感染。我们的结果也将是
适用于治愈水痘带状疱疹病毒的努力,这是另一种像HSV一样在
感觉神经元。此外,生成的数据将与其他其他治疗方法高度相关
慢性或潜在病毒感染,例如丙型肝炎病毒,HIV或人乳头瘤病毒。
在SA1中:解决有效体内HSV基因编辑的剩余障碍,我们将比较1)新的
AAV血清型与我们当前的AAV血清型,用于通过不同途径给药后传递转基因,
2)CRISPR/CAS9与HES的基因编辑能力。在SA2中:优化体内基因的功效
编辑并确定对病毒发病机理的影响,我们将评估是否同时
两个HSV位点的靶向具有优于靶向单个位点的优势功效和基因的功效
影响病毒发病机理所必需的编辑。在SA3中:评估我们的体内基因编辑的安全性
鼠标模型,我们将使用潜在HSV感染的鼠标模型来评估耐受性,安全性和
核酸酶暴露的遗传毒性。
预计该项目将证明我们针对的治疗方法的可行性
消除体内HSV发病机理,并为开发较大的关键信息提供关键信息
将这种新的治疗方法带到诊所所必需的规模动物研究。
项目成果
期刊论文数量(1)
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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{{ truncateString('KEITH R JEROME', 18)}}的其他基金
Endonuclease-mediated disruption of latent HSV as curative therapy
核酸内切酶介导的潜伏 HSV 破坏作为治疗方法
- 批准号:
10182099 - 财政年份:2018
- 资助金额:
$ 43.77万 - 项目类别:
Endonuclease-mediated disruption of latent HSV as curative therapy
核酸内切酶介导的潜伏 HSV 破坏作为治疗方法
- 批准号:
10155424 - 财政年份:2018
- 资助金额:
$ 43.77万 - 项目类别:
Endonuclease-mediated disruption of latent HSV as curative therapy
核酸内切酶介导的潜伏 HSV 破坏作为治疗方法
- 批准号:
9597105 - 财政年份:2018
- 资助金额:
$ 43.77万 - 项目类别:
Endonuclease-mediated disruption of latent HSV as curative therapy
核酸内切酶介导的潜伏 HSV 破坏作为治疗方法
- 批准号:
9927580 - 财政年份:2018
- 资助金额:
$ 43.77万 - 项目类别:
Endonuclease-mediated disruption of latent HSV as curative therapy
核酸内切酶介导的潜伏 HSV 破坏作为治疗方法
- 批准号:
10593355 - 财政年份:2018
- 资助金额:
$ 43.77万 - 项目类别:
In vivo inactivation of latent HSV by endonuclease-mediated mutagenesis
通过核酸内切酶介导的诱变体内潜伏 HSV 灭活
- 批准号:
9199202 - 财政年份:2016
- 资助金额:
$ 43.77万 - 项目类别:
In vivo inactivation of latent HSV by endonuclease-mediated mutagenesis
通过核酸内切酶介导的诱变体内潜伏 HSV 灭活
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