A Novel Vector Platform to Actualize T Cell Modification In Vivo
一种在体内实现 T 细胞修饰的新型载体平台
基本信息
- 批准号:10663022
- 负责人:
- 金额:$ 42.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-04 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AblationAddressAdenovirusesAdvanced DevelopmentBCAR1 geneCapsidCellsChimera organismChronicClinicalClustered Regularly Interspaced Short Palindromic RepeatsDependovirusDevelopmentDiseaseEngineeringFiberFosteringGene DeliveryGene TransferGenerationsGenesGeneticGenomeHumanImmunotherapyIn SituInterventionLiverLocalesMalignant NeoplasmsMethodsModificationMusOrganPatientsSerotypingSimian AdenovirusesSingle-Stranded DNASumSurfaceSystemT-LymphocyteTechniquesTechnologyTimeTissuesTransgenesTropismViralVirusVirus Diseasesbase editingchimeric antigen receptorchimeric antigen receptor T cellscostdesignflexibilitygene delivery systemimprovedin vivomouse modelneoplasticnovelnovel strategiesparticlepractical applicationrepairedtechnology platformtherapeutic genome editingtherapy outcometransduction efficiencyvector
项目摘要
ABSTRACT
To address the need for improved gene editing delivery systems, we propose constructing a chimeric “AdAAV”
vector consisting of an adenovirus (Ad) with multiple adeno-associated viruses (AAVs) conjugated to its capsid's
surface. We plan to employ the SpyTag/SpyCatcher technology to conjugate AAVs onto the Ad capsid. Of note
in this regard, Ads are able to selectively target certain tissues (such as the liver in the case of huAd5) with high
transduction efficiencies. Furthermore, our group has been able to engineer Ad fibers to facilitate tissue-specific
targeting of T cells. In addition, by choosing an appropriate AAV serotype, and/or through capsid engineering
AAVs can also selectively target desired tissues as well. AdAAVs may therefore provide superior targeting
through the combined effects of both engineered Ad fiber and AAV capsid (which are matched to target the same
tissue type). As a proof-of-concept, we plan to target T cells with AdAAVs. In addition, because AAVs carry
single-stranded DNA, they can provide single-stranded donor templates, which are known to enhance the editing
efficiency of homology directed repair (HDR). Within an AdAAV, the Cas protein can be encoded by the Ad
genome while the single-stranded DNA template can be embodied within the genome of the AAVs. By virtue of
the advantages of single-stranded donor templates for HDR, and by virtue of the high copy number of donor
templates carried by the multiple AAVs associated with each Ad, this design might substantially increase editing
efficiency. Finally, the AdAAV would possess a large packaging capacity since it would consist of a sum of the
Ad's capacity (which is already high) and the AAV's capacity. Due to these factors, we suggest that AdAAVs
may form a powerful and versatile new delivery system for gene editing therapies which overcomes many of the
limitations associated with existing approaches. Our highly original AdAAV delivery system will greatly enhance
the versatility of existing CRISPR-Cas gene editing therapies by circumventing several key obstacles to their
broader applicability. The design features of AdAAV will potentially make it an ideal vector by which to address
the challenges of gene editing delivery and thereby broadly enhance the general feasibility of gene editing-based
therapies.
抽象的
为了满足改进基因编辑传递系统的需求,我们建议构建嵌合“AdAAV”
由腺病毒 (Ad) 和与其衣壳缀合的多个腺相关病毒 (AAV) 组成的载体
表面。我们计划采用 SpyTag/SpyCatcher 技术将 AAV 结合到 Ad 衣壳上。值得注意的是
在这方面,广告能够选择性地针对某些组织(例如 huAd5 的肝脏),具有高
转导效率。此外,我们的团队已经能够设计Ad纤维以促进组织特异性
T 细胞的靶向。此外,通过选择合适的 AAV 血清型和/或通过衣壳工程
AAV 还可以选择性地靶向所需的组织。因此,AdAAV 可能提供卓越的靶向性
通过工程化 Ad 纤维和 AAV 衣壳(它们与相同的目标相匹配)的综合作用
组织类型)。作为概念验证,我们计划用 AdAAV 靶向 T 细胞。此外,由于 AAV 携带
单链 DNA,他们可以提供单链供体模板,已知可以增强编辑
同源定向修复(HDR)的效率。在 AdAAV 中,Cas 蛋白可以由 Ad 编码
基因组,而单链 DNA 模板可以包含在 AAV 的基因组内。凭借
HDR单链供体模板的优点,并凭借供体的高拷贝数
与每个广告关联的多个 AAV 携带的模板,这种设计可能会大大增加编辑量
效率。最后,AdAAV 将拥有很大的包装容量,因为它将包含以下总和:
广告的容量(已经很高)和 AAV 的容量。由于这些因素,我们建议 AdAAV
可能会形成一个强大且多功能的基因编辑疗法新传递系统,克服许多问题
与现有方法相关的局限性。我们高度原创的AdAAV传输系统将大大增强
现有 CRISPR-Cas 基因编辑疗法的多功能性,克服了其应用的几个关键障碍
更广泛的适用性。 AdAAV 的设计特征将有可能使其成为解决以下问题的理想载体:
基因编辑交付的挑战,从而广泛增强基于基因编辑的总体可行性
疗法。
项目成果
期刊论文数量(0)
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David Terry Curiel其他文献
David Terry Curiel的其他文献
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{{ truncateString('David Terry Curiel', 18)}}的其他基金
Endothelial-targeted adenovirus for organ-selective gene editing in vivo
用于体内器官选择性基因编辑的内皮靶向腺病毒
- 批准号:
10228031 - 财政年份:2019
- 资助金额:
$ 42.76万 - 项目类别:
Endothelial-targeted adenovirus for organ-selective gene editing in vivo
用于体内器官选择性基因编辑的内皮靶向腺病毒
- 批准号:
9810634 - 财政年份:2019
- 资助金额:
$ 42.76万 - 项目类别:
A 3D IN VITRO DISEASE MODEL OF ATRIAL CONDUCTION
心房传导 3D 体外疾病模型
- 批准号:
10166441 - 财政年份:2017
- 资助金额:
$ 42.76万 - 项目类别:
A 3D IN VITRO DISEASE MODEL OF ATRIAL CONDUCTION
心房传导 3D 体外疾病模型
- 批准号:
10228624 - 财政年份:2017
- 资助金额:
$ 42.76万 - 项目类别:
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