Novel targeted adenovirus

新型靶向腺病毒

基本信息

批准号：
10163752
负责人：
David Terry Curiel
金额：
$ 34.88万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-19 至 2023-05-31
项目状态：
已结题

项目摘要

ABSTRACT A central mandate to realize effective gene therapy is the ability to accomplish cell specific delivery. Capitalizing on the in vivo delivery efficacy of adenoviral vectors (Ad), recent studies have highlighted the capacity of targeted Ad to accomplish cell selectivity in this stringent delivery context. Systemic employment of Ad for gene delivery, however, is currently limited by vector particle sequestration in the liver. Recent work in several laboratories, however, has identified the biologic dictates of vector hepatotropism. Based on this understanding, it has now been possible to "un-target" the liver thereby facilitating strategies designed to achieve cell specific gene delivery in the context of systemic vector administration. Of note, we have recently shown that such liver un-targeting strategies can synergize with described vector targeting methods such as those based upon restricting delivered transgene expression to target cells with a tissue/tumor selective promoter ("transcriptional targeting"). The dramatic synergistic specificity gains noted with combination of these two approaches logically suggests that further gains may accrue additional targeting methods exploited in combination. In this regard, strategies have been proposed to target Ad based upon re-directing vector binding to target cell specific cell surface markers. Such "transductional" targeting methods would offer potential synergies with the targeting methods we note above. Such an endeavor has been limited to this point by the inability of current vector engineering to achieve capsid incorporation of antibody targeting species. Herein we seek to address this key limit. First, we have developed a method to replace the native adenovirus fiber with a substitute chimera devoid of the native fiber's knob binding domain. This maneuver eliminates native tropism and allows for the incorporation of a wider range of large/complex candidate targeting ligands. Second, we have demonstrated that the single domain antibody species derived from camelids (sdAb) possess the unique attributes allowing biologic compatibility with adenovirus capsid synthesis and assembly. In the aggregate, these two technologies now allow for the functional incorporation of antibody targeting species into the Ad capsid for the achievement of cell-specific targeting. This additional level of targeting provides for potential synergies with the defined liver un-targeting and transcriptional vector targeting methods we have explored.

抽象的实现有效基因治疗的核心任务是能够实现细胞特异性送货。最近的研究利用腺病毒载体（Ad）的体内递送功效强调了靶向广告在这种严格的条件下实现细胞选择性的能力交付上下文。然而，Ad 在基因传递中的系统应用目前受到以下因素的限制：矢量粒子隔离在肝脏中。然而，最近几个实验室的工作已经确定了载体向肝性的生物学决定。基于这样的认识，现在有可能“非靶向”肝脏，从而促进旨在实现细胞目标的策略系统载体管理背景下的特定基因递送。值得注意的是，我们最近研究表明，这种肝脏非靶向策略可以与所述载体靶向协同作用方法，例如基于限制递送转基因表达至靶细胞的方法具有组织/肿瘤选择性启动子（“转录靶向”）。戏剧性的协同作用结合这两种方法所获得的特异性收益从逻辑上表明，进一步组合使用的目标方法可能会带来收益。对此，已提出基于重定向载体与靶细胞结合来靶向 Ad 的策略特定的细胞表面标记。这种“转导”靶向方法将提供潜在的与我们上面提到的定位方法的协同作用。这样的努力仅限于此当前的载体工程无法实现抗体衣壳的掺入目标物种。在这里，我们寻求解决这个关键限制。首先，我们开发了一种方法用没有天然纤维旋钮的替代嵌合体取代天然腺病毒纤维结合域。这种策略消除了天然向性并允许结合更广泛的大型/复杂候选靶向配体。其次，我们已经证明了源自骆驼科动物的单域抗体 (sdAb) 具有独特的属性允许与腺病毒衣壳合成和组装具有生物相容性。总的来说，这两种技术现在允许抗体靶向物种的功能整合进入Ad衣壳以实现细胞特异性靶向。这种额外的定位水平与定义的肝脏非靶向和转录载体提供潜在的协同作用我们探索过的靶向方法。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vector Strategies to Actualize B Cell-Based Gene Therapies.

实现基于 B 细胞的基因疗法的载体策略。

DOI：
发表时间：
2021-08-01
期刊：
影响因子：
0
作者：
Jeske, Amanda M;Boucher, Paul;Curiel, David T;Voss, James E
通讯作者：
Voss, James E

Efficient Genome Editing Achieved via Plug-and-Play Adenovirus Piggyback Transport of Cas9/gRNA Complex on Viral Capsid Surface.

通过即插即用腺病毒在病毒衣壳表面搭载 Cas9/gRNA 复合物实现高效基因组编辑。

DOI：
发表时间：
2022-07-26
期刊：
影响因子：
17.1
作者：
Lu, Zhi Hong;Li, Jie;Dmitriev, Igor P;Kashentseva, Elena A;Curiel, David T
通讯作者：
Curiel, David T

Engineering a Novel Modular Adenoviral mRNA Delivery Platform Based on Tag/Catcher Bioconjugation.

设计基于标签/捕手生物共轭的新型模块化腺病毒 mRNA 传递平台。

DOI：
发表时间：
2023-11-20
期刊：
影响因子：
0
作者：
Geng, Kexin;Rice;Kashentseva, Elena A;Dmitriev, Igor P;Lu, Zhi Hong;Goedegebuure, S Peter;Gillanders, William E;Curiel, David T
通讯作者：
Curiel, David T

A New Gorilla Adenoviral Vector with Natural Lung Tropism Avoids Liver Toxicity and Is Amenable to Capsid Engineering and Vector Retargeting.

一种具有天然肺向性的新大猩猩腺病毒载体可避免肝脏毒性，并适合衣壳工程和载体重定向。