Improved targeting of human CD4+ T cells by nanobody-modified AAV2 gene therapy vectors.
Improved targeting of human CD4+ T cells by nanobody-modified AAV2 gene therapy vectors.
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DOI：
10.1371/journal.pone.0261269
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Hauber J
中科院分区：
文献类型：
--
作者：
Hamann MV;Beschorner N;Vu XK;Hauber I;Lange UC;Traenkle B;Kaiser PD;Foth D;Schneider C;Büning H;Rothbauer U;Hauber J
腺相关病毒（AAV）被认为在人类中是非致病性的，因此已经被开发成用于体内基因治疗的强大载体平台。虽然各种AAV血清型显示出广泛的嗜性，经常感染多种组织和细胞类型，但用于特异性和有效靶向人CD4+ T淋巴细胞的载体在很大程度上缺失。事实上，在治疗性基因转移领域中存在大量的翻译瓶颈，其需要体内递送到外周疾病相关的淋巴细胞中用于随后的基因组编辑。为了解决这个问题，用于重靶向AAV向性的衣壳修饰，进而提高载体效力，被认为是一种有前景的策略。在这里，我们用一组对人CD4受体具有高亲和力的新型纳米抗体对次要AAV2衣壳蛋白VP1和VP2进行了遗传修饰。这些新型载体变体证明了对人CD4+细胞的靶向改善，包括原代人外周血单核细胞（PBMC）和纯化的人CD4+ T淋巴细胞。因此，这里提出的技术方法提供了一个有前途的策略，用于开发特定的基因治疗载体，特别是针对疾病相关的外周血CD4+白细胞。
Adeno-associated viruses (AAV) are considered non-pathogenic in humans, and thus have been developed into powerful vector platforms for in vivo gene therapy. Although the various AAV serotypes display broad tropism, frequently infecting multiple tissues and cell types, vectors for specific and efficient targeting of human CD4+ T lymphocytes are largely missing. In fact, a substantial translational bottleneck exists in the field of therapeutic gene transfer that would require in vivo delivery into peripheral disease-related lymphocytes for subsequent genome editing. To solve this issue, capsid modification for retargeting AAV tropism, and in turn improving vector potency, is considered a promising strategy. Here, we genetically modified the minor AAV2 capsid proteins, VP1 and VP2, with a set of novel nanobodies with high-affinity for the human CD4 receptor. These novel vector variants demonstrated improved targeting of human CD4+ cells, including primary human peripheral blood mononuclear cells (PBMC) and purified human CD4+ T lymphocytes. Thus, the technical approach presented here provides a promising strategy for developing specific gene therapy vectors, particularly targeting disease-related peripheral blood CD4+ leukocytes.
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影响因子：
12.4
作者：
Muench, Robert C.;Janicki, Hanna;Buchholz, Christian J.
通讯作者：
Buchholz, Christian J.
DOI：
10.1016/j.omtm.2019.09.003
发表时间：
2019-12-13
影响因子：
4.7
作者：
Eichhoff, Anna Marei;Boerner, Kathleen;Koch-Nolte, Friedrich
通讯作者：
Koch-Nolte, Friedrich
DOI：
10.1007/978-1-4939-9170-9_8
发表时间：
2019-01-01
期刊：
CRISPR GENE EDITING
影响因子：
--
作者：
Fakhiri, Julia;Nickl, Manuela;Grimm, Dirk
通讯作者：
Grimm, Dirk
影响因子：
12.4
作者：
Agarwal, Shiwani;Hanauer, Julia D. S.;Buchholz, Christian J.
通讯作者：
Buchholz, Christian J.
影响因子：
5.7
作者：
Krotova, Karina;Day, Andrew;Aslanidi, George
通讯作者：
Aslanidi, George