Answered and Unanswered Questions in Early-Stage Viral Vector Transduction Biology and Innate Primary Cell Toxicity for Ex-Vivo Gene Editing.
Answered and Unanswered Questions in Early-Stage Viral Vector Transduction Biology and Innate Primary Cell Toxicity for Ex-Vivo Gene Editing.
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DOI：
10.3389/fimmu.2021.660302
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发表时间：
2021
影响因子：
7.3
通讯作者：
Porteus MH
中科院分区：
文献类型：
--
作者：
Dudek AM;Porteus MH
腺相关病毒是一种高效的 DNA 递送载体，用于基因组编辑策略，采用 CRISPR/Cas9 和 DNA 供体进行同源定向修复。许多团体已使用这种策略来开发血液和免疫疾病（例如镰状细胞贫血和严重联合免疫缺陷）的疗法。然而，最近发生的事件对 AAV 作为基因治疗载体的免疫原性以及对该载体的免疫反应所决定的安全性提出了质疑。人们对决定这种反应的靶细胞以及决定细胞对 AAV 反应的分子机制知之甚少。在这里，我们将研究目前已知的 AAV 衣壳和基因组在早期载体转导过程中与细胞蛋白的相互作用，以及这些相互作用如何影响先天细胞反应。我们将讨论目前对 AAV 的先天免疫激活和 DNA 损伤反应的理解，以及目前已知的局限性。特别是，我们将重点关注细胞系与原代细胞的途径差异，重点关注离体基因编辑背景下的造血干细胞和祖细胞 (HSPC)，以及我们可以从其他细小病毒感染 HSPC 中学到什么。最后，我们将讨论随着这些基因编辑策略走向临床，这些高度敏感的干细胞群中的先天免疫和 DNA 损伤反应途径激活如何影响长期植入和临床结果，目的是提出与 AAV 介导的基因组编辑后改善造血干细胞存活和长期植入相关的途径。
Adeno-associated virus is a highly efficient DNA delivery vehicle for genome editing strategies that employ CRISPR/Cas9 and a DNA donor for homology-directed repair. Many groups have used this strategy in development of therapies for blood and immune disorders such as sickle-cell anemia and severe-combined immunodeficiency. However, recent events have called into question the immunogenicity of AAV as a gene therapy vector and the safety profile dictated by the immune response to this vector. The target cells dictating this response and the molecular mechanisms dictating cellular response to AAV are poorly understood. Here, we will investigate the current known AAV capsid and genome interactions with cellular proteins during early stage vector transduction and how these interactions may influence innate cellular responses. We will discuss the current understanding of innate immune activation and DNA damage response to AAV, and the limitations of what is currently known. In particular, we will focus on pathway differences in cell line verses primary cells, with a focus on hematopoietic stem and progenitor cells (HSPCs) in the context of ex-vivo gene editing, and what we can learn from HSPC infection by other parvoviruses. Finally, we will discuss how innate immune and DNA damage response pathway activation in these highly sensitive stem cell populations may impact long-term engraftment and clinical outcomes as these gene-editing strategies move towards the clinic, with the aim to propose pathways relevant for improved hematopoietic stem cell survival and long-term engraftment after AAV-mediated genome editing.
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