Safety and efficacy evaluations of an adeno-associated virus variant for preparing IL10-secreting human neural stem cell-based therapeutics
Safety and efficacy evaluations of an adeno-associated virus variant for preparing IL10-secreting human neural stem cell-based therapeutics
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用于制备分泌 IL10 的人神经干细胞疗法的腺相关病毒变体的安全性和有效性评估
DOI：
10.1038/s41434-019-0057-8
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发表时间：
2019
期刊：
影响因子：
5.1
通讯作者：
Jae‐Hyung Jang
中科院分区：
文献类型：
--
作者：
Mira Cho;Kwangsoo Jung;Seung;Il;Miri Kim;M. Shin;Haeshin Lee;K. Park;Jae‐Hyung Jang
基因治疗技术不可避免地需要提高细胞疗法的治疗性能;因此，验证专门用于制备细胞疗法的基因载体的功效是评估基因和细胞组合疗法的治疗能力的先决条件。本文中，检查重组腺相关病毒衍生物（rAAVr3.45）的功效以评估其作为基因载体用于遗传操纵分泌白介素-10（IL 10）的人神经干细胞（hNSCs）的潜力，所述人神经干细胞可潜在地治疗缺血性损伤或神经病症。研究了病毒制备或病毒感染过程中可能出现的安全性问题;在最终细胞悬液中未检测到有复制能力的AAV，转基因表达大多是瞬时的，并且未发生病毒感染对内源性基因表达的严重干扰。来自被编码IL 10的rAAVr3.45感染的hNSC的IL 10分泌没有改变任何基因的转录谱超过三倍，但是外源性增强的IL 10足以在缺血性脑损伤动物模型中引起免疫调节作用，从而加速神经缺陷的恢复和脑梗死体积的减小。这项研究提供的证据表明，rAAVr3.45可以作为一种基因载体，以制备干细胞治疗。
Gene therapy technologies are inevitably required to boost the therapeutic performance of cell therapies; thus, validating the efficacy of gene carriers specifically used for preparing cellular therapeutics is a prerequisite for evaluating the therapeutic capabilities of gene and cell combinatorial therapies. Herein, the efficacy of a recombinant adeno-associated virus derivative (rAAVr3.45) was examined to evaluate its potential as a gene carrier for genetically manipulating interleukin-10 (IL10)-secreting human neural stem cells (hNSCs) that can potentially treat ischemic injuries or neurological disorders. Safety issues that could arise during the virus preparation or viral infection were investigated; no replication-competent AAVs were detected in the final cell suspensions, transgene expression was mostly transient, and no severe interference on endogenous gene expression by viral infection occurred. IL10 secretion from hNSCs infected by rAAVr3.45 encoding IL10 did not alter the transcriptional profile of any gene by more than threefold, but the exogenously boosted IL10 was sufficient to provoke immunomodulatory effects in an ischemic brain injury animal model, thereby accelerating the recovery of neurological deficits and the reduction of brain infarction volume. This study presents evidence that rAAVr3.45 can be potentially used as a gene carrier to prepare stem cell therapeutics.
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影响因子：
12.4
作者：
Petrs-Silva, Hilda;Dinculescu, Astra;Hauswirth, William W.
通讯作者：
Hauswirth, William W.
DOI：
10.1073/pnas.0404474101
发表时间：
2004-08-10
影响因子：
11.1
作者：
Kelly, S;Bliss, TM;Steinberg, GK
通讯作者：
Steinberg, GK
影响因子：
7
作者：
DeKelver, Russell C.;Choi, Vivian M.;Urnov, Fyodor D.
通讯作者：
Urnov, Fyodor D.
影响因子：
14
作者：
Huang BJ;Hu JC;Athanasiou KA
通讯作者：
Athanasiou KA
影响因子：
4.2
作者：
Allay, James A.;Sleep, Susan;Gray, John T.
通讯作者：
Gray, John T.