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用于预防化疗引起的周围神经病变的可调节转基因表达

Regulatable Transgene Expression for Prevention of Chemotherapy-Induced Peripheral Neuropathy.

作者信息

Kawata Daisuke, Wu Zetang

机构信息

Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.

VA Ann Arbor Healthcare System, Ann Arbor, MI 48109, USA.

出版信息

Mol Ther Methods Clin Dev. 2017 Jun 21;6:91-101. doi: 10.1016/j.omtm.2017.06.004. eCollection 2017 Sep 15.

DOI:10.1016/j.omtm.2017.06.004
PMID:28702476
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5557294/
Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating complication associated with drug treatment of cancer for which there are no effective strategies of prevention or treatment. In this study, we examined the effect of intermittent expression of neurotophin-3 (NT-3) or interleukin-10 (IL-10) from replication-defective herpes simplex virus (HSV)-based regulatable vectors delivered by subcutaneous inoculation to the dorsal root ganglion (DRG) on the development of paclitaxel-induced peripheral neuropathy. We constructed two different tetracycline (tet)-on-based regulatable HSV vectors, one expressing NT-3 and the other expressing IL-10, in which the transactivator expression in the tet-on system was under the control of HSV latency-associated promoter 2 (LAP-2), and expression of the transgene was controlled by doxycycline (DOX). We examined the therapeutic effect of intermittent expression of the transgene in animals with paclitaxel-induced peripheral neuropathy modeled by intraperitoneal injection of paclitaxel (16 mg/kg) once a week for 5 weeks. Intermittent expression of either NT-3 or IL-10 3 days before and 1 day after paclitaxel administration protected animals against paclitaxel-induced peripheral neuropathy over the course of 5 weeks. These results suggest the potential of regulatable vectors for prevention of chemotherapy-induced peripheral neuropathy.

摘要

化疗引起的周围神经病变（CIPN）是一种与癌症药物治疗相关的使人衰弱的并发症，对此尚无有效的预防或治疗策略。在本研究中，我们通过皮下接种将基于复制缺陷型单纯疱疹病毒（HSV）的可调控载体递送至背根神经节（DRG），研究了间歇性表达神经营养因子-3（NT-3）或白细胞介素-10（IL-10）对紫杉醇诱导的周围神经病变发展的影响。我们构建了两种不同的基于四环素（tet）调控的可调控HSV载体，一种表达NT-3，另一种表达IL-10，其中tet-on系统中的反式激活因子表达受HSV潜伏相关启动子2（LAP-2）控制，转基因表达受强力霉素（DOX）控制。我们研究了通过每周一次腹腔注射紫杉醇（16mg/kg），持续5周建立的紫杉醇诱导的周围神经病变动物模型中，间歇性表达转基因的治疗效果。在紫杉醇给药前3天和给药后1天间歇性表达NT-3或IL-10，可在5周内保护动物免受紫杉醇诱导的周围神经病变。这些结果表明可调控载体在预防化疗引起的周围神经病变方面具有潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed46/6434900/1d6e224b2ec8/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed46/6434900/005db9470b3b/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed46/6434900/8e90f3832d9f/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed46/6434900/0dff41b6a650/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed46/6434900/645455a32bbf/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed46/6434900/779222d1ef99/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed46/6434900/1d6e224b2ec8/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed46/6434900/005db9470b3b/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed46/6434900/8e90f3832d9f/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed46/6434900/0dff41b6a650/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed46/6434900/645455a32bbf/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed46/6434900/779222d1ef99/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ed46/6434900/1d6e224b2ec8/gr6.jpg

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本文引用的文献

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Pharmacokinetic evaluation of Paclitaxel in South Indian cancer patients: a prospective study.紫杉醇在南印度癌症患者中的药代动力学评估：一项前瞻性研究。
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Prolonged regulatable expression of EPO from an HSV vector using the LAP2 promoter element.
利用 LAP2 启动子元件从 HSV 载体中进行 EPO 的可调节延长表达。
Gene Ther. 2012 Nov;19(11):1107-13. doi: 10.1038/gt.2011.188. Epub 2011 Nov 17.
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Prevention of diabetic neuropathy by regulatable expression of HSV-mediated erythropoietin.通过可调节表达 HSV 介导的促红细胞生成素预防糖尿病性神经病。
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