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单纯疱疹病毒 1 型（HSV-1）嵌合载体的构建及其感觉神经元选择性启动子的评估。

Development and Assessment of Herpes Simplex Virus Type 1 (HSV-1) Amplicon Vectors with Sensory Neuron-Selective Promoters.

机构信息

UMR INSERM U1179-Université de Versailles Saint Quentin en Yvelines/Paris Saclay, UFR des Sciences de la Santé Simone Veil, 2, Avenue de la Source de la Bièvre, 78180 Montigny-le-Bretonneux, France.

Neuro-Urology R. Poincaré Hospital AP-HP, 104 bvd R. Poincaré, 92380 Garches, France.

出版信息

Int J Mol Sci. 2022 Jul 30;23(15):8474. doi: 10.3390/ijms23158474.

DOI:10.3390/ijms23158474
PMID:35955608
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9369297/
Abstract

BACKGROUND

Neurogenic detrusor overactivity (NDO) is a severe pathological condition characterized by involuntary detrusor contractions leading to urine leakage. This condition is frequent after spinal cord injury (SCI). Gene therapy for NDO requires the development of vectors that express therapeutic transgenes driven by sensory neuron-specific promoters. The aim of this study was to develop and assess tools for the characterization of sensory neuron-specific promoters in dorsal root ganglia (DRG) neurons after transduction with herpes simplex virus type 1 (HSV-1)-based amplicon defective vectors.

METHODS

The HSV-1 vector genome encoded two independent transcription cassettes: one expressed firefly luciferase (FLuc) driven by different promoters' candidates (rTRPV1, rASIC3, rCGRP, or hCGRP), and the other expressed a reporter gene driven by an invariable promoter. The strength and selectivity of promoters was assessed in organotypic cultures of explanted adult DRG, or sympathetic and parasympathetic ganglia from control and SCI rats.

RESULTS

The rCGRP promoter induced selective expression in the DRG of normal rats. The rTRPV-1 promoter, which did not display selective activity in control rats, induced selective expression in DRG explanted from SCI rats.

CONCLUSIONS

This study provides a methodology to assess sensory neuron-specific promoters, opening new perspectives for future gene therapy for NDO.

摘要

背景

神经原性逼尿肌过度活动（NDO）是一种严重的病理状况，其特征是逼尿肌不自主收缩导致尿液漏出。这种情况在脊髓损伤（SCI）后很常见。NDO 的基因治疗需要开发表达由感觉神经元特异性启动子驱动的治疗性转基因的载体。本研究的目的是开发和评估工具，用于在转导单纯疱疹病毒 1 （HSV-1）-基于扩增子缺陷载体后，对背根神经节（DRG）神经元中的感觉神经元特异性启动子进行特征描述。

方法

HSV-1 载体基因组编码两个独立的转录盒：一个表达萤火虫荧光素酶（FLuc），由不同启动子候选物（rTRPV1、rASIC3、rCGRP 或 hCGRP）驱动，另一个表达由不变启动子驱动的报告基因。在正常大鼠和 SCI 大鼠的交感神经和副交感神经节离体 DRG 器官型培养物中，评估启动子的强度和选择性。

结果

rCGRP 启动子诱导正常大鼠 DRG 中的选择性表达。在正常大鼠中没有表现出选择性活性的 rTRPV-1 启动子，在 SCI 大鼠离体 DRG 中诱导了选择性表达。

结论

本研究提供了一种评估感觉神经元特异性启动子的方法，为 NDO 的未来基因治疗开辟了新的前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f780/9369297/678e09482a93/ijms-23-08474-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f780/9369297/6b530a958b6d/ijms-23-08474-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f780/9369297/8769a694b2d8/ijms-23-08474-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f780/9369297/69aee751714c/ijms-23-08474-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f780/9369297/22116e693db3/ijms-23-08474-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f780/9369297/678e09482a93/ijms-23-08474-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f780/9369297/6b530a958b6d/ijms-23-08474-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f780/9369297/8769a694b2d8/ijms-23-08474-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f780/9369297/69aee751714c/ijms-23-08474-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f780/9369297/22116e693db3/ijms-23-08474-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f780/9369297/678e09482a93/ijms-23-08474-g005.jpg

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