Genetic mutations in HSV-1 replication-defective vectors: Implications for their safety in gene therapy applications.

IF 4.5 3区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Stefano Cattaneo, Barbara Bettegazzi, Selene Ingusci, Gianluca Verlengia, Tascini Anna Sofia, Zucchini Silvia, Franca Codazzi, Marco J Morelli, Marco Marzulli, Joseph C Glorioso, Michele Simonato
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引用次数: 0

Abstract

Beyond its well-known role in orofacial recurrent infections, HSV-1 has garnered significant attention in neuroscience for contrasting reasons. On one hand, it has been found to be involved in neurodegenerative processes; on the other, it may represent a versatile platform for gene therapy of brain diseases, due to its large genome that enables the delivery of sizable or multiple genes. These opposite features underscore the importance of understanding HSV-1 interactions with neural tissues in view of its employment as a gene therapy platform. We recently developed a new generation of highly defective backbones that proved very efficient and safe after direct injection in the brain parenchyma. Here we aimed at probing in depth the safety of viral batches that lack obvious unwanted (specifically, fusogenic) activities during production and, therefore, may escape negative selection. We employed whole-genome sequencing, electrophysiology, and viral engineering to compare different viral batches. We identified mutations (in particular A to I at position 549 in the UL27 gene) that confer fusogenic capacity to the envelop glycoprotein gB, inducing a hyperexcitable phenotype in transduced neurons. Such syncytial variants should be identified and avoided for any application of HSV-1 vectors implicating their direct injection in the nervous system.

HSV-1复制缺陷载体的基因突变:对其在基因治疗应用中的安全性的影响。
除了它在口腔面部复发性感染中的众所周知的作用外,单纯疱疹病毒-1在神经科学领域也因相反的原因引起了极大的关注。一方面,它被发现与神经退行性过程有关;另一方面,由于其庞大的基因组能够传递相当大的或多个基因,它可能代表了脑疾病基因治疗的多功能平台。这些相反的特征强调了理解HSV-1作为基因治疗平台与神经组织相互作用的重要性。我们最近开发了新一代高度缺陷的骨干,经证明直接注射到脑实质后非常有效和安全。在这里,我们的目的是深入探讨在生产过程中缺乏明显不需要的(特别是,融合性)活性的病毒批次的安全性,因此可能逃避负选择。我们采用全基因组测序、电生理学和病毒工程来比较不同的病毒批次。我们发现突变(特别是UL27基因549位的A到I)赋予包膜糖蛋白gB促融合能力,在转导的神经元中诱导过度兴奋表型。这种合胞体变异应被识别并避免任何涉及直接注射到神经系统的HSV-1载体的应用。
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来源期刊
Gene Therapy
Gene Therapy 医学-生化与分子生物学
CiteScore
9.70
自引率
2.00%
发文量
67
审稿时长
4-8 weeks
期刊介绍: Gene Therapy covers both the research and clinical applications of novel therapeutic techniques based on a genetic component. Over the last few decades, significant advances in technologies ranging from identifying novel genetic targets that cause disease through to clinical studies, which show therapeutic benefit, have elevated this multidisciplinary field to the forefront of modern medicine.
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