塞内卡谷病毒复制子包装在反式中,具有克服病毒转基因表达限制的能力。

IF 5.3 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Jeffrey D Bryant, Jennifer S Lee, Ana De Almeida, Judy Jacques, Ching-Hung Chang, William Fassler, Christophe Quéva, Lorena Lerner, Edward M Kennedy
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引用次数: 0

摘要

溶瘤病毒(OVs)通过自身的复制和随后的肿瘤细胞裂解,促进抗肿瘤免疫应答,从而触发免疫感应通路的激活。通过表达具有促进免疫细胞募集和激活潜力的转基因来武装OVs是增强OVs治疗益处的一种有吸引力的策略。对于具有临床经验的小核糖核酸病毒家族,转基因的表达受到多种因素的限制:基因组物理包装限制、高重组率和病毒介导的转基因分泌抑制。在这里,我们评估了用相关的免疫调节转基因武装塞内卡谷病毒(SVV)的策略。特别是在武装SVV的背景下,我们评估了转基因的最大尺寸和稳定性,转基因分泌,以及转基因包涵体对病毒适应性的影响。我们发现SVV不能表达分泌的有效载荷,其转基因包装能力约为病毒基因组大小的10%。为了实现转基因表达,我们开发了具有更大转基因大小容量和分泌能力的SVV复制子。SVV复制子可以被病毒包装在共感染细胞的反式中,在周围细胞中表达免疫调节基因,从而提供了一种增强这种治疗方法的潜力,以增强抗肿瘤免疫反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Seneca Valley virus replicons are packaged in <i>trans</i> and have the capacity to overcome the limitations of viral transgene expression.

Seneca Valley virus replicons are packaged in <i>trans</i> and have the capacity to overcome the limitations of viral transgene expression.

Seneca Valley virus replicons are packaged in <i>trans</i> and have the capacity to overcome the limitations of viral transgene expression.

Seneca Valley virus replicons are packaged in trans and have the capacity to overcome the limitations of viral transgene expression.

Oncolytic viruses (OVs) promote the anti-tumor immune response as their replication, and the subsequent lysis of tumor cells, triggers the activation of immune-sensing pathways. Arming OVs by expressing transgenes with the potential to promote immune cell recruitment and activation is an attractive strategy to enhance OVs' therapeutic benefit. For picornaviruses, a family of OVs with clinical experience, the expression of a transgene is limited by multiple factors: genome physical packaging limits, high rates of recombination, and viral-mediated inhibition of transgene secretion. Here, we evaluated strategies for arming Seneca Valley virus (SVV) with relevant immunomodulatory transgenes. Specificially in the contex of arming SVV, we evaluated transgene maximum size and stabiltity, transgene secretion, and the impact of transgene inclusion on viral fitness. We find that SVV is not capable of expressing secreted payloads and has a transgene packaging capacity of ∼10% of viral genome size. To enable transgene expression, we developed SVV replicons with greater transgene size capacity and secretion capabilities. SVV replicons can be packaged in trans by virus in co-infected cells to express immunomodulatory transgenes in surrounding cells, thus providing a means to enhance the potential of this therapeutic to augment the anti-tumor immune response.

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来源期刊
Molecular Therapy Oncolytics
Molecular Therapy Oncolytics Medicine-Oncology
CiteScore
10.90
自引率
3.50%
发文量
152
审稿时长
6 weeks
期刊介绍: Molecular Therapy — Oncolytics is an international, online-only, open access journal focusing on the development and clinical testing of viral, cellular, and other biological therapies targeting cancer.
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