Tight control of transgene expression is key to ensure the efficacy of a wide range of gene therapy interventions, in which the magnitude and duration of gene expression have to be adjusted to therapeutic needs, thereby limiting secondary effects. The development of upgraded strategies to link transgene expression to pathological stress episodes is an unmet need in gene therapy. Here, we propose an expression strategy that associates transgene expression to an intracellular stress coping mechanism, the unfolded protein response. Specifically, we harnessed the cis elements required to sustain the noncanonical splicing of X-box binding protein 1 (XBP1) messenger RNA (mRNA) in response to the dysfunction of the endoplasmic reticulum (ER), a situation commonly known as ER stress, to drive the expression of heterologous genes. Since ER stress features a wide variety of pathological conditions, including viral infections, cancer, or metabolic disorders, this new expression module stimulates the synthesis of therapeutic genes as a response to cellular damage, and ensures their expression only when necessary. Validation of this inducible expression system was performed in vitro and in vivo, and its potential to limit/inhibit viral infections has been shown in proof-of principle experiments.

中文翻译：

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将治疗基因的表达与未折叠的蛋白质反应联系起来：抗乙型肝炎病毒基因治疗的新选择

对转基因表达的严格控制是确保广泛基因治疗干预效果的关键，其中基因表达的幅度和持续时间必须根据治疗需要进行调整，从而限制次要效应。将转基因表达与病理性应激事件联系起来的升级策略的发展是基因治疗中未满足的需求。在这里，我们提出了一种表达策略，将转基因表达与细胞内应激应对机制（未折叠蛋白反应）联系起来。具体来说，我们利用了顺式维持 X-box 结合蛋白 1 (XBP1) 信使 RNA (mRNA) 以响应内质网 (ER) 功能障碍（通常称为 ER 应激的情况）的非规范剪接所需的元素，以驱动异源基因的表达. 由于 ER 应激具有多种病理状况，包括病毒感染、癌症或代谢紊乱，这种新的表达模块可刺激治疗基因的合成，作为对细胞损伤的反应，并确保它们仅在必要时表达。这种诱导型表达系统在体外和体内进行了验证，其限制/抑制病毒感染的潜力已在原理验证实验中得到证实。