Department of Molecular Biology and Genetics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Department of Biology, Johns Hopkins University, Baltimore, MD, USA.
Methods Mol Biol. 2024;2723:161-172. doi: 10.1007/978-1-0716-3481-3_10.
Posttranscriptional RNA modification has become a revolutionary clinical tool to improve the underlying condition in genetic disorders. The cell achieves translational regulation through sequence and/or structural elements that recruit specific positive- or negative-acting factors to mRNAs. Targeting mRNA expression offers a less invasive therapeutic approach than other well-known gene therapy approaches. We have utilized our understanding of mRNA translational regulation to develop a novel disease-modifying treatment called the "Tethered mRNA Amplifier." Specifically, our approach forces a key positive-acting mRNA regulator, polyadenosine binding protein (PABPC1), to bind and remain resident on the target mRNA. This enhances the target mRNA's expression precisely and restores deficient protein levels to normal. This approach effectively increases the steady-state expression level of several transcripts associated with haploinsufficiency disorders in cell culture.
转录后 RNA 修饰已成为改善遗传疾病基础状况的革命性临床工具。细胞通过招募特定正向或负向作用因子到 mRNA 的序列和/或结构元件来实现翻译调控。与其他著名的基因治疗方法相比，靶向 mRNA 表达是一种侵袭性较小的治疗方法。我们利用对 mRNA 翻译调控的理解，开发了一种名为“连接 mRNA 放大器”的新型疾病修饰治疗方法。具体来说，我们的方法迫使关键的正向作用的 mRNA 调节剂聚腺苷酸结合蛋白 (PABPC1) 结合并驻留在靶 mRNA 上。这精确地增强了靶 mRNA 的表达，并将缺失的蛋白质水平恢复到正常水平。该方法可有效提高细胞培养中与单倍体不足疾病相关的几种转录本的稳态表达水平。
