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为ALS/FTD精准医学创建新的加密拼接

Oscar G Wilkins^1,2, Max Z Y J Chien^1,2, Josette J Wlaschin³

¹UCL Queen Square Motor Neuron Disease Centre, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, UCL; London, WC1N 3BG, UK.

bioRxiv : the preprint server for biology

|November 28, 2023

概括

一个新的精准医学平台,TDP-REG,使用人工智能在患病细胞中创造治疗性蛋白质表达,为ALS和FTD等神经退行性疾病提供更安全的治疗方法.

科学领域:

遗传学和分子生物学
神经科学是一个神经科学.
生物技术是生物技术.

背景情况:

由于安全问题,患病细胞中治疗性蛋白质表达具有挑战性.
肌缩侧面硬化症 (ALS) 和前性痴呆症 (FTD) 是与TDP-43相关的神经退行性疾病.
TDP-43功能丧失 (TDP-LOF) 在受影响细胞中引起异常的神秘拼接事件.

研究的目的:

开发一种精确医学系统 (TDP-REG) 用于在TDP-LOF细胞中向治疗性蛋白质表达.
使用深度学习算法设计可定制的加密拼接事件.
为更安全的神经退行性疾病治疗创造一个平台.

主要方法:

开发了TDP-REG,这是一个利用由TDP-LOF驱动的加密拼接事件的系统.
利用深度学习算法来生成可定制的加密拼接事件.
嵌入的编码序列在新奇的密码外型中,将蛋白质表达与TDP-LOF结合起来.
产生光和发光的记者.
进行了TDP-LOF-依赖的基因组原始编辑.
设计的自调节载体编码TDP-43/Raver1融合蛋白.

主要成果:

蛋白质表达在体外和体内都被TDP-LOF成功激活.
该系统在驱动疾病细胞的表达方面表现出有效性.
用基因组主要编辑来切除UNC13A神秘的供体拼接部位.
工程载体拯救了关键的病理隐秘拼接事件.
该平台展示了预防性治疗的潜力.

结论:

TDP-REG为精密医学提供了一个复杂的拼接传感器平台.
该系统可实现严格控制的,TDP-LOF依赖的蛋白质表达.
这种方法显著提高了神经退行性疾病治疗药物的安全性.
该平台对高危人群的预防性治疗策略有前途.

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