Prospective collagen IVα345 therapies for Alport syndrome.
Prospective collagen IVα345 therapies for Alport syndrome.
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DOI：
10.1097/mnh.0000000000000789
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发表时间：
2022-05-01
影响因子：
3.2
通讯作者：
Hudson, Billy G.
中科院分区：
文献类型：
--
作者：
Boudko, Sergei P.;Pokidysheva, Elena;Hudson, Billy G.
关键词：
在Alport综合征中，COL4A3、COL4A4和COL4A5基因中超过1，700种遗传变异导致IV型胶原α345支架（肾小球基底膜（GBM）的重要组成部分）缺失或发生故障。治疗仅限于用ACE抑制剂治疗以减缓疾病的进展。在此，我们综述了近年来在替代支架或恢复其功能方面的进展。最近出现了多种方法来开发针对GBM中胶原IVα345支架的不同生产和组装阶段的疗法。这些方法基于1）允许破译构成支架组装和功能障碍的致病机制的技术的最新进展，2）用于基因治疗的DNA编辑工具的开发，3）RNA剪接干扰，以及4）mRNA翻译的控制。越来越多的人相信，这些方法最终将为Alport患者提供治愈。通过深入了解IV型胶原α345支架折叠、组装和功能的机制，将加速治疗的发展。
In Alport syndrome, over 1,700 genetic variants in the COL4A3, COL4A4, and COL4A5 genes cause the absence or malfunctioning of the collagen IVα345 scaffold – an essential component of the glomerular basement membrane (GBM). Therapies are limited to treatment with ACE inhibitors to slow progression of the disease. Here, we review recent progress in therapy development to replace the scaffold or restore its function. Multiple approaches emerged recently for development of therapies that target different stages of production and assembly of the collagen IVα345 scaffold in the GBM. These approaches are based on 1) recent advances in technologies allowing to decipher pathogenic mechanisms that underlie scaffold assembly and dysfunction, 2) development of DNA editing tools for gene therapy, 3) RNA splicing interference, and 4) control of mRNA translation. There is a growing confidence that these approaches will ultimately provide cure for Alport patients. Development of therapy will be accelerated by studies that provide a deeper understanding of mechanisms that underlie folding, assembly, and function of the collagen IVα345 scaffold.