美国国立卫生研究院Francis S. Collins课题组取得一项新突破。他们提出了一种Hutchinson–Gilford早衰综合征（HGPS）靶向反义治疗方案。该研究于2021年3月11日发表于国际一流学术期刊《自然-医学》杂志上。
他们提出了一种潜在的遗传治疗策略，该策略利用反义肽共轭的二氨基磷酸二氨基吗啉代低聚物（PPMOs）来阻止突变体转录本的致病性剪接。在几个候选物中，PPMO SRP-2001能使患者成纤维细胞中早老蛋白转录本的明显减少。
将SRP-2001静脉内递送至HGPS的转基因小鼠模型后，主动脉（HGPS中特别关键的靶标组织）中的早老蛋白转录物显著减少。SRP-2001的长期连续治疗可延长大动脉的寿命，并挽救61.6％的血管平滑肌细胞损失。这些结果为进行人体试验提供了依据。
据介绍，HGPS是一种罕见的加速衰老疾病，其特征在于因心肌梗塞或中风而过早死亡。它是由LMNA基因中的从头单核苷酸突变引起的，该突变激活了一个隐秘的剪接供体位点，导致产生了lamin A的有毒形式，称为progerin。
附：英文原文
Title: A targeted antisense therapeutic approach for Hutchinson–Gilford progeria syndrome
Author: Michael R. Erdos, Wayne A. Cabral, Urraca L. Tavarez, Kan Cao, Jelena Gvozdenovic-Jeremic, Narisu Narisu, Patricia M. Zerfas, Stacy Crumley, Yoseph Boku, Gunnar Hanson, Dan V. Mourich, Ryszard Kole, Michael A. Eckhaus, Leslie B. Gordon, Francis S. Collins
Issue&Volume: 2021-03-11
Abstract: Hutchinson–Gilford progeria syndrome (HGPS) is a rare accelerated aging disorder characterized by premature death from myocardial infarction or stroke. It is caused by de novo single-nucleotide mutations in the LMNA gene that activate a cryptic splice donor site, resulting in the production of a toxic form of lamin A, which is termed progerin. Here we present a potential genetic therapeutic strategy that utilizes antisense peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) to block pathogenic splicing of mutant transcripts. Of several candidates, PPMO SRP-2001 provided the most significant decrease in progerin transcripts in patient fibroblasts. Intravenous delivery of SRP-2001 to a transgenic mouse model of HGPS produced significant reduction of progerin transcripts in the aorta, a particularly critical target tissue in HGPS. Long-term continuous treatment with SRP-2001 yielded a 61.6% increase in lifespan and rescue of vascular smooth muscle cell loss in large arteries. These results provide a rationale for proceeding to human trials.
DOI: 10.1038/s41591-021-01274-0
Source: https://www.nature.com/articles/s41591-021-01274-0
Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex
本期文章：《自然—医学》：Online/在线发表
