小柯机器人

美国波士顿儿童医院Timothy W. Yu等研究人员合作开发出个体化剪接转换寡核苷酸治疗的一个框架。这一研究成果于2023年7月12日在线发表在国际学术期刊《自然》上。

研究人员进行了全基因组测序分析，以描述235名共济失调-特朗日病患者（来自209个家庭）的遗传变异特征。共济失调-特朗日病是一种严重衰弱且危及生命的隐性遗传疾病，几乎所有患者都得到了完整的分子诊断。研究人员开发了一种预测性分类法来评估每个个体对剪接转换反义寡核苷酸（ASO）干预的适应性；分别有9%和6%的个体的变异“大概”或“可能”适合ASO剪接调节。大多数适配变异位于外显子靶向测序无法进入的深内含子区。研究人员开发的ASO成功地挽救了患者成纤维细胞中两个复发性变异的剪接错误和ATM细胞信号。

在一项试验性临床研究中，其中一种ASO被用于治疗一名出生后不久即被诊断为共济失调-特朗日病的患儿，结果显示该药物具有良好的耐受性，且在三年内未出现严重不良反应。这项研究为前瞻性地识别可能受益于剪接转换ASO治疗方法的遗传疾病患者提供了一个框架。

据介绍，剪接转换ASO可用于治疗部分遗传疾病患者，但系统性地鉴定这类患者仍是一项挑战。

附：英文原文

Title: A framework for individualized splice-switching oligonucleotide therapy

Author: Kim, Jinkuk, Woo, Sijae, de Gusmao, Claudio M., Zhao, Boxun, Chin, Diana H., DiDonato, Renata L., Nguyen, Minh A., Nakayama, Tojo, Hu, Chunguang April, Soucy, Aubrie, Kuniholm, Ashley, Thornton, Jennifer Karlin, Riccardi, Olivia, Friedman, Danielle A., El Achkar, Christelle Moufawad, Dash, Zane, Cornelissen, Laura, Donado, Carolina, Faour, Kamli N. W., Bush, Lynn W., Suslovitch, Victoria, Lentucci, Claudia, Park, Peter J., Lee, Eunjung Alice, Patterson, Al, Philippakis, Anthony A., Margus, Brad, Berde, Charles B., Yu, Timothy W.

Issue&Volume: 2023-07-12

Abstract: Splice-switching antisense oligonucleotides (ASOs) could be used to treat a subset of individuals with genetic diseases1, but the systematic identification of such individuals remains a challenge. Here we performed whole-genome sequencing analyses to characterize genetic variation in 235 individuals (from 209 families) with ataxia-telangiectasia, a severely debilitating and life-threatening recessive genetic disorder2,3, yielding a complete molecular diagnosis in almost all individuals. We developed a predictive taxonomy to assess the amenability of each individual to splice-switching ASO intervention; 9% and 6% of the individuals had variants that were ‘probably’ or ‘possibly’ amenable to ASO splice modulation, respectively. Most amenable variants were in deep intronic regions that are inaccessible to exon-targeted sequencing. We developed ASOs that successfully rescued mis-splicing and ATM cellular signalling in patient fibroblasts for two recurrent variants. In a pilot clinical study, one of these ASOs was used to treat a child who had been diagnosed with ataxia-telangiectasia soon after birth, and showed good tolerability without serious adverse events for three years. Our study provides a framework for the prospective identification of individuals with genetic diseases who might benefit from a therapeutic approach involving splice-switching ASOs.

DOI: 10.1038/s41586-023-06277-0

Source: https://www.nature.com/articles/s41586-023-06277-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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