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开发一种AAV传递的微RNA基因疗法,用于治疗1型肌性衰竭

Giulio S Tomassy¹, Wei Fan¹, Shuwen Cao¹

¹Genomic Medicine Unit, Sanofi; Waltham, MA, 02451.

Molecular therapy : the journal of the American Society of Gene Therapy

|September 4, 2025

概括

一种新型的AAV-RNAi疗法有效地减少了1型肌性衰竭 (DM1) 模型中的DMPKRNA. 这种方法改善了疾病的特征,并证明了非人类灵长类动物的安全性,提供了一个有前途的治疗策略.

科学领域:

遗传学
分子生物学
神经学

背景情况:

肌性缩1型 (DM1) 是一种由DMPK基因中CTG重复扩张引起的进展性神经肌肉疾病.
这种扩张导致有毒的核点,RNA结合蛋白的封存和异常拼接,导致肌肉衰弱和其他严重症状.
目前对DM1的治疗方法有限,这凸显了针对性治疗策略的需要.

研究的目的:

开发和评估一种基于腺相关病毒 (AAV) 的RNA干扰 (RNAi) 策略,用于降低DM1中的DMPKRNA水平.
在DM1的临床前模型中评估这种AAV- RNAi治疗的疗效和安全性,包括非人类灵长类动物.

主要方法:

设计了一种针对肌肉的AAV载体系统,其中包括一种高效的AAV囊,一种强大的肌肉特异性促进剂,以及一种针对DMPK的人工miRNA (amiR^DMPK).
AAV-amiR^DMPK疗法用于DM1的细胞和动物模型以及非人类灵长类动物.
评估了DMPKRNA水平,分子标记,病理特征和临床结果. 在非人类灵长类动物中评估了安全性和耐受性.

主要成果:

在DM1模型中,amiR^DMPK的AAV输送显著降低了DMPKRNA水平.
治疗改善了与DM1相关的分子,病理和临床相关的疾病特征.
在非人类灵长类动物中,AAV-amiR^DMPK/ SAR446268得到了良好的耐受性,并且在主要肌肉群中实现了剂量依赖的DMPK mRNA下调 (高达90%).

结论:

针对DMPKRNA的AAV-RNAi策略是一种有前途的治疗方法.
在临床前模型中,包括非人类灵长类动物中,SAR446268在减少疾病病理方面表现出显著的有效性.
这些发现支持SAR446268的进一步临床开发用于DM1的治疗.

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