Systemically delivered lipid nanoparticle-mRNA encoding lysosomal acid β-glucosidase restores the enzyme deficiency in a murine Gaucher disease model.

IF 4.5 3区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yuanqing Liu, Shasha Wang, Yanni Chen, Zhang Zhang, Xiaojiang Quan, Zhijun Guo, Zihao Wang
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引用次数: 0

Abstract

Gaucher disease (GD) is a rare genetically inherited illness caused by loss of lysosomal acid β-glucosidase (β-GCase) that leads to progressive accumulation of substrates, sphingolipid glucosylceramide (GL1) and glucosylsphingosine (lyso-GL1). The protein-based enzyme replacement therapy (ERT) requires frequent dosing due to short drug half-life causing challenges in long-term patient compliance. JCXH-301 is a lipid nanoparticle (LNP) encapsulated messenger RNA (mRNA) encoding β-GCase. Intravenous administration of JCXH-301 delivered the target mRNA to various tissues in mice with intracellular expression of β-GCase predominantly in macrophages and dendritic cells in the spleen and bone marrow. In GBA1 D427V homozygous mice treated with JCXH-301, the dose-dependent in vivo production of functional β-GCase resulted in reduction of serum lyso-GL1, a key biomarker of GD. The therapeutic effect of JCXH-301 was sustained for a duration significantly longer than that of protein-based ERT Cerezyme. JCXH-301 administration induced minimal pro-inflammatory cytokines in the liver and spleen. Taken together, these results provide proof-of-concept for using LNP-delivered mRNA as a new drug modality to restore the β-GCase genetic deficiency for GD treatment.

系统递送脂质纳米颗粒-编码溶酶体酸β-葡萄糖苷酶的mrna可恢复小鼠戈谢病模型中的酶缺乏。
戈谢病(GD)是一种罕见的遗传性疾病,由溶酶体酸β-葡萄糖苷酶(β-GCase)的丧失引起底物鞘脂糖基神经酰胺(GL1)和葡萄糖-鞘糖苷(lyso-GL1)的逐渐积累引起。基于蛋白质的酶替代疗法(ERT)需要频繁给药,因为药物半衰期短,对患者的长期依从性构成挑战。JCXH-301是一种脂质纳米颗粒(LNP)封装的信使RNA (mRNA)编码β-GCase。静脉给药JCXH-301将靶mRNA递送至小鼠各组织,细胞内β-GCase主要在脾脏和骨髓的巨噬细胞和树突状细胞中表达。在用JCXH-301处理的GBA1 D427V纯合子小鼠中,体内产生的功能性β-GCase的剂量依赖性导致血清溶酶gl1 (GD的关键生物标志物)的减少。JCXH-301的治疗效果持续时间明显长于基于蛋白质的ERT Cerezyme。JCXH-301在肝脏和脾脏中诱导少量促炎细胞因子。综上所述,这些结果为使用lnp传递的mRNA作为一种新的药物模式来恢复GD治疗中β-GCase基因缺陷提供了概念证明。
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来源期刊
Gene Therapy
Gene Therapy 医学-生化与分子生物学
CiteScore
9.70
自引率
2.00%
发文量
67
审稿时长
4-8 weeks
期刊介绍: Gene Therapy covers both the research and clinical applications of novel therapeutic techniques based on a genetic component. Over the last few decades, significant advances in technologies ranging from identifying novel genetic targets that cause disease through to clinical studies, which show therapeutic benefit, have elevated this multidisciplinary field to the forefront of modern medicine.
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