Improved Efficacy in a Fabry Disease Model Using a Systemic mRNA Liver Depot System as Compared to Enzyme Replacement Therapy
Improved Efficacy in a Fabry Disease Model Using a Systemic mRNA Liver Depot System as Compared to Enzyme Replacement Therapy
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DOI：
10.1016/j.ymthe.2019.03.001
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发表时间：
2019-04-10
影响因子：
12.4
通讯作者：
Heartlein, Michael W.
中科院分区：
文献类型：
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作者：
DeRosa, Frank;Smith, Lianne;Heartlein, Michael W.
法布里病是一种由α-半乳糖苷酶A缺乏引起的溶酶体贮积症。酶缺乏会导致肾和心脏功能进行性下降，导致心肌病和终末期肾病。目前可用的治疗方法，包括酶替代疗法，已经为患者带来了显着的益处；然而，医疗需求仍未得到满足。 mRNA疗法具有类似药物的特性，具有内源性产生治疗性蛋白质的独特能力。在这里，我们描述了通过纳米颗粒配制的 mRNA 在小鼠和非人灵长类动物体内持续递送治疗性人类 α-半乳糖苷酶蛋白，并通过小鼠法布里病模型中临床相关生物标志物的减少证明了疗效。开发了用脂质和类脂质材料配制的多组分纳米颗粒，用于递送编码人α-半乳糖苷酶蛋白的mRNA。将人类 GLA mRNA 递送至小鼠后，血清 GLA 蛋白水平高达正常生理值的 1,330 倍。
Fabry disease is a lysosomal storage disorder caused by the deficiency of alpha-galactosidase A. Enzyme deficiency results in a progressive decline in renal and cardiac function, leading to cardiomyopathy and end-stage renal disease. Current treatments available, including enzyme replacement therapies, have provided significant benefit to patients; however, unmet medical needs remain. mRNA therapy, with drug-like properties, has the unique ability to produce therapeutic proteins endogenously. Here we describe the sustained delivery of therapeutic human alpha-galactosidase protein in vivo via nanoparticle-formulated mRNA in mouse and non-human primate, with a demonstration of efficacy through clinically relevant biomarker reduction in a mouse Fabry disease model. Multi-component nanoparticles formulated with lipids and lipid-like materials were developed for the delivery of mRNA encoding human alpha-galactosidase protein. Upon delivery of human GLA mRNA to mice, serum GLA protein levels reached as high as similar to 1,330-fold over normal physiological values.