Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system.
Therapeutic efficacy in a hemophilia B model using a biosynthetic mRNA liver depot system.
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DOI：
10.1038/gt.2016.46
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发表时间：
2016-10
期刊：
影响因子：
5.1
通讯作者：
Heartlein, M. W.
中科院分区：
文献类型：
--
作者：
DeRosa, F.;Guild, B.;Karve, S.;Smith, L.;Love, K.;Dorkin, J. R.;Kauffman, K. J.;Zhang, J.;Yahalom, B.;Anderson, D. G.;Heartlein, M. W.
基于DNA的基因治疗具有相当大的治疗潜力，但与递送相关的挑战继续限制进展。信使RNA（mRNA）具有提供治疗性蛋白质的瞬时产生的潜力，而不需要核递送并且没有插入诱变的风险。在这里，我们描述了通过纳米颗粒配制的mRNA在啮齿动物和非人灵长类动物体内持续递送治疗性蛋白质。开发了用脂质和脂质样材料配制的纳米颗粒，用于递送编码人促红细胞生成素（hEPO）或因子IX（hFIX）蛋白的两种单独的mRNA转录物。对于每个mRNA构建体观察到剂量依赖性蛋白质产生。在小鼠中递送hEPO mRNA后，血清EPO蛋白水平达到正常生理值的几个数量级（> 125000倍）。此外，建立了血细胞比容（Hct）的增加，表明外源性mRNA衍生的蛋白质保持正常活性。通过递送配制的mRNA在非人灵长类动物中产生EPO的能力也被证明为在72小时的时间过程中观察到升高的EPO蛋白水平。举例说明mRNA药物可能的广泛用途，在小鼠中单次静脉内给药负载hFIX mRNA的脂质纳米颗粒后实现了治疗相关量的人FIX（hFIX）蛋白。此外，在血友病B（FIX敲除（KO））小鼠模型中，通过证明FIX KO小鼠损伤（切口）后Hct损失显著降低，确立了治疗价值。
DNA-based gene therapy has considerable therapeutic potential, but the challenges associated with delivery continue to limit progress. Messenger RNA (mRNA) has the potential to provide for transient production of therapeutic proteins, without the need for nuclear delivery and without the risk of insertional mutagenesis. Here we describe the sustained delivery of therapeutic proteins in vivo in both rodents and non-human primates via nanoparticle-formulated mRNA. Nanoparticles formulated with lipids and lipid-like materials were developed for delivery of two separate mRNA transcripts encoding either human erythropoietin (hEPO) or factor IX (hFIX) protein. Dose-dependent protein production was observed for each mRNA construct. Upon delivery of hEPO mRNA in mice, serum EPO protein levels reached several orders of magnitude (>125 000-fold) over normal physiological values. Further, an increase in hematocrit (Hct) was established, demonstrating that the exogenous mRNA-derived protein maintained normal activity. The capacity of producing EPO in non-human primates via delivery of formulated mRNA was also demonstrated as elevated EPO protein levels were observed over a 72-h time course. Exemplifying the possible broad utility of mRNA drugs, therapeutically relevant amounts of human FIX (hFIX) protein were achieved upon a single intravenous dose of hFIX mRNA-loaded lipid nanoparticles in mice. In addition, therapeutic value was established within a hemophilia B (FIX knockout (KO)) mouse model by demonstrating a marked reduction in Hct loss following injury (incision) to FIX KO mice.
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影响因子：
8
作者：
Chen, Cheng-Wei;Lu, Da-Wen;Chiang, Chiao-Hsi
通讯作者：
Chiang, Chiao-Hsi
影响因子：
15
作者：
Chen, Delai;Love, Kevin T.;Anderson, Daniel G.
通讯作者：
Anderson, Daniel G.
聚（糖氨基胺）刷子在体内制定了用于全身siRNA和mRNA递送的纳米材料。
影响因子：
10.8
作者：
Dong Y;Dorkin JR;Wang W;Chang PH;Webber MJ;Tang BC;Yang J;Abutbul-Ionita I;Danino D;DeRosa F;Heartlein M;Langer R;Anderson DG
通讯作者：
Anderson DG
影响因子：
5.4
作者：
Bunn, H. Franklin
通讯作者：
Bunn, H. Franklin
DOI：
10.1111/j.1440-1681.2006.04403.x
发表时间：
2006-05-01
影响因子：
2.9
作者：
Chan, JHP;Lim, SH;Wong, WSF
通讯作者：
Wong, WSF