Preclinical PK and PD studies on 2'-O-methyl-phosphorothioate RNA antisense oligonucleotides in the mdx mouse model.
Preclinical PK and PD studies on 2'-O-methyl-phosphorothioate RNA antisense oligonucleotides in the mdx mouse model.
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DOI：
10.1038/mt.2010.72
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发表时间：
2010-06
影响因子：
12.4
通讯作者：
van Deutekom, Judith C. T.
中科院分区：
文献类型：
--
作者：
Heemskerk, Hans;de Winter, Christa;van Kuik, Petra;Heuvelmans, Niki;Sabatelli, Patrizia;Rimessi, Paola;Braghetta, Paola;van Ommen, Gert-Jan B.;de Kimpe, Sjef;Ferlini, Alessandra;Aartsma-Rus, Annemieke;van Deutekom, Judith C. T.
反义寡核苷酸（AON）正在被开发为用于Duchenne肌营养不良症的RNA治疗分子。对于具有2′-O-甲基-硫代磷酸酯（2 OMePS）RNA化学的寡核苷酸，已在患者特异性肌细胞培养物、小鼠和犬疾病模型中获得了概念证明，最近还在Duchenne患者中进行了局部给药。为了进一步探索这种化学类别的寡核苷酸的药代动力学（PK）/药效学（PD）特性，我们在小鼠中进行了一系列临床前研究。结果表明，肌营养不良蛋白缺陷的肌纤维中的寡核苷酸水平远高于健康纤维，导致更高的外显子跳跃水平。特定肌肉群的寡核苷酸水平和半衰期不同，心肌的水平最低，但半衰期最长（约46天）。静脉注射（i. v.），皮下（s.c.），和腹膜内（i. p.）直接比较递送方法。对于每种方法，在所有肌肉中观察到外显子跳跃和新型肌营养不良蛋白表达，包括皮肤活检中的立毛肌皮利平滑肌。静脉给药后，血浆、肝脏和肾脏中的寡核苷酸峰水平高于皮下给药后。或腹膜内注射。然而，由于生物利用度相似，并且在s.c.在给药后，我们选择这种方便患者的递送方法用于未来的临床研究方案。
Antisense oligonucleotides (AONs) are being developed as RNA therapeutic molecules for Duchenne muscular dystrophy. For oligonucleotides with the 2′-O-methyl-phosphorothioate (2OMePS) RNA chemistry, proof of concept has been obtained in patient-specific muscle cell cultures, the mouse and dog disease models, and recently by local administration in Duchenne patients. To further explore the pharmacokinetic (PK)/pharmacodynamic (PD) properties of this chemical class of oligonucleotides, we performed a series of preclinical studies in mice. The results demonstrate that the levels of oligonucleotides in dystrophin-deficient muscle fibers are much higher than in healthy fibers, leading to higher exon-skipping levels. Oligonucleotide levels and half-life differed for specific muscle groups, with heart muscle showing the lowest levels but longest half-life (~46 days). Intravenous (i.v.), subcutaneous (s.c.), and intraperitoneal (i.p.) delivery methods were directly compared. For each method, exon-skipping and novel dystrophin expression were observed in all muscles, including arrector pili smooth muscle in skin biopsies. After i.v. administration, the oligonucleotide peak levels in plasma, liver, and kidney were higher than after s.c. or i.p. injections. However, as the bioavailability was similar, and the levels of oligonucleotide, exon-skipping, and dystrophin steadily accumulated overtime after s.c. administration, we selected this patient-convenient delivery method for future clinical study protocols.
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影响因子：
5.1
作者：
McClorey, G.;Moulton, H. M.;Wilton, S. D.
通讯作者：
Wilton, S. D.
影响因子：
3.5
作者：
Heemskerk, Hans A.;de Winter, Christa L.;Aartsma-Rus, Annemieke
通讯作者：
Aartsma-Rus, Annemieke
影响因子：
5.1
作者：
Aartsma-Rus, A;Kaman, WE;van Deutekom, JCT
通讯作者：
van Deutekom, JCT
影响因子：
1.9
作者：
Tanveer, Nadeem;Sharma, Mehar C.;Bhatia, Rohit
通讯作者：
Bhatia, Rohit
影响因子：
3.5
作者：
Mann, CJ;Honeyman, K;Wilton, SD
通讯作者：
Wilton, SD