Preclinical studies on intestinal administration of antisense oligonucleotides as a model for oral delivery for treatment of duchenne muscular dystrophy.
Preclinical studies on intestinal administration of antisense oligonucleotides as a model for oral delivery for treatment of duchenne muscular dystrophy.
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DOI：
10.1038/mtna.2014.62
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发表时间：
2014-11-18
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--
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用于重构杜氏肌营养不良症 (DMD) 患者肌营养不良蛋白 mRNA 转录本的反义寡核苷酸 (AON) 正在临床试验中进行测试。在这里，AON 通过皮下和静脉注射给药，而侵入性较小的口服途径是首选。口服补充有渗透促进剂癸酸钠的封装 AON 已成功用于靶向肝脏中肿瘤坏死因子 (TNF)-α 的表达。为了测试口服 AON 治疗 DMD 的可行性，我们将 2'-O-甲基硫代磷酸酯 AON（添加或不添加癸酸钠）直接施用于 mdx 小鼠的肠道，并比较了静脉内、腹膜内和皮下递送的药代动力学和动力学。肠内输注的 AON 被吸收，但与其他输送途径相比，其血浆水平较低，尽管通过补充癸酸钠可以大大提高生物利用度。肠输注后，所有组织中的 AON 水平均低于其他给药途径，靶器官与非靶器官水平的比率也是如此，但膈肌和心脏除外，观察到了可比较的水平和比率。对于每种给药途径，在 AON 给药后 3 小时观察到三头肌中低水平的外显子跳跃。这些数据表明，口服裸露的 2'-O-甲基硫代磷酸酯 AON 可能是可行的，但前提是高浓度的 AON 与癸酸钠联合使用。
Antisense oligonucleotides (AONs) used to reframe dystrophin mRNA transcripts for Duchenne muscular dystrophy (DMD) patients are tested in clinical trials. Here, AONs are administered subcutaneously and intravenously, while the less invasive oral route would be preferred. Oral delivery of encapsulated AONs supplemented with a permeation enhancer, sodium caprate, has been successfully used to target tumor necrosis factor (TNF)-α expression in liver. To test the feasibility of orally delivered AONs for DMD, we applied 2′-O-methyl phosphorothioate AONs (with or without sodium caprate supplementation) directly to the intestine of mdx mice and compared pharmacokinetics and -dynamics with intravenous, intraperitoneal, and subcutaneous delivery. Intestinally infused AONs were taken up, but resulted in lower plasma levels compared to other delivery routes, although bioavailability could be largely improved by supplementation of sodium caprate. After intestinal infusion, AON levels in all tissues were lower than for other administration routes, as were the ratios of target versus nontarget organ levels, except for diaphragm and heart where comparable levels and ratios were observed. For each administration route, low levels of exon skipping in triceps was observed 3 hours post-AON administration. These data suggest that oral administration of naked 2′-O-methyl phosphorothioate AONs may be feasible, but only when high AON concentrations are used in combination with sodium caprate.
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影响因子：
2.1
作者：
Jang, Shih-Fan;Goins, Betha.;McConville, Jason T.
通讯作者：
McConville, Jason T.
DOI：
10.1038/mtna.2012.30
发表时间：
2012-08-14
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
通讯作者：
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影响因子：
158.5
作者：
Goemans, Nathalie M.;Tulinius, Mar;van Deutekom, Judith C.
通讯作者：
van Deutekom, Judith C.
影响因子：
11
作者：
Kohler, M.;Clarenbach, C. F.;Bloch, K. E.
通讯作者：
Bloch, K. E.
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