Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Mol Ther Nucleic Acids. 2012 Sep 4;1(9):e44. doi: 10.1038/mtna.2012.38.
Antisense-mediated exon skipping for Duchenne muscular dystrophy (DMD) is currently tested in phase 3 clinical trials. The aim of this approach is to modulate splicing by skipping a specific exon to reframe disrupted dystrophin transcripts, allowing the synthesis of a partly functional dystrophin protein. Studies in animal models allow detailed analysis of the pharmacokinetic and pharmacodynamic profile of antisense oligonucleotides (AONs). Here, we tested the safety and efficacy of subcutaneously administered 2'-O-methyl phosphorothioate AON at 200 mg/kg/week for up to 6 months in mouse models with varying levels of disease severity: mdx mice (mild phenotype) and mdx mice with one utrophin allele (mdx/utrn(+/-); more severe phenotype). Long-term treatment was well tolerated and exon skipping and dystrophin restoration confirmed for all animals. Notably, in the more severely affected mdx/utrn(+/-) mice the therapeutic effect was larger: creatine kinase (CK) levels were more decreased and rotarod running time was more increased. This suggests that the mdx/utrn(+/-) model may be a more suitable model to test potential therapies than the regular mdx mouse. Our results also indicate that long-term subcutaneous treatment in dystrophic mouse models with these AONs is safe and beneficial.Molecular Therapy-Nucleic Acids (2012) 1, e44; doi:10.1038/mtna.2012.38; published online 4 September 2012.
反义寡核苷酸介导的杜氏肌营养不良症（DMD）exon 跳跃治疗目前正在进行 3 期临床试验。该方法的目的是通过跳过特定的exon 来调节剪接，重新构建被破坏的肌营养不良蛋白转录本，从而合成部分功能正常的肌营养不良蛋白。在动物模型中的研究允许对反义寡核苷酸（AON）的药代动力学和药效学特征进行详细分析。在这里，我们在具有不同疾病严重程度的小鼠模型中测试了皮下给予 2'-O-甲基硫代磷酸酯 AON 200mg/kg/周长达 6 个月的安全性和疗效：mdx 小鼠（轻度表型）和具有一个 utrophin 等位基因的 mdx 小鼠（mdx/utrn(+/-)；更严重的表型）。长期治疗耐受性良好，所有动物均证实存在 exon 跳跃和肌营养不良蛋白恢复。值得注意的是，在更为严重的 mdx/utrn(+/-)小鼠中，治疗效果更大：肌酸激酶（CK）水平降低更多，旋转棒跑步时间增加更多。这表明 mdx/utrn(+/-)模型可能比常规 mdx 小鼠更适合测试潜在的治疗方法。我们的结果还表明，这些 AON 在进行性肌营养不良症小鼠模型中的长期皮下治疗是安全且有益的。Molecular Therapy-Nucleic Acids (2012) 1, e44; doi:10.1038/mtna.2012.38; published online 4 September 2012.
