Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study.
Exon skipping and dystrophin restoration in patients with Duchenne muscular dystrophy after systemic phosphorodiamidate morpholino oligomer treatment: an open-label, phase 2, dose-escalation study.
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DOI：
10.1016/s0140-6736(11)60756-3
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发表时间：
2011-08-13
期刊：
影响因子：
168.9
通讯作者：
Muntoni, Francesco
中科院分区：
文献类型：
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作者：
Cirak, Sebahattin;Arechavala-Gomeza, Virginia;Guglieri, Michela;Feng, Lucy;Torelli, Silvia;Anthony, Karen;Abbs, Stephen;Garralda, Maria Elena;Bourke, John;Wells, Dominic J.;Dickson, George;Wood, Matthew J. A.;Wilton, Steve D.;Straub, Volker;Kole, Ryszard;Shrewsbury, Stephen B.;Sewry, Caroline;Morgan, Jennifer E.;Bushby, Kate;Muntoni, Francesco
我们报告了静脉注射AVI-4658磷酰二胺吗啉寡聚体（PMO）治疗杜氏肌营养不良症患者的剂量范围研究的临床安全性和生化疗效。我们在5-15岁的DMD缺失型Duchenne型肌营养不良症非卧床患者中进行了一项开放标签、II期、剂量递增研究（0·5、1·0、2·0、4·0、10·0和20·0 mg/kg体重）。参与者在开始治疗前和每周静脉输注AVI-4658 12次后进行肌肉活检。主要研究目的是评估AVI-4658的安全性和耐受性。次要目的是通过RT-PCR、免疫组织化学和免疫印迹法研究AVI-4658的药代动力学特性和诱导51号外显子跳跃和肌营养不良蛋白恢复的能力。该研究已注册，编号为NCT 00844597。19名患者参加了这项研究。AVI-4658耐受性良好，没有药物相关的严重不良事件。AVI-4658在所有队列中诱导外显子51跳读，并在队列3（剂量2 mg/kg）以后的男孩中以显著剂量依赖性（p= 0.0203）但可变的方式诱导新的肌营养不良蛋白表达。7例患者对治疗有反应，治疗后平均肌营养不良蛋白荧光强度从正常对照的8.9%（95%CI 7.1 - 10.6）增加到16.4%（10.8 - 22.0）（p= 0.0287）。对治疗反应最大的三名患者在治疗后有21%、15%和55%的肌营养不良蛋白阳性纤维，这些发现得到了蛋白质印迹的证实，蛋白质印迹显示治疗后蛋白质水平分别从正常肌肉的2%增加到18%、从0.9%增加到17%和从0%增加到7.7%。肌营养不良蛋白相关蛋白α-肌聚糖和神经元型一氧化氮合酶也在肌膜上恢复。对炎性浸润的分析表明，在两个高剂量队列中，治疗后肌肉活检中的细胞毒性T细胞减少。我们目前的安全性和生化功效表明AVI-4658有潜力成为杜氏肌营养不良症的疾病修饰药物。英国医学研究理事会; AVI生物制药公司。
We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy. We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5–15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597. 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0·0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8·9% (95% CI 7·1–10·6) to 16·4% (10·8–22·0) of normal control after treatment (p=0·0287). The three patients with the greatest responses to treatment had 21%, 15%, and 55% dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2% to 18%, from 0·9% to 17%, and from 0% to 7·7% of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts. The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy. UK Medical Research Council; AVI BioPharma.