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Sarepta公司DMD基因疗法初步临床结果积极

2018-10-06 MedSci MedSci原创

位于马萨诸塞州剑桥市的Sarepta Therapeutics一直致力于发现和开发针对罕见神经肌肉疾病的精准基因疗法。该公司日前宣布,其治疗杜氏肌营养不良症(DMD)的在研基因疗法AAVrh74.MHCK7.micro-Dystrophin(以下简称AAVrh74),在拥有四名DMD患者的临床试验中获得积极结果。通过免疫组化与免疫印迹检测,参与试验的四名患者均显示出了明显的微抗肌萎缩蛋白(micr

位于马萨诸塞州剑桥市的Sarepta Therapeutics一直致力于发现和开发针对罕见神经肌肉疾病的精准基因疗法。该公司日前宣布,其治疗杜氏肌营养不良症(DMD)的在研基因疗法AAVrh74.MHCK7.micro-Dystrophin(以下简称AAVrh74),在拥有四名DMD患者的临床试验中获得积极结果。通过免疫组化与免疫印迹检测,参与试验的四名患者均显示出了明显的微抗肌萎缩蛋白(micro-dystrophin)水平,并获得了良好的功能性改良结果,且未出现任何严重不良事件(SAEs)。

DMD是一种严重的遗传性渐进性肌肉萎缩症,由抗肌萎缩蛋白(dystrophin)基因突变引起,该蛋白主要存在于骨骼肌和心肌细胞中,也在神经细胞中有表达,是肌肉细胞行使正常功能所必需的蛋白。由于致病基因存在于X染色体上,该疾病主要影响男性,通常在3-5岁开始显现症状,表现为进行性肌肉退化和无力。肌肉衰弱首先影响臀部、骨盆、大腿和肩膀的肌肉,进而影响胳膊、腿部和躯干的肌肉。到青少年时期,患者通常会丧失行走能力,心脏和呼吸肌也受到影响,最终导致过早死亡。DMD是世界范围内最常见的肌营养不良症,每3500到5000名男婴中就有1名患者。DMD目前无法治愈,患者平均预期寿命只有26岁左右。这些患者急需一款有效的疗法来帮助他们延长寿命。

Sarepta的在研药物有望为患者们带来创新的基因疗法选择。其技术平台利用化学合成的二氨基磷酸酯吗啉代寡聚物(PMOs)来影响RNA的剪接和转译过程,从而改变蛋白质合成。PMOs能够与特定的RNA序列相结合,进而影响RNA剪接机制对RNA序列的识别。DMD患者由于基因突变导致抗肌萎缩蛋白转译中止,使肌肉细胞不能正常生成抗肌萎缩蛋白。Sarepta公司研发的PMOs能够让RNA剪接机制跳过发生突变的外显子生成成熟mRNA,虽然这种mRNA转译产生的蛋白的功能可能有所减弱,但可以在一定程度上弥补抗肌萎缩蛋白缺失带来的功能缺陷。

▲PMO引导剪接机制跳过产生突变的外显子示意图(图片来源:Sarepta公司官网)

本次公布的试验结果显示,通过免疫组化测量,所有参与试验的患者均获得了明显的微抗肌萎缩蛋白转译反应,且适当地定位于肌肉肌膜。患者的微抗肌萎缩蛋白阳性纤维的平均基因表达率达到了正常对照组的81.2%,且平均肌肉纤维密度达到了正常对照组的96.0%。通过免疫印迹检测,所有治疗后活检均获得了明显的微抗肌萎缩蛋白表达水平,其平均值达到了正常水平的74.3%。最新参与试验的第四名患者基因表达情况尤其明显,使用免疫组化方法测量,其微抗肌萎缩蛋白阳性纤维平均基因表达率达到了正常对照组的96.2%,平均纤维密度达到了160%,而微抗肌萎缩蛋白水平达到了182.7%。

除此之外,所有患者的血清肌酸激酶(CK)水平显著降低,CK的平均降低幅度超过87%。且在研究中未观察到严重不良事件(SAE)。此次公布的试验数据也包括了全部四名患者的基于北极星移动量表(NSAA)及其他评估标准的试验终点。试验结果显示,所有参与试验的男童患者NSAA数值与基线相比平均增长了6.5分,显示出了明显的功能性改良结果。值得注意的是,本次试验为一次小型无对照试验,所获得的积极数据还需通过更大规模的含对照组的试验来证实。

本次临床试验的首席研究员——来自全美儿童医院(Nationwide Children’s Hospital)的Jerry Mendell博士说:“这次试验的目标是证实临床前模型中的各种设想。试验结果显示,AAVrh74在不同种类肌肉中均显示出了良好的转染能力,MHCK7启动子也使微抗肌肉萎缩蛋白在骨骼肌中出现了明显的表达,除此之外,CK水平也降低了,试验也显示出了良好的安全性。在这次早期试验中,我们获得了与临床前模型近似的明显效果,显示出这一新疗法有很大的潜力可以缓解疾病恶化。”

▲Sarepta总裁兼首席执行官Doug Ingram博士(图片来源:Sarepta公司官网)

Sarepta总裁兼首席执行官Doug Ingram博士说:“这次在新加入试验的第四位患者身上看到的积极结果使我们更有信心加速推进研发的进程,开展下一步的临床试验。我们期望能将这一疗法尽快带给全世界深受疾病折磨的杜氏肌营养不良症患者。我们计划与FDA及其他监管机构合作,商讨进一步的发展计划。”

我们祝贺此次Sarepta获得的积极试验结果,并期待这一新型基因疗法可以早日与患者见面。

参考资料:

[1] Sarepta Therapeutics Announces that at the 23rd International Congress of the World Muscle Society, Jerry Mendell, M.D., Presented Positive Updated Results from the Four Children Dosed in the Gene Therapy Micro-dystrophin Trial to Treat Patients with Duchenne Muscular Dystrophy. Retrieved October 4, 2018, from http://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-23rd-international-congress-world

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    2019-01-03 gaoxiaoe
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    2018-10-08 紫砂壶
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    2018-10-07 kafei

    学习了谢谢

    0

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    2018-10-06 医者仁心5538

    学习了

    0

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