Science:口服RNA剪切药物有望治疗脊髓性肌萎缩症

2014-08-12 佚名 生物通

  运动神经元负责将神经系统的信号传递给肌肉纤维。在脊髓性肌萎缩症(SMA)患者中,运动神经元缺乏生存所需的一种蛋白,结果神经元逐步死亡而患者肌肉日渐萎缩。目前,这种疾病还是个不治之症。 罗氏制药(pRED)、PTC Therapeutics、SMA基金会、南加州大学和哈佛大学的研究者们,合作开发了一个可以口服的小分子药物,这种药物能够改变特定mRNA的剪切,在运动神经元中恢复关

 

运动神经元负责将神经系统的信号传递给肌肉纤维。在脊髓性肌萎缩症(SMA)患者中,运动神经元缺乏生存所需的一种蛋白,结果神经元逐步死亡而患者肌肉日渐萎缩。目前,这种疾病还是个不治之症。

罗氏制药(pRED)、PTC Therapeutics、SMA基金会、南加州大学和哈佛大学的研究者们,合作开发了一个可以口服的小分子药物,这种药物能够改变特定mRNA的剪切,在运动神经元中恢复关键蛋白的合成。他们用这种药物对SMA小鼠模型进行治疗,成功改善了小鼠的肌肉量、运动机能和生存情况。这一令人兴奋的成果发表在本期的Science杂志上。

SMA是一种由SMN1基因突变或缺失引起的遗传学疾病,每一万新生儿中就有一名受到这种疾病的影响。SMA主要影响包括胸部肋间肌在内的近端肌肉,患者往往会因为呼吸系统并发症而死亡。

SMN2是SMN1的同源基因,因为选择性剪切缩短了转录本,只能生成低水平的功能性SMN蛋白。研究人员筛选得到的口服药物,是SMN2基因的剪切调节物,能够选择性改变SMN2 pre-mRNA的剪切,生成稳定的全长SMN蛋白。

研究显示,持续服药能够延长SMA小鼠的寿命,恢复其正常体重,阻止SMA的运动障碍和神经肌肉缺陷。

“这项研究向人们展示,SMN2剪切调节物的确能够矫正引起SMA的分子缺陷,” 罗氏制药的Luca Santarelli说。“我们的工作是治疗这种不治之症的重要一步。现在,我们正在对这一药物进行早期临床试验,以确定它的安全性和可耐受性。”

“我们的化合物是首个可以口服的SMN2剪切调节子,”PTC Therapeutics公司的CEO Stuart W. Peltz评论道。“这种药物正在我们的共同努力下快速向走向临床。”

研究人员对受到SMA影响的组织进行检测(大脑、脊髓和肌肉),发现SMN2剪切调节物能够很好的渗透这些组织,并通过改变RNA剪切提高SMN蛋白的产量。这种药物不仅阻止了小鼠的SMA发展,也在SMA患者的细胞中发挥了作用,包括那些衍生自干细胞的运动神经元。据介绍,该药物的I期临床试验已经于今年早些时候启动。

“这个临床前研究对我们理解SMA有很大的帮助,进一步说明用小分子上调SMN是个有效的治疗策略,”SMA基金会主席Loren Eng说。“我们对此很自豪,相信这一成果能够为SMA患者带来实质性的影响。”

原始出处:

Nikolai A. Naryshkin1,Marla Weetall1,Amal Dakka1,Jana Narasimhan1,Xin Zhao1,Zhihua Feng2,Karen K. Y. Ling2,Gary M. Karp1,Hongyan Qi1,Matthew G. Woll1,Guangming Chen1,Nanjing Zhang1,Vijayalakshmi Gabbeta1,Priya Vazirani1,Anuradha Bhattacharyya1,Bansri Furia1,Nicole Risher1,Josephine Sheedy1,Ronald Kong1,Jiyuan Ma1,Anthony Turpoff1,Chang-Sun Lee1,Xiaoyan Zhang1,Young-Choon Moon1,Panayiota Trifillis1,Ellen M. Welch1,Joseph M. Colacino1,John Babiak1,Neil G. Almstead1,Stuart W. Peltz1,*,Loren A. Eng3,Karen S. Chen3,Jesse L. Mull4,Maureen S. Lynes4,Lee L. Rubin4,Paulo Fontoura5,Luca Santarelli5,Daniel Haehnke5,Kathleen D. McCarthy3,Roland Schmucki5,Martin Ebeling5,Manaswini Sivaramakrishnan5,Chien-Ping Ko2,Sergey V. Paushkin3,Hasane Ratni5,Irene Gerlach5,Anirvan Ghosh5,Friedrich Metzger5,*SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.Science 8 August 2014:Vol. 345 no. 6197 pp. 688-693.DOI: 10.1126/science.1250127 


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    2014-08-23 chendoc252
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    2014-10-10 zyzyyan

    还有为什么只能针对SMN2剪切,而不是补足SMN1?

    0

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    2014-10-10 zyzyyan

    这个这个,口服可能吗?不会被各种消化酶消化?

    0

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    2014-08-14 rosa00tong

    口服的基因剪切调节子,这是新药的研发方向,期待能有前景

    0

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    2014-08-14 jichang
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    2014-08-14 zhouqu_8