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运动神经元疾病. 在患有脊柱肌肉缩的小鼠中,SMN2剪接修饰剂改善了运动功能和寿命

Nikolai A Naryshkin¹, Marla Weetall¹, Amal Dakka¹

¹PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.

Science (New York, N.Y.)

|August 9, 2014

概括

研究人员发现了增强SMN2基因拼接的小分子,增加了功能性SMN蛋白水平. 这种方法通过在小鼠模型中改善运动功能和生存来显示脊柱肌肉缩 (SMA) 的治疗潜力.

科学领域:

遗传学是一个遗传学.
神经科学是一个神经科学.
药理学药理学是指药理学的学科.

背景情况:

脊髓肌肉缩 (SMA) 是一种遗传性疾病,由运动神经元1 (SMN1) 基因生存突变引起.
由于替代拼接,SMN2基因产生不足的功能性SMN蛋白质,导致神经肌肉退化.
目前的治疗方法旨在增加SMN蛋白水平,但需要新的治疗策略.

研究的目的:

识别和优化可口获得的调节SMN2基因拼接的小分子.
评估这些化合物的有效性在严重的SMA小鼠模型中.
评估这些分子对SMN蛋白水平,运动功能,神经肌肉完整性和生存的影响.

主要方法:

高通量化学选用于识别拼接修饰剂.
确定化合物的优化用于口服生物可用性和选择性.
在体内研究使用SMA的D7小鼠模型.
评估SMN蛋白水平,运动性能,神经肌肉结合完整性和生存率.

主要成果:

识别可口服的小分子,选择性地促进全长SMN2mRNA的产生.
在接受治疗的D7小鼠中,SMN蛋白水平明显增加.
观察到运动功能的显著改善和神经肌肉电路的保存.
用已识别的化合物治疗的SMA模型小鼠的寿命延长.

结论:

选择性SMN2拼接修饰剂代表了SMA的一个有前途的治疗策略.
口服可用的小分子可以有效地增加SMN蛋白质并改善SMA表型.
这些化合物的进一步开发可能为脊柱肌肉缩患者提供新的治疗选择.

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