Hensel Niko, Kubinski Sabrina, Claus Peter
Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany.
Center of Systems Neuroscience (ZSN), Hannover, Germany.
Front Neurol. 2020 Feb 3;11:45. doi: 10.3389/fneur.2020.00045. eCollection 2020.
Spinal Muscular Atrophy (SMA) is monogenic motoneuron disease caused by low levels of the Survival of Motoneuron protein (SMN). Recently, two different drugs were approved for the treatment of the disease. The antisense oligonucleotide Nusinersen/Spinraza® and the gene replacement therapy Onasemnogene Abeparvovec/Zolgensma® both enhance SMN levels. These treatments result in impressive benefits for the patients. However, there is a significant number of non-responders and an intervention delay has a strong negative impact on the efficacy. Obviously, later stages of motoneuron degeneration cannot be reversed by SMN-restoration. Therefore, complementary, SMN-independent strategies are needed which are able to address such SMN-irreversible degenerative processes. Those are defined as pathological alterations which are not reversed by SMN-restoration for a given dose and intervention delay. It is crucial to tailor SMN-independent approaches to the novel clinical situation with SMN-restoring treatments. On the molecular level, such SMN-irreversible changes become manifest in altered signaling modules as described by molecular systems biology. Based on our current knowledge about altered signaling, we introduce a network approach for an informed decision for the most potent SMN-independent treatment targets. Finally, we present recommendations for the identification of novel treatments which can be combined with SMN-restoring drugs.
脊髓性肌萎缩症（SMA）是一种由运动神经元存活蛋白（SMN）水平低下引起的单基因运动神经元疾病。最近，两种不同的药物被批准用于治疗该疾病。反义寡核苷酸Nusinersen/Spinraza®和基因替代疗法Onasemnogene Abeparvovec/Zolgensma®都能提高SMN水平。这些治疗给患者带来了显著的益处。然而，有相当数量的患者无反应，而且干预延迟对疗效有很大的负面影响。显然，运动神经元变性的后期阶段无法通过恢复SMN来逆转。因此，需要补充性的、不依赖SMN的策略，以应对这种SMN不可逆的退行性过程。这些过程被定义为在给定剂量和干预延迟下，不会因恢复SMN而逆转的病理改变。根据恢复SMN的治疗方法，调整不依赖SMN的方法以适应新的临床情况至关重要。在分子水平上，正如分子系统生物学所描述的，这种SMN不可逆的变化在改变的信号模块中表现出来。基于我们目前对信号改变的了解，我们引入一种网络方法，以便明智地决定最有效的不依赖SMN的治疗靶点。最后，我们提出了识别可与恢复SMN的药物联合使用的新治疗方法的建议。
