Therapeutic targeting of ALS pathways: Refocusing an incomplete picture.
Therapeutic targeting of ALS pathways: Refocusing an incomplete picture.
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DOI：
10.1002/acn3.51887
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发表时间：
2023-11
影响因子：
5.3
通讯作者：
Weiss, Michael D.
中科院分区：
文献类型：
--
作者：
Maragakis, Nicholas J.;de Carvalho, Mamede;Weiss, Michael D.
许多潜在的肌萎缩侧索硬化症 (ALS) 相关途径已在临床前进行了假设和研究，随后转化为临床试验。然而，几乎没有观察到成功且效果有限。随着对 ALS 作为一种神经退行性疾病的认识有所提高但不完整，更复杂和多样化的体外和体内临床前建模平台以及临床试验设计也在不断发展。我们重点介绍了所提出的病理途径，这些途径已成为研究化合物的主要治疗靶点。如此多的治疗化合物的失败可能不是因为缺乏疗效，而是因为缺乏有助于定义适当疾病途径的临床前模型，以及未能建立目标参与。这些挑战因临床试验设计的缺陷而变得更加复杂，包括缺乏可以预测临床成功的生物标志物以及研究动力不足。尽管研究投资为新的 ALS 相关途径提供了丰富的见解，但大多数尚未得到更充分的开发以进行临床研究。在这篇综述中，我们详细介绍了一些重要的、完善的途径、针对它们的治疗方法以及随后的临床设计。了解了过去三十年 ALS 研究转化工作中的一些缺点后，我们建议科学家和临床医生可以选择重新审视本文回顾的一些治疗途径，着眼于改进临床前模型、生物标志物开发以及对更复杂的临床试验设计的投资。
Numerous potential amyotrophic lateral sclerosis (ALS)‐relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial. However, few successes have been observed with only modest effects. Along with an improved but incomplete understanding of ALS as a neurodegenerative disease is the evolution of more sophisticated and diverse in vitro and in vivo preclinical modeling platforms, as well as clinical trial designs. We highlight proposed pathological pathways that have been major therapeutic targets for investigational compounds. It is likely that the failures of so many of these therapeutic compounds may not have occurred because of lack of efficacy but rather because of a lack of preclinical modeling that would help define an appropriate disease pathway, as well as a failure to establish target engagement. These challenges are compounded by shortcomings in clinical trial design, including lack of biomarkers that could predict clinical success and studies that are underpowered. Although research investments have provided abundant insights into new ALS‐relevant pathways, most have not yet been developed more fully to result in clinical study. In this review, we detail some of the important, well‐established pathways, the therapeutics targeting them, and the subsequent clinical design. With an understanding of some of the shortcomings in translational efforts over the last three decades of ALS investigation, we propose that scientists and clinicians may choose to revisit some of these therapeutic pathways reviewed here with an eye toward improving preclinical modeling, biomarker development, and the investment in more sophisticated clinical trial designs.
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DOI：
10.1111/cts.12241
发表时间：
2015-02
期刊：
Clinical and translational science
影响因子：
--
作者：
Nalbandian A;Ghimbovschi S;Wang Z;Knoblach S;Llewellyn KJ;Vesa J;Hoffman EP;Kimonis VE
通讯作者：
Kimonis VE
影响因子：
14.8
作者：
Barmada, Sami J.;Serio, Andrea;Arjun, Arpana;Bilican, Bilada;Daub, Aaron;Ando, D. Michael;Tsvetkov, Andrey;Pleiss, Michael;Li, Xingli;Peisach, Daniel;Shaw, Christopher;Chandran, Siddharthan;Finkbeiner, Steven
通讯作者：
Finkbeiner, Steven
影响因子：
38.1
作者：
Boulis, Nicholas M.;Federici, Thais;Feldman, Eva L.
通讯作者：
Feldman, Eva L.
影响因子：
15.9
作者：
Azzouz, M;Le, T;Mazarakis, ND
通讯作者：
Mazarakis, ND
影响因子：
9.9
作者：
Borasio, GD;Robberecht, W;Dobbins, T
通讯作者：
Dobbins, T