Therapeutic targeting ofALSpathways: Refocusing an incomplete picture

Abstract

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.

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

“…There has recently been renewed efforts in the development of therapeutics for ALS [ 216 ] invoking the potential role of mitochondria [ 217 ] and the gut–brain axis [ 218 ], as well as anti-sense therapies [ 219 ] and personalized immunotherapy [ 220 ]. Future efforts to better understand the pathogenesis of ALS and screen for effective treatments will use human organoids composed of iPSC [ 221 , 222 ] discussed in the last section.…”