Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating disease caused by degeneration of motor neurons. As with all major neurodegenerative disorders, development of disease-modifying therapies has proven challenging for multiple reasons. Nevertheless, ALS is one of the few neurodegenerative diseases for which disease-modifying therapies are approved. Significant discoveries and advances have been made in ALS preclinical models, genetics, pathology, biomarkers, imaging and clinical readouts over the last 10–15 years. At the same time, novel therapeutic paradigms are being applied in areas of high unmet medical need, including neurodegenerative disorders. These developments have evolved our knowledge base, allowing identification of targeted candidate therapies for ALS with diverse mechanisms of action. In this Review, we discuss how this advanced knowledge, aligned with new approaches, can enable effective translation of therapeutic agents from preclinical studies through to clinical benefit for patients with ALS. We anticipate that this approach in ALS will also positively impact the field of drug discovery for neurodegenerative disorders more broadly.

ROCK1 orchestrates B cell differentiation in response to PAMPs and heme by controlling the heme-regulated proteins Bach2 and HRI

“…The surprising role of ROCK1 in limiting inflammatory responses and restraining the assembly of p62 aggregates, furthermore, highlights the challenges of therapeutically targeting this family of kinases, a feat that is being undertaken for several age-related disorders like cardiovascular and, more recently, neurodegenerative diseases including ALS 65,66 . It is indeed likely that the inhibitory roles of ROCK1 that we have identified are not confined to the B cell compartment but may extend to other cell types such as myeloid cells where the combination of PAMPs and heme has recently been shown to drive panoptosis 67 and neurons, which have high bioenergetic demands rendering them more susceptible to environmental insults.…”

Deregulation of Plasma microRNA Expression in a TARDBP-ALS Family

“…Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) is a progressive degenerative disease affecting motor neurons (MNs) with a multifactorial etiology in which both environmental and genetic variables play a crucial role [ 1 , 2 ]. ALS appears to be a heterogeneous disease, not only regarding the age of onset or clinical phenotype but, most importantly, related to its rate of progression [ 3 , 4 ].…”

Biofluid Biomarkers in the Prognosis of Amyotrophic Lateral Sclerosis: Recent Developments and Therapeutic Applications

“…Despite advances in our knowledge, repeated efforts to translate it into effective therapy have been unfruitful. There are several possible causes for these failures, but one of the factors that has been consistently highlighted is the need for robust and reliable biomarkers in ALS [ 7 , 8 ]. The statements from the TRICALS consortium (Treatment Research Initiative to Cure ALS) and the revised Airlie House ALS Clinical Trials Consensus Guidelines are remarkable examples of this consensus within the international ALS community [ 9 , 10 ].…”