Field Of Amyotrophic Lateral Sclerosis Research Articles

Considerations for Amyotrophic Lateral Sclerosis (ALS) Clinical Trial Design.

Thoughtful clinical trial design is critical for efficient therapeutic development, particularly in the field of amyotrophic lateral sclerosis (ALS), where trials often aim to detect modest treatment effects among a population with heterogeneous disease progression. Appropriate outcome measure selection is necessary for trials to provide decisive and informative results. Investigators must consider the outcome measure’s reliability, responsiveness to detect change when change has actually occurred, clinical relevance, and psychometric performance. ALS clinical trials can also be performed more efficiently by utilizing statistical enrichment techniques. Innovations in ALS prediction models allow for selection of participants with less heterogeneity in disease progression rates without requiring a lead-in period, or participants can be stratified according to predicted progression. Statistical enrichment can reduce the needed sample size and improve study power, but investigators must find a balance between optimizing statistical efficiency and retaining generalizability of study findings to the broader ALS population. Additional progress is still needed for biomarker development and validation to confirm target engagement in ALS treatment trials. Selection of an appropriate biofluid biomarker depends on the treatment mechanism of interest, and biomarker studies should be incorporated into early phase trials. Inclusion of patients with ALS as advisors and advocates can strengthen clinical trial design and study retention, but more engagement efforts are needed to improve diversity and equity in ALS research studies. Another challenge for ALS therapeutic development is identifying ways to respect patient autonomy and improve access to experimental treatment, something that is strongly desired by many patients with ALS and ALS advocacy organizations. Expanded access programs that run concurrently to well-designed and adequately powered randomized controlled trials may provide an opportunity to broaden access to promising therapeutics without compromising scientific integrity or rushing regulatory approval of therapies without adequate proof of efficacy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01271-2.

Circulating cell-free DNA as potential diagnostic tools for amyotrophic lateral sclerosis

DNA methylation has garnered much attention in recent years for its diagnostic potential in multiple conditions including cancer and neurodegenerative diseases. Conversely, advances regarding the potential diagnostic relevance of DNA methylation status have been sparse in the field of amyotrophic lateral sclerosis (ALS) even though patients diagnosed with this condition would significantly benefit from improved molecular assays aimed at furthering the current diagnostic and therapeutic options available. This review will provide an overview of the current diagnostic approaches available for ALS diagnosis and discuss the potential clinical usefulness of DNA methylation. We will also present examples of DNA methylation as a diagnostic tool in various types of cancer and neurodegenerative conditions and expand on how circulating cfDNA methylation may be leveraged for the early detection of ALS. In general, this article will reinforce the importance of cfDNA methylation as diagnostic tools and will further highlight its clinical relevance for persons diagnosed with ALS.

Clinical trials in amyotrophic lateral sclerosis.

To review new developments in the field of amyotrophic lateral sclerosis (ALS) clinical trial design and to review the implications of the latest ALS clinical trials. There has been substantial reflection on how clinical trials in ALS are best conducted. The revised Airlie House recommendations are an important milestone and should guide trial design. In addition, innovations using individualized risk-based eligibility criteria, adaptive designs, joint modelling, patient-centred approaches, and remote collection of data show real promise. Edaravone was shown to have benefit on function in a well defined subset of patients with ALS, although there are concerns about the generalizability of the findings. Studies of arimoclomol, inosine, and cellular therapies have demonstrated promising signals in early phase work and are being taken forward into larger studies. Well conducted studies of rasagaline did not show an effect on primary outcome measures. For many decades there has been regular disappointment with the results of clinical trials. With the innovations in trial design and advances in our basic understanding of the biology of ALS, the prospects for a step change in treatments for people affected by ALS are strong.

ALS biomarkers for therapy development: State of the field and future directions.

Biomarkers have become the focus of intense research in the field of amyotrophic lateral sclerosis (ALS), with the hope that they might aid therapy development efforts. Notwithstanding the discovery of many candidate biomarkers, none have yet emerged as validated tools for drug development. In this review we present a nuanced view of biomarkers based on the perspective of the Food and Drug Administration; highlight the distinction between discovery and validation; describe existing and emerging resources; review leading biological fluid-based, electrophysiological, and neuroimaging candidates relevant to therapy development efforts; discuss lessons learned from biomarker initiatives in related neurodegenerative diseases; and outline specific steps that we, as a field, might take to hasten the development and validation of biomarkers that will prove useful in enhancing efforts to develop effective treatments for ALS patients. Most important among these is the proposal to establish a federated ALS Biomarker Consortium in which all interested and willing stakeholders may participate with equal opportunity to contribute to the broader mission of biomarker development and validation.

Enhancing clinical trials in neurodegenerative disorders

This review article is focused on strategies that may enhance clinical trial efficiency in neurodegenerative disorders, as demonstrated within the research field of amyotrophic lateral sclerosis (ALS). Unravelling ALS pathophysiology will result in an increased number of candidate therapeutics. Recent ALS clinical trials have employed novel study designs that expedite the drug development process and limit sample size, including futility, lead-in, selection, adaptive and sequential designs. The search for sensitive and specific biomarkers in ALS continues to develop, and they are essential in accelerating the drug discovery process. Several candidate cerebrospinal fluid (CSF), neuroimaging and electrophysiological biomarkers have been recently described in ALS, and some have been successfully employed as secondary outcome measures in clinical trials. The advent of web-based technologies has provided a complementary platform to expedite clinical trials, through electronic data capture, teleconferencing and online registries. In addition, the formation of ALS consortia has enhanced collaborative multicentre studies. ALS research studies have employed novel strategies to accelerate the efficiency and pace of drug discovery. The importance of adapting to novel measures that enhance study efficiency is not unique to ALS and can be applied to other neurodegenerative diseases in search of effective treatments.

Amyotrophic lateral sclerosis

The field of amyotrophic lateral sclerosis (ALS) has seen a number of remarkable advances during recent years that will be summarized in this review. In particular, the progress in the molecular neuropathology with the discovery of pathogenic mutations in TAR DNA binding protein (TARDBP), fused in sarcoma (FUS), ubiquilin2 (UBQLN2) and most recently C9ORF72 (abbreviation for the open reading frame 72 on chromosome 9) has further substantiated the - clinically temporarily forgotten - relation of classic ALS to frontotemporal degeneration (FTD). Also, major progress has been made by the discovery of genes relevant for the disease, and pathogenetic concepts have been suggested which imply that not one, but multiple genetic and cell biological hits are involved in the causation of the disease. Progress in interventional therapies has remained poor; important recent examples are the failure of the interventional lithium and pioglitazone trials. However, a study of a third interventional compound - dexpramipexol - raises substantial hopes that the class of chemicals originally represented by riluzole - benzothiazoles - may provide additional therapeutic progress for ALS patients. Tremendous progress has been made in the field of ALS based on recent neuropathological and genetic discoveries. Moreover, the role of metabolism and nutrition in the pathogenesis of the disease is debated and may potentially serve as a future therapeutic target. For the facilitation and cost reduction of clinical trials, the development and international standardization of disease-specific 'wet' and 'dry' biomarkers is essential.

Amyotrophic Lateral Sclerosis and Novel Therapeutic Strategies

Research and key discoveries in the field of amyotrophic lateral sclerosis (ALS) have exponentially increased since the announcement in 1993 of the first ALS-causing mutations in the gene for the well-studied antioxidant enzyme Cu,Zn superoxide dismutase (SOD1). The etiology of sporadic ALS largely remains unknown and the mechanisms of motor neuron degeneration are still being investigated. The only FDA drug approved for the treatment of ALS is riluzole with only modest benefit to patients, but multiple drugs are currently in the development pipeline and in human ALS clinical trials. In this special issue, K. Venkova-Hristova et al. thoroughly reviewed studies of experimental therapeutics in animal models of ALS, including specific examples of those that proceeded into human clinical trials. Since none of the ALS human clinical trials succeeded despite positive results in animal models, the question of “why” has been on everyone's mind, with efforts to develop superior alternatives. This review discusses the potential reasons for the universal failure of preclinical successes to translate into positive clinical outcomes. It has become obvious that the lack of understanding of the precise mechanisms of motor neuron degeneration presents a major obstacle in the development of effective therapy for ALS. This review discusses the details of several major pathogenic pathways in ALS and the efforts of various groups to block one toxic pathway at a time, ranging from oxidative stress to protein aggregation. The authors discuss the pros and cons of ALS models and propose simultaneous targeting of multiple pathways as a more efficient strategy, due to the multifactorial nature of ALS pathology.