Biomarker Qualification for Neurofilament Light Chain in Amyotrophic Lateral Sclerosis: Theory and Practice.

Objective: To explore whether the utility of neurofilament light chain (NfL), as a biomarker to aid amyotrophic lateral sclerosis (ALS) therapy development, would be enhanced by obtaining formal qualification from the US Food and Drug Administration for a defined context-of-use.

Methods: Consensus discussion among academic, industry, and patient advocacy group representatives.

Results: A wealth of scientific evidence supports the use of NfL as a prognostic, response, and potential safety biomarker in the broad ALS population, and as a risk/susceptibility biomarker among the subset of SOD1 pathogenic variant carriers.

Understanding the needs of people with ALS: a national survey of patients and caregivers.

: Amyotrophic lateral sclerosis (ALS) has profound effects on people with ALS (PALS) and caregivers. There is a paucity of research detailing and comparing PALS and caregiver day-to-day perspectives of ALS. : A survey developed collaboratively by The ALS Association and a panel of experts in ALS care was designed to broadly sample the experience of PALS and caregivers with respect to physical and emotional symptoms, the efficacy of treatment approaches, and goals for future treatments.

ALS drug development guidances and trial guidelines: Consensus and opportunities for alignment.

The US Food and Drug Administration (FDA) developed a draft guidance for drug development in amyotrophic lateral sclerosis (ALS) that was issued in February 2018. The FDA draft guidance considered the recommendations developed by the ALS community that incorporated the views of a large group of clinical investigators, industry representatives, advocacy groups, patients, and caregivers. This external input from the ALS community reviewed the current state of clinical research in ALS, made suggestions over a wide range of drug development topics, and served as an educational tool to provide the agency with additional inputs about ALS, the state of the science, and the community's views on key topics.

The Right Therapy for Neurological Disorders: From Randomized Trials to Clinical Practice - Patients versus Investigator Expectations and Needs.

Background: People living with amyotrophic lateral sclerosis (ALS) are now more proactive in making decisions about their treatment options, in particular with increased awareness through social media and the Internet. Together with increased awareness about the disease comes increased frustration that there is still only one Food and Drug Administration (FDA)-approved drug that modestly improves survival.

Summary: While efforts are underway to improve clinical trial design, patient involvement in trial design, clinical outcomes, and risk/benefit evaluations have become more recognized and will play a major role in the future success of clinical trials.

Modeling ALS with motor neurons derived from human induced pluripotent stem cells.

Directing the differentiation of induced pluripotent stem cells into motor neurons has allowed investigators to develop new models of amyotrophic lateral sclerosis (ALS). However, techniques vary between laboratories and the cells do not appear to mature into fully functional adult motor neurons. Here we discuss common developmental principles of both lower and upper motor neuron development that have led to specific derivation techniques.

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.

Opportunities for improving therapy development in ALS.

In May 2013, The ALS Association and The Northeast ALS Consortium (NEALS) convened a meeting of stakeholders for a round-table discussion of ways to improve therapy development in ALS. The following overview summarizes issues raised and potential new directions discussed at the meeting. We recommend that future phase II clinical trials in ALS proceed when the proposed treatment is directed at targets that are likely to be involved in ALS pathogenesis in a defined subgroup of patients, and be accompanied by one or more biomarkers to track both clinical progression and pharmacodynamic engagement of the target.

Funding agencies and disease organizations: resources and recommendations to facilitate ALS clinical research.

Ten groups presented their perspectives on facilitating clinical research in ALS including four federal agencies, four disease organizations, one foundation and one advocacy group. The federal agencies (National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, Office of Rare Diseases Research, Department of Defense) encourage fostering a team approach between pre-clinical and clinical research investigators, coordinating with patient groups in the early phases of clinical studies, enhancing private and public partnerships, and investigating the interplay between genetic susceptibility and environmental exposure. The disease organizations (Muscular Dystrophy Association, ALS Association, ALS Society of Canada, and the Motor Neurone Disease Association UK) support fellowship training programs to develop ALS clinician scientists, and encourage work on the epidemiology of ALS, on genetic and epigenetic mechanisms that are relevant to ALS pathogenesis, on developing ALS registries and biobanks, and building bridges of collaboration among study groups.

Mechanisms, models and biomarkers in amyotrophic lateral sclerosis.

The last 30 years have seen a major advance in the understanding of the clinical and pathological heterogeneity of amyotrophic lateral sclerosis (ALS), and its overlap with frontotemporal dementia. Multiple, seemingly disparate biochemical pathways converge on a common clinical syndrome characterized by progressive loss of upper and lower motor neurons. Pathogenic themes in ALS include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, altered energy metabolism, and most recently RNA mis-processing.

Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1.

Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. Individuals with ALS rapidly progress to paralysis and die from respiratory failure within 3 to 5 years after symptom onset. Epidemiological factors explain only a modest amount of the risk for ALS.

Meeting report of the International Consortium of Stem Cell Networks' Workshop Towards Clinical Trials Using Stem Cells for Amyotrophic Lateral Sclerosis/Motor Neuron Disease.

The International Consortium of Stem Cell Networks' (ICSCN) Workshop Towards Clinical Trials Using Stem Cells for Amyotrophic Lateral Sclerosis (ALS)/Motor Neuron Disease (MND) was held on 24-25 January 2011. Twenty scientific talks addressed aspects of cell derivation and characterization; preclinical research and phased clinical trials involving stem cells; latest developments in induced pluripotent (iPS) cell technology; industry involvement and investment. Three moderated panel discussions focused on unregulated ALS/MND treatments, and the state of the art and barriers to future progress in using stem cells for ALS/MND.

Consensus criteria for the diagnosis of frontotemporal cognitive and behavioural syndromes in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is increasingly recognized to be a multisystem disorder which includes both clinical and neuropathological features of a frontotemporal lobar degeneration (FTLD). In order to provide a common framework within which to discuss the characteristics of the cognitive and behavioural syndromes of ALS, and with which to conduct clinical and neuropathological research, an international research workshop on frontotemporal dementia (FTD) and ALS was held in London, Canada in June 2007. The recommendations arising from this research workshop address the requirement for a concise clinical diagnosis of the underlying motor neuron disease (Axis I), defining the cognitive and behavioural dysfunction (Axis II), describing additional non-motor manifestations (Axis III) and identifying the presence of disease modifiers (Axis IV).

A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis.

The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance.

Amyotrophic lateral sclerosis: an emerging era of collaborative gene discovery.

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND). It is currently incurable and treatment is largely limited to supportive care. Family history is associated with an increased risk of ALS, and many Mendelian causes have been discovered.

Genome-wide genotyping in amyotrophic lateral sclerosis and neurologically normal controls: first stage analysis and public release of data.

Background: The cause of sporadic ALS is currently unknown. Despite evidence for a role for genetics, no common genetic variants have been unequivocally linked to sporadic ALS. We sought to identify genetic variants associated with an increased or decreased risk for developing ALS in a cohort of American sporadic cases.

Therapeutic targets for amyotrophic lateral sclerosis: current treatments and prospects for more effective therapies.

Although amyotrophic lateral sclerosis (ALS) was described more than 130 years ago, the cause(s) of most cases of this adult motor neuron disease remains a mystery. With the discovery of mutations in one gene (Cu/Zn superoxide dismutase) as a primary cause of some forms of ALS, model systems have been developed that have helped us begin to understand mechanisms involved in motor neuron death and enabled testing of potential new therapies. Several other genes have been implicated as risk factors in motor neuron diseases, including neurofilaments, cytoplasmic dynein and dynactin, vascular endothelial growth factor, and angiogenin.

Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression.

Glutamate is the principal excitatory neurotransmitter in the nervous system. Inactivation of synaptic glutamate is handled by the glutamate transporter GLT1 (also known as EAAT2; refs 1, 2), the physiologically dominant astroglial protein. In spite of its critical importance in normal and abnormal synaptic activity, no practical pharmaceutical can positively modulate this protein.

Distinct patterns of tau-dependent process formation in mammalian cell lines.

Tau is a microtubule-associated protein involved in axonal elongation and central to the pathogenesis of a number of neurodegenerative conditions. To better establish the contribution of the cellular context to tau-dependent microtubule organization, we compared the phenotypes resulting from heterologous tau expression in different mammalian cell lines after disruption of the actin cytoskeleton. After cytochalasin D treatment, tau-expressing CHO cells display one or two long neurite-like extensions whereas cells transfected with MAP2c developed multiple shorter processes.

Unraveling the mechanisms involved in motor neuron degeneration in ALS.

Although Charcot described amyotrophic lateral sclerosis (ALS) more than 130 years ago, the mechanism underlying the characteristic selective degeneration and death of motor neurons in this common adult motor neuron disease has remained a mystery. There is no effective remedy for this progressive, fatal disorder. Modern genetics has now identified mutations in one gene [Cu/Zn superoxide dismutase (SOD1)] as a primary cause and implicated others [encoding neurofilaments, cytoplasmic dynein and its processivity factor dynactin, and vascular endothelial growth factor (VEGF)] as contributors to, or causes of, motor neuron diseases.