Research Focus
Click on each puzzle piece to see more
Deep Phenotyping
- Motor
- Cognitive
- Phenotype-Genotype
Causes & Modifiers
- Genetics
- Environment
- Gene x Environment
Biomarker Discovery & Validation
- Biofluid
- Imaging
- Electrical
- Physiological
Novel Data Collection Methods
- Remote assessments
- EHR-based
Disease Biology & Drug Discovery
- iPSC models
- Drug screening
Clinical Trials
- Disease modifying
- Disease prevention
Participate in Research
Collaborative and translational research to find and fill the gaps in our knowledge about the causes and treatment of ALS
Current Studies
Pre-fALS
Enrolling: Pre-symptomatic mutation carriers
Recruiting
Study Type: Observational
Biogen ATLAS Trial
Enrolling: Pre-symptomatic SOD1 mutation carriers
Recruiting
Study Type: Drug Trial
CReATe PGB2
Enrolling: ALS, PMA, PLS, HSP, MSP
Recruiting
Study Type: Observational
CReATe CAPTURE-ALS
Enrolling: Patients in Multidisciplinary ALS Clinic
Recruiting
Study Type: Observational
CReATe TRIAL READY
Enrolling: Controls, ALS
Active - Not Recruiting
Study Type: Observational
Healey Platform Trial
Enrolling: ALS
Active - Not Recruiting
Study Type: Drug Trial
CRiALS Biomarker
Enrolling: ALS, ALS related disorders, Controls
Recruiting
Study Type: Observational
CRiALS Genetics
Enrolling: ALS, ALS related disorders, Family members
Recruiting
Study Type: Observational
CRiALS PRESS-ALS
Enrolling: ALS, Controls
Active-Not Recruiting
Study Type: Observational
CReATe PGB1
Enrolling: ALS, PMA, PLS, HSP, MSP
Active-Not Recruiting
Study Type: Observational
Completed Studies
Publications & Talks
Four Research Vignettes
The Story of
Pre-fALS
The Story of
Biomarkers
The Story of
Arimoclomol
The Story of
CAPTURE-ALS
Deep Phenotyping
- ALS and related disorders are characterized by complex phenotypes that are an amalgam of upper and lower motor neuron degeneration and frontotemporal spectrum dysfunction.
- Understanding the nuances of these phenotypes (for example, the onset and evolution of motor, cognitive and behavioral manifestations) through detailed assessments – i.e. “deep phenotyping” – is critical to therapeutic development.
- We study individuals with ALS or a related disorder (e.g. ALS-FTD, MSP, PMA, PLS, HSP); those at elevated genetic risk for ALS; as well as healthy controls.
Causes & Modifiers
- Genetic makeup (genotype), environmental exposures, and advancing age are the three most important risk factors for ALS. In some patients, a single gene mutation may be responsible for causing disease. In many others, we suspect that disease results from a complex interplay between genes, environment, and age.
- In collaboration with colleagues who study ALS genetics/genomics and environmental exposures, we seek to identify the cause(s) of ALS (and related disorders); to identify modifiers of the clinical phenotype; and to explore gene x environment interactions.
Biomarker Discovery & Validation
- Biomarkers are quantifiable biological markers of disease. The appropriate use of biomarkers could greatly aid therapy development.
- Importantly, before its use in a clinical trial, a biomarker must first be clinically validated to be “fit for purpose”. (For example, EMG, as a biomarker, is suitable for diagnosing ALS, but not for predicting prognosis or measuring treatment response.)
- We focus on both biomarker discovery and validation, with particular interest in biochemical markers in biofluids (e.g. blood, urine, spinal fluid); imaging (e.g. MRI) markers; and both electrical and physiological measures of nerve and muscle function.
Novel Data Collection Methods
- Traditionally, research data are collected during in-person visits to a research center. This approach, though the gold standard, places a heavy burden on study participants as well as research teams.
- We have long championed the value—and demonstrated the feasibility—of using remote assessments (e.g. home spirometry) to collect research data when in-person visits to study site are not feasible. This approach has become especially relevant given the COVID-19 pandemic.
- We have also developed approaches to explore whether electronic health record (EHR) data, collected at the point of care in multidisciplinary ALS clinics, might be used for research purposes and to improve the quality of care.
Disease Biology & Drug Discovery
- The single greatest challenge to effective therapy development for ALS (and related disorders) is our lack of understanding of the underlying causes and mechanisms of disease.
- Through collaborative work with Dr. Zane Zeier and others, we are using induced pluripotent stem cells (iPSCs), as well as motor neurons and brain organoids derived from iPCSs, to investigate the underlying biology of disease and to conduct pre-clinical drug screening.
- Benatar has been at the forefront of championing the need for greater methodological rigor in pre-clinical therapeutic studies, which is critical to the success of translating promising therapeutics in animal models of ALS, into meaningful therapies for patients with ALS.
Clinical Trials
- Clinical trials, or interventional studies, are essential for determining whether a new experimental treatment is effective, harmful, or inert (i.e. safe but not effective).
- We have been at the forefront of promoting innovative ALS trial designs that use, for example, enrichment strategies to facilitate detection of therapeutic effect.
- We also participate in multi-center trials of promising agents, and we are leading the effort to discover opportunities to prevent (or delay the onset of) ALS, at least among those at genetic risk for disease.
The Story of Arimoclomol
Our interest in Arimoclomol emerged from Dr. Benatar’s systematic review of the literature focused on therapy development in the SOD1 mouse. Arimoclomol emerged has one of the few compounds tested with sufficient rigor that we had enough confidence in the pre-clinical results to justify a human clinical trial. Moreover, the mechanism of action – co-inducing the heat shock protein response (HSP70) and promoting refolding or disposal of misfolded toxic proteins – was both relevant and novel. In designing a phase 2 clinical trial, we employed a novel enrichment strategy by including only patients with a subset of SOD1 mutations that are associated with rapidly progressive disease. This enabled us to enroll a study population that was relatively homogeneous from both a biological and a phenotypic perspective.
The results of pre-specified analyses in this small phase 2 trial were encouraging, with the impact on both survival and functional decline directionally favoring Arimoclomol. Based on these promising results, Orphazyme (a Danish Biotechnology company that acquired the rights to Arimoclomol during the course of our SOD1 phase 2 trial), decided to move forward with a biomarker-informed, international phase 3 clinical trial enrolling all ALS patients, with Dr. Benatar serving as the international coordinating investigator. We anticipate the results of this trial in the first half of 2021.
The Story of Biomarkers
We have long believed that biomarkers are critical tools to help advance ALS therapy development. The word biomarker is a hybrid of two other words – biological and marker. The meaning of the term is best illustrated through examples. Serum cholesterol and blood pressure are prognostic biomarkers of future cardiovascular risk. A urinary pregnancy test is a diagnostic biomarker of an underlying pregnancy, and COVID-19 antibodies are biomarkers of prior COVID infection or immunization. Our focus on biomarkers began with the recognition that these can be useful tools to aid drug development, but that a nuanced view was needed insofar as biomarkers need to be “fit for purpose” rather than “one size fits all”. We also recognized the need for a multimodal approach, exploring not only biological fluid-based biomarkers, but also neuroimaging and neurophysiological measures. Our approach has been informed by the need for discovery of new biomarkers, as well as analytic and clinical validation of promising biomarker candidates.
In recent years, much of our work has focused on neurofilaments, which are structural components of nerve cells that are released into the cerebrospinal fluid (CSF) and blood following nerve injury or neurodegeneration. We have found that serum neurofilament (light), but not phosphorylated neurofilament heavy (pNfH) has prognostic value, with higher blood levels at baseline predicting more rapid future progression of disease. Our data also suggest that serum NfL may have value for monitoring treatment effect in future phase 2 clinical trials. In addition to these findings, our contribution to the field has been through conceptual innovation, clarification and education.
The Story of Pre-fALS
In 2007 we initiated Pref-ALS (Pre-Symptomatic Familial ALS), a natural history and biomarker study in people at genetic risk for ALS. We aimed to identify biomarkers of pre-symptomatic disease (for example, biomarkers that might predict the timing of phenoconversion to clinically manifest ALS), with the overarching goal of preparing for early intervention, or even disease prevention, trials. Pre-fALS focused on people at elevated genetic risk for ALS based on their harboring a mutation in a gene known to cause ALS (e.g. SOD1, C9ORF72), as this is currently the only population in whom the study of pre-symptomatic ALS is possible.
A key discovery from Pre-fALS has been the finding that blood concentration of neurofilament light (NfL) increases prior to the emerge of clinical manifestations of ALS and, as such, that it may be a useful predictor of when clinical disease may emerge. This discovery has been critical in enabling us to design a trial focused on pre-symptomatic therapeutic intervention with the goal of delaying (or even preventing) the emergence of clinically manifest disease. The ATLAS trial, which is sponsored by Biogen, will focus on the use of tofersen, an intrathecally administered antisense oligonucleotide (ASO), in clinically pre-symptomatic people with a subset of mutations in the SOD1 gene that are highly/completely penetrant and associated with rapidly progressive disease.
The Story of CAPTURE-ALS
The Clinical Procedures to Support Research in ALS (CAPTURE-ALS) study was born out of the recognition that most ALS patients receive care through multi-disciplinary clinics at specialized centers, but only a small proportion participate in research, and that there are few opportunities for assessing and improving the quality of ALS patient care. The over-arching goals of CAPTURE-ALS are to ensure that most ALS patients can contribute to research, if they so choose, and thereby to achieve a more complete understanding of ALS while simultaneously empowering and offering hope to the ALS patient community. CAPTURE-ALS aims to accomplish these goals by harnessing the power of the electronic health record (EHR). CAPTURE-ALS utilizes the ALS Toolkit, a module built within the EHR that enables clinicians to systematically collect structured data from all ALS patients at the point of care. Research questions we aim to address include: is EHR data suitable for research use? Can we broaden our understanding of ALS through the use of EHR data? And can regular, systematic review of EHR data improve the quality of ALS patient care?