Passionately working toward a cure
Our research program focuses on advancing ALS therapy development by identifying and filling knowledge gaps that have, in the past, hampered the development of effective treatments. This approach has required us to work at the forefront and the intersection of “deep” phenotyping (i.e. detailed characterization of clinical features), natural history studies, pre-symptomatic disease, biomarker development, genetics, neuroimaging, environmental exposures, novel data collection methods, and clinical trials. Success in addressing a subject as complex as ALS therapy development requires a breadth of expertise, necessitating a highly inter-disciplinary, broadly collaborative, and seamlessly translational approach to research. We therefore work extensively with researchers across the U.S. and internationally. The name of our group – the ALS Research Collaboration – aims to capture this ethos.
Our approach to research
Sound Science
- Strong rationale and study design
- Rigorous data and biospecimen collection
- Thoughtful analysis and results interpretation
Collaborative Research
- Inter-disciplinary team science
- Working with established ALS investigators, and attracting investigators from other fields who have relevant expertise
- Seamlessly translational
- Sharing of data, resources, and expertise
Commitment to Patients & Families
- Participant-friendly approach to research
- Opportunities for all to participate in research
- Responsible custodians of data and biological samples
Meet our team
We are a clinical/translational research group led by Dr. Michael Benatar and Joanne Wuu at the University of Miami. Members of the group include neurologists, biostatistician, neuroscientists, genetic counselor, neuropsychologist, project and data managers, research coordinators, and students.
Making ALS History
Founded in 2006 and led by Dr. Michael Benatar and Joanne Wuu, the ALS Research Collaboration at the University of Miami has been the vanguard of ALS therapy development through a series of landmark studies focused on pre-symptomatic ALS, the discovery and validation of biomarkers that are fit-for-purpose, pioneering use of remote technology to facilitate ALS research, and ALS prevention.
Clickable Highlight
AUG 2006
Launched National ALS Registry Georgia Pilot Project
APR 2007
“Lost in Translation”
AUG 2007
Launched Pre-fALS study
AUG 2007
Launched CRiALS Biomarker study
JUN 2008
Launched Arimoclomol SOD1 Phase II trial
DEC 2009
“Tackling the Challenges of ALS from a Familial Perspective”
SEP 2010
“Preparing for a U.S. National ALS Registry”
DEC 2010
“Telemedicine to Facilitate ALS Research”
APR 2011
Published methods for pre-symptomatic ALS genetic counseling
SEP 2011
Published first MRI biomarker of pre-symptomatic ALS
DEC 2011
“MRI Evidence of Disease in Pre-Symptomatic SOD1+”
JAN 2011
Launched IBMPFD-ALS study
OCT 2012
“Pre-symptomatic Studies in ALS: Rationale, Challenges, and Approach”
DEC 2012
Defined phenotypic overlap between ALS and multisystem proteinopathy
MAY 2013
Published results from the IBMPFD-ALS study
MAR 2014
Identified p75 as the first biochemical marker of ALS progression
SEP 2014
Established the CReATe Consortium
DEC 2014
“The Challenge of Early Therapeutic Intervention in ALS”
DEC 2014
Launched CRiALS PRESS-ALS study
APR 2015
Launched CReATe PGB multi-center study
DEC 2015
“ALS Biomarkers for Therapy Development”
DEC 2015
Presented guidelines for pre-symptomatic ALS genetic counseling
JUN 2016
Published guidelines for pre-symptomatic ALS genetic counseling
DEC 2016
Presented results of Arimoclomol SOD1 phase II trial
DEC 2016
Q-motor as pre-symptomatic ALS biomarker
MAY 2017
Criteria for ALS-FTSD
DEC 2017
Presented NfL as pre-symptomatic ALS biomarker
FEB 2018
Empowering the use of EHR for research
FEB 2018
Launched CReATe CAPTURE-ALS multi-center study
FEB 2018
Arimoclomol advanced from phase II to phase III
JUL 2018
Published NfL as pre-symptomatic ALS biomarker
DEC 2018
“When Does ALS Begin?”
JAN 2019
Launched CReATe TRIAL READY multi-center study
JUL 2019
Clinical validation of neurofilaments for ALS therapy development
AUG 2019
“Defining Pre-Symptomatic Amyotrophic Lateral Sclerosis”
NOV 2019
Neurofilament & genotype in pre-symptomatic ALS
JAN 2020
First International Pre-Symptomatic ALS Workshop
JAN 2021
Launched CReATe PGB2 multi-center study
APR 2021
Presented ATLAS study design
MAY 2021
Arimoclomol phase III results
JUN 2021
Enrolled the first participant in ATLAS study
OCT 2021
“Preventing ALS: Insights from Pre-symptomatic ALS & Other Neurodegenerative Diseases”
MAY 2022
“Mild Motor Impairment as Prodromal State in ALS: A New Diagnostic Entity”
May 2022
Published ATLAS trial design
JUN 2022
“Progress Towards ALS Prevention”
JUN 2022
A Conceptual Framework for MCI and MBI in ALS-FTSD
OCT 2022
“NfL in ALS Drug Development: A Critical Appraisal”
DEC 2022
“MMI and Prodromal Disease Markers”
“MMI and Prodromal Disease Markers”
Plenary speaker (Benatar) at the 33rd International Symposium on ALS/MND (virtual).
“NfL in ALS Drug Development: A Critical Appraisal”
A Conceptual Framework for MCI and MBI in ALS-FTSD
Platform presentation (McHutchison) at the European Network to Cure ALS (ENCALS) Annual Meeting.
“Progress Towards ALS Prevention”
Keynote speaker (Benatar) at the ALS Association 2022 Virtual Advocacy Conference.
An account of how our pioneering work in the study of natural history and biomarkers have directly led to the design and implementation of the first-ever ALS prevention trial.
Providing a roadmap for other efforts to prevent ALS.
Published ATLAS trial design
Published the innovative study design of this first-ever therapeutic intervention study in pre-symptomatic ALS.
Inspiring similar efforts in other neurodegenerative diseases (e.g. FTD), with trial designs modeled after ATLAS.
“Mild Motor Impairment as Prodromal State in ALS: A New Diagnostic Entity”
Manuscript describing mild motor impairment (MMI) as a novel clinical syndrome that is prodromal to clinically manifest ALS.
Recognizing MMI yields opportunities to study pre-symptomatic ALS in sporadic ALS, to shorten diagnostic delay, and to permit earlier therapeutic intervention.
Launched CReATe PGB multi-center study
PGB = Phenotype-Genotype-Biomarkers.
This study also examines the role of environmental exposures.
“The Challenge of Early Therapeutic Intervention in ALS”
Invited platform presentation at the International Symposium on ALS/MND.
Deconstructed the reasons why treatment is typically so delayed in ALS, and discussed strategies for early therapeutic intervention.
Established the CReATe Consortium
An international alliance of physicians, scientists, and patient advocacy groups focused on therapy development for ALS and related disorders (ALS, ALS-FTD, PMA, PLS, HSP, MSP).
One of the ~20 consortia in the NIH-funded Rare Diseases Clinical Research Network.
Identified p75 as the first biochemical marker of ALS progression
This work was done in collaboration with Dr. Mary-Louise Rogers, Flinders University, Australia.
As of 2021, urinary p75 remains the only biofluid-based biomarker of disease progression in patients with clinically manifest ALS.
Published results from the IBMPFD-ALS study
This study demonstrated, for the first time, that patients with IBMPFD (inclusion body myopathy with Paget’s disease and frontotemporal dementia), may also show clinical evidence of motor neuron disease (including ALS).
These observations, combined with parallel discoveries about the underlying biology of this disease, led us to propose the term multisystem proteinopathy (MSP) as a more suitable name for this complex clinical syndrome.
Defined phenotypic overlap between ALS and multisystem proteinopathy
Platform presentation at International Symposium on ALS/MND: “Motor Neuron Involvement in Multisystem Proteinopathy: Implications for ALS/MND”
“Pre-symptomatic Studies in ALS: Rationale, Challenges, and Approach”
Published this conceptual, state-of-the art review paper laying out the rationale for studying pre-symptomatic ALS; describing the scientific approach and methodology required; sharing our experiences from Pre-fALS as to how one might overcome the challenges of conducting such studies; and articulating a roadmap for future research in this field.
“MRI Evidence of Disease in Pre-Symptomatic SOD1+”
Platform presentation at the International Symposium on ALS/MND: “MRI Evidence of Disease in Pre-Symptomatic SOD1+ Individuals at Risk for Developing Familial ALS”
Published first MRI biomarker of pre-symptomatic ALS
Published the MRS finding that cervical spinal cord metabolite concentrations in pre-symptomatic ALS are intermediate between, and overlapping with, levels in ALS and healthy controls.
Published methods for pre-symptomatic ALS genetic counseling
Published findings that pre-symptomatic genetic counseling could be safely and effectively performed via phone, despite prevailing opinion at the time to the contrary.
“Telemedicine to Facilitate ALS Research”
Platform presentations at the International Symposium on ALS/MND.
Showed the feasibility and hilighted the usefulness of remote assessments in facilitating ALS research and reducing participant burden.
“Preparing for a U.S. National ALS Registry”
Published results of our National ALS Registry Georgia Pilot Project.
The methods developed in this pilot project were adopted by the CDC for use in the National ALS Registry.
“Tackling the Challenges of ALS from a Familial Perspective”
Platform presentation at the International Symposium on ALS/MND.
Articulated the opportunities for therapeutic advances in genetic/familial ALS, and how these are relevant to sporadic ALS.
Launched Arimoclomol SOD1 Phase II trial
This was the first ALS trial (multi-center) initiated in a genetically and phenotypically homogeneous population.
This trial pioneered an approach in which the evaluation of safety and efficacy relied heavily on remote assessments in order to alleviate participant burden.
“Lost in Translation”
Benatar initiated this project to better understand why therapeutic success in the pre-clinical SOD1 mouse model of ALS had failed to translate into meaningful treatments for ALS patients.
He found serious methodological flaws in these animal studies–which are well recognized today, but underappreciated at the time.
Through this review, he identified arimoclomol as one of the few compounds with strong (and relatively rigorous) pre-clinical data, which was the impetus for our phase II trial of arimoclomol in SOD1 ALS.
“ALS Biomarkers for Therapy Development”
Benatar et al outlined a conceptual framework for ALS biomarker development in the paper titled “ALS biomarkers for therapy development: State of the field and future directions”
The authors articulated the nuanced but important point that the use of biomarkers must be “fit for purpose.”
Launched CReATe PGB2 multi-center study
PGB = Phenotype-Genotype-Biomarkers.
This study also examines the role of environmental exposures.
Arimoclomol phase III results
Arimoclomol Phase III trial shows safety, but did not meet its primary or secondary efficacy objectives.
Q-motor as pre-symptomatic ALS biomarker
Platform presentation at International Symposium on ALS/MND: “Quantitative Motor Testing: Biomarker of Pre-Symptomatic ALS?”
Criteria for ALS-FTSD
Benatar contributed to development of the revised Strong criteria for ALS frontotemporal spectrum disorder
Empowering the use of EHR for research
Launched the ALS Toolkit in Epic electronic health record (EHR) system
The ALS Toolkit enables the systematic collection of structured data during multidisciplinary ALS clinic visits, with the goal of using these data for quality improvement and research.
Routine use of the ALS Toolkit during clinic visits serves as the foundation for the CReATe CAPTURE-ALS study.
“When Does ALS Begin?”
Platform presentation at International Symposium on ALS/MND: “When Does ALS Begin? Insights from Serum and CSF Neurofilaments Light and Heavy”
Expanding on our previous work, we highlight the relative utility of NfL and pNfH as biomarkers of pre-symptomatic ALS, and hypothesize that the duration of the pre-symptomatic period varies based on genotype.
First International Pre-Symptomatic ALS Workshop
Organized and hosted the 1st International Workshop on Pre-Symptomatic ALS.
The Workshop brought together specialists from a wide range of disciplines, united by their expertise in the study of pre-symptomatic neurodegenerative diseases, including ALS.
The Workshop facilitated development of a roadmap to advance the study of, and potential early therapeutic intervention for, pre-symptomatic ALS.
Clinical validation of neurofilaments for ALS therapy development
Published clinical validation of serum NfL (but not pNfH) as biomarker for ALS therapy development.
NfL has utility as both prognostic and potential pharmacodynamic biomarkers.
Used as a prognostic marker, NfL might yield modest sample size savings in phase II ALS trials.
Used as a pharmacodynamic marker, NfL could dramatically reduce sample size in phase II ALS trials.
Published NfL as pre-symptomatic ALS biomarker
Published serum neurofilament light chain (NfL) as the first biochemical marker of pre-symptomatic ALS.
Presented NfL as pre-symptomatic ALS biomarker
Identified neurofilament light chain (NfL) as the first biochemical marker of pre-symptomatic ALS.
Platform presentation at International Symposium on ALS/MND: “Blood and CSF Neurofilament Levels as Biomarkers of Pre-Symptomatic Disease”
We found that NfL is increased in both cerebrospinal fluid (CSF) and blood (serum) prior to the emergence of clinically manifest ALS.
The striking NfL signal in blood is critically important, because (contrary to CSF) blood-based monitoring is feasible and immediately relevant for practical use in clinical trials.
This work was done in collaboration with Dr. Andrea Malaspina, University College London, UK.
Presented guidelines for pre-symptomatic ALS genetic counseling
Platform presentation at International Symposium on ALS/MND: “Pre-Symptomatic ALS Genetic Counseling and Testing: Experience and Recommendations”
“Defining Pre-Symptomatic Amyotrophic Lateral Sclerosis”
Proposed and published an updated conceptual framework for studying the pre-symptomatic phase of ALS, based on experience and discoveries through Pre-fALS.
This work was done in collaboration with Dr. Martin Turner, University of Oxford, UK.
Published guidelines for pre-symptomatic ALS genetic counseling
Published guidelines for ALS pre-symptomatic genetic testing & counseling.
Arimoclomol advanced from phase II to phase III
Published Arimoclomol SOD1 Phase II trial results.
This trial employed a novel enrichment design to enroll an etiologically, biologically, and phenotypically homogeneous population.
The trial demonstrated that, using an appropriate enrichment design, it is possible to observe a therapeutic signal even with a small sample size.
The promising finding of this phase II trial has led to the launch of Orphazyme’s Arimoclomol Phase III trial in the general ALS population, with Benatar as the International Coordinating Investigator.
Neurofilament & genotype in pre-symptomatic ALS
Published our work on NfL and pNfH in pre-symptomatic ALS, which indicates that that pre-symptomatic disease duration varies depending on genotype.
Presented ATLAS study design
First therapeutic intervention study in pre-symptomatic ALS, designed in collaboration with Biogen.
Oral presentation at AAN annual meeting: “Design of a Phase 3, Randomized, Placebo-Controlled Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Mutation Carriers: The ATLAS Study”
Launched CReATe TRIAL READY multi-center study
To clinically validate leading prognostic and pharmacodynamic biomarker candidates.
Arimoclomol phase III results
Arimoclomol Phase III trial shows safety, but did not meet its primary or secondary efficacy objectives.
“Preventing ALS: Insights from Pre-symptomatic ALS & Other Neurodegenerative Diseases”
Manuscript emanating from the First International Pre-Symptomatic ALS Workshop
Highlights key lessons for ALS from studies in pre-symptomatic AD, PD, HD, FTD, and SMA.
Defines mild motor impairment (MMI), mild cognitive impairment (MCI), and mild behavioral impairment (MBI) as prodromal stages in ALS.
Presents a roadmap to ALS early intervention, and perhaps even disease prevention.
Presented results of Arimoclomol SOD1 phase II trial
Platform presentation in the late-breaking session of the annual International Symposium on ALS/MND: “Randomized, Phase II Trial of Arimoclomol in Rapidly Progressive SOD1 ALS”
The promising finding of this phase II trial has led to the 2018 launch of a phase III trial in the general ALS population.
Passionately working toward a cure (full text)
Our research program focuses on advancing ALS therapy development by identifying and filling knowledge gaps that have, in the past, hampered the development of effective treatments. This approach has required us to work at the forefront and the intersection of “deep” phenotyping (i.e. detailed characterization of clinical features), natural history studies, pre-symptomatic disease, biomarker development, genetics, neuroimaging, environmental exposures, novel data collection methods, and clinical trials.
A major part of our current work began in 2007 with the launch of the Pre-Symptomatic Familial ALS (Pre-fALS) study. Pre-fALS was motivated, in large part, by our belief that successful treatment of a neurodegenerative disease such as ALS would require early, and perhaps even pre-symptomatic, intervention. Our focus on the familial/genetic form of ALS was out of necessity: Individuals who carry an ALS-causing gene mutation are the only group known to be at an elevated risk (compared to the general population) for developing ALS – and therefore the only group in whom the study of pre-symptomatic ALS is feasible. Critical to studying the earliest stages of ALS and to advancing our goal of preventing ALS, has been the development of biomarkers of pre-symptomatic disease, an area in which we have been leaders in the field.
In 2014, we established the multi-center and multi-national CReATe Consortium, an NIH-designated Rare Diseases Clinical Research Consortium focused on therapy development for ALS and related disorders. Initially, the CReATe Consortium was focused on the complex relationship between clinical phenotype and genotype, and on the discovery and validation of biomarkers relevant to therapy development in symptomatic ALS. More recently, the CReATe Consortium has expanded its focus to include other topics encompassed by the term clinical trial readiness. Some examples: discerning the underlying causes and biology of disease; understanding the determinants of phenotypic heterogeneity; reducing the delay from diagnosis to treatment initiation; and developing biomarkers and patient-reported outcomes relevant to therapy development.
Our participation over the years in multi-center studies and trials initiated by other researchers in academia and industry represents the third major component of our research program. One notable example is Orphazyme’s phase III trial of arimoclomol in ALS, which was built upon the promising results of a phase II trial that we had designed and led in SOD1 ALS. In addition, we currently participate in a range of observational studies and phase I-III clinical trials, including the Healey ALS Platform Trial.
Ultimately, success in addressing a subject as complex as ALS therapy development requires a breadth of expertise, necessitating a highly inter-disciplinary, broadly collaborative, and seamlessly translational approach to research. We therefore work extensively with researchers across the U.S. and internationally. The name of our group – the ALS Research Collaboration – aims to capture this ethos.