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Consortium Spotlight: Advancing Discoveries in Amyotrophic Lateral Sclerosis and Related Disorders

July 28, 2022

The Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium is a group of scientists, clinicians, patients, and advocates working together to advance therapeutic development for amyotrophic lateral sclerosis (ALS) and related neurodegenerative disorders. Here, CReATe leaders share the history of the consortium, current research, and future plans.

 


What are the overall goals of CReATe?

The CReATe Consortium is a collaborative effort with the shared goal of improving the success of future clinical trials in a group of related neurodegenerative disorders. We aim to accomplish this by addressing a series of obstacles to therapy development that include the etiological, biological, and phenotypic heterogeneity of the diseases we study; the limitations of existing clinical outcome measures; the paucity of biomarkers that have been validated as fit-for-purpose; and the relatively late stage in disease when treatment is initiated.

How did the CReATe team come together, and how did you become a part of the RDCRN?

CReATe emerged from the need to bring together clinicians, clinical investigators, molecular neuroscientists, geneticists, computational biologists, epidemiologists, and statisticians with the common goal of addressing a series of challenges that we collectively believed were hampering therapy development for ALS and related disorders. Many of the investigators in CReATe had previously worked together on a variety of projects over a period of many years, but we formally coalesced into a consortium when we joined the RDCRN in 2014.

Can you tell us more about the rare diseases you study?

The CReATe Consortium is focused on ALS and a group of related disorders that includes ALS-frontotemporal dementia(FTD), primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), and progressive muscular atrophy (PMA). Each of these disorders is characterized by degeneration of lower motor neurons, upper motor neurons, or both; sometimes accompanied by a spectrum of frontotemporal pathology. These disorders also have some degree of shared genetic susceptibility and a common pathological substrate in the form of TDP-43 deposition. Insights into one of these disease areas are likely to be relevant to the other diseases that we study.

What are your current research projects?

Phenotype, Genotype & Biomarkers in ALS and Related Disorders (PGB)

PGB is a natural history and biomarker study that aims to collect multimodal data from a large cohort of patients with ALS and related disorders. We include deep motor and cognitive/behavioral phenotypic data, information about environmental exposures, and whole genome sequence data. We also collect an array of biological specimens using standardized operating procedures to facilitate the discovery and validation of biomarkers relevant to therapy development. PGB enables us to better define the natural history of the common genetic forms of ALS and provides a platform for evaluating remote technologies for participant evaluation (e.g. home spirometry), for validating patient reported outcome measures, and for better understanding patient perspectives on clinically meaningful changes in standard outcome measures.

TRIAL READY

TRIAL READY has effectively established a cohort of healthy controls who are being characterized using the same modalities we use in PGB. Biological specimens collected through this protocol are critical to our efforts to develop disease-related biomarkers and normative data for some of our cognitive tools that will enable more robust interpretation of data from PGB.

Clinical Procedures To Support Research (CAPTURE-ALS)

The purpose of the CAPTURE-ALS study is to develop and disseminate the ALS Toolkit—an instrument for systematically collecting structured data through the medical record at the point of clinical care—and to demonstrate the utility of such an approach to improving quality of care and empowering pragmatic clinical research studies that are more inclusive of the full diversity of patients affected by ALS.

Limited Phenotype DNA Sequencing (LPSeq)

LPSeq is a complementary protocol to PGB insofar as it enables us to acquire whole genome sequence data from patients with ALS or a related disorder, but in whom we lack the depth of phenotypic data that are acquired through PGB.

How has your research impacted patients?

In addition to the hope that our patients derive from participating in research and advancing our scientific understanding of this group of disorders, we have made significant progress in discovering new biomarkers and validating leading candidate biomarkers as tools for ALS therapy development. Through initiatives such as CAPTURE-ALS, we have been able to bring research opportunities to vast segments of the ALS patient population that typically do not participate in research. Moreover, our focus on the patient perspective has enabled us to develop the first ALS-specific patient reported outcome measure.

What new research directions or goals are you pursuing?

We are significantly expanding our efforts to understand the role environmental exposures play in causing disease and in modulating the speed with which disease progresses. Combined with whole genome sequence data, we will also have an opportunity to explore the role of gene x environment interactions.

How has being part of the RDCRN impacted the work of CReATe?

There is no question that we have benefited enormously from immersion in a community of investigators and patient advocacy groups focused on therapy development for rare diseases. We have much to learn from each other, leveraging our collective experience for the larger goal of improving the lives of patients and families affected by a broad range of rare diseases.

How do you envision that the diseases you study can ultimately be cured?

Critical to a cure is a more complete understanding of the causes and biological mechanisms that underpin ALS and related disorders. For the subset of ALS patients in whom the genetic cause of disease is known, progress towards meaningfully effective therapies is being made through approaches that target the fundamental mechanisms of disease. Such progress is forging a path for similar approaches in other forms of disease.

 


 

The Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). CReATe is funded under grant number U54NS092091 as a collaboration between NCATS and the National Institute of Neurological Disorders and Stroke (NINDS).

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