Clinical Research in ALS (CRiALS)
There is an enormous need for a better understanding of the clinical, demographic, and genetic features that underlie the phenotypic variability of ALS. Indeed, it may be more accurate to define ALS as a “syndrome” defined by the commonality of clinical features and progression. The syndrome of ALS may encompass a number disease mechanisms that will require different approaches for therapeutic intervention, and one could hypothesize that our failures in clinical trials for ALS are due to the inclusion of multiple disease types, some of which are not responsive to the experimental drug under investigation. Thus, we need to better understand whether multiple mechanisms of ALS truly exist, and to do that we need to better define the disease by documenting phenotypes along with genetic, serologic, and physiological features of disease. This improved categorization of disease will result in the definition of specific disease features that will allow for clinical trials targeting specific disease mechanisms. The CRiALS project, supported by MDA funding, has generated a world-class clinical database and biobank for use locally, nationally, and internationally for discovery research focused on better defining the mechanisms of ALS, which will lead to drug targets and directed therapeutics.
Digital Object Identifier (DOI)
Grantee: Jonathan Glass, MD
Grant type: Restricted Research Grant
Award total: $105,515.00
Institution: Emory University
Country: USA
Quantifying Gait Velocity with the ActiMyo Wearable Devices in ALS
ALS trials depend on quantifiable measures of function to detect if an experimental therapy is working. Current ALS outcomes, like the ALS Functional Rating Scale – Revised (ALSFRS-R) and vital capacity, are collected in clinic and thus are recorded infrequently and yield small trial datasets. Advances in machine learning and artificial intelligence are revolutionizing medicine but require large datasets. Mobile apps and wearable sensors can collect large datasets about daily function while participants do very little except wear a device or answer questions on a mobile app. The ActiMyo device is a wearable sensor for the ankle and wrist that collects information regarding movement of the limbs. Algorithms calculate activity and walking metrics – specifically the 95th percentile stride velocity (SV95C), which regulators have accepted as a trial endpoint in muscular dystrophy. The Beiwe smartphone app obtains activity data and delivers questionnaires to evaluate the effect of ALS on people’s daily life. We will conduct a 12-month study of 30 participants with ALS wearing the ActiMyo device and using the Beiwe smartphone app to compare the SV95C and other digital outcome measures to traditional in-clinic ALS trial outcome measures, including the ALSFRS-R. Our goal is to collect more data, more rapidly and more easily to hasten ALS drug development. Specifically, we will confirm the utility of the SV95C and other digital features of movement as trial endpoints in ALS.
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Grantee: James Berry, M.D.
Grant type: Research Grant
Award total: $200,000.00
Institution: Massachusetts General Hospital (Mass General)
Country: United States
Clinical Research in ALS (CRiALS): A comprehensive resource for human research
There is an enormous need for a better understanding of the clinical, demographic, and genetic features that underlie the phenotypic variability of ALS. Indeed, it may be more accurate to define ALS as a “syndrome” defined by the commonality of clinical features and progression. The syndrome of ALS may encompass a number disease mechanisms that will require different approaches for therapeutic intervention, and one could hypothesize that our failures in clinical trials for ALS are due to the inclusion of multiple disease types, some of which are not responsive to the experimental drug under investigation. Thus, we need to better understand whether multiple mechanisms of ALS truly exist, and to do that we need to better define the disease by documenting phenotypes along with genetic, serologic, and physiological features of disease. This improved categorization of disease will result in the definition of specific disease features that will allow for clinical trials targeting specific disease mechanisms. The CRiALS project, supported by MDA funding, has generated a world-class clinical database and biobank for use locally, nationally, and internationally for discovery research focused on better defining the mechanisms of ALS, which will lead to drug targets and directed therapeutics.
Grantee: Jonathan Glass, MD
Grant type: Restricted Research Grant
Award total: $154,797.00
Institution: Emory University
Country: United States
Astrocyte-microglia crosstalk in C9orf72 ALS/FTD
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are now recognized as a spectrum disease with approximately 50% of ALS patients exhibiting cognitive impairments and about 15% of FTD patients developing motor deficits. Most studies aimed at elucidating mechanisms of cognitive impairments in this spectrum disease focused on disease mechanisms of neuronal cells in the brain, while non-neuronal cells, so called glial cells, have been largely ignored and overlooked. The development of induced pluripotent stem cell (iPSC) technologies has facilitated the generation of disease models for ALS/FTD. This technology allows us to create a ‘brain in a dish’, which consists of patient-derived iPSCs converted into brain-like cells. To better understand how patients with C9orf72 ALS/FTD, the most prevalent genetic mutation leading to this disease spectrum, develop cognitive impairments and most importantly, how we can provide specific treatments for these patients, we propose to focus our studies on glial cell-to-cell communication and regulation using iPSCs derived from C9orf72 ALS-FTD patients. In specific, we aim to study how astrocytes and microglia, two distinct glial cell types in the brain, co-regulate each other using molecular and cellular techniques. We will also test how this regulation impacts neuronal function, but most importantly, how this glia-glia co-regulation goes rouge during disease and contributes to neuronal dysfunction in C9orf72 ALS/FTD.
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Grantee: Rita Sattler, Ph.D.
Grant type: Research Grant
Award total: $300,000.00
Institution: Dignity Health dba St. Joseph's Hospital & Medical Center, Phoenix, AZ
Country: United States
A novel RNA treatment for Amyotrophic lateral sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is a progressive condition affecting the nerves supplying muscles (motor neurons), resulting in weakness, paralysis, and death. ALS is surprisingly common, occurring in ~1:400 individuals, with no effective treatment options existing. One of the first pathological processes occurring in ALS is the disruption of the meeting point of the neuron and the muscle— the neuromuscular junction (NMJ). Based on previous data from our laboratory, we propose that a small RNA molecule called miR126-5P can regulate several biochemical pathways that are essential to maintain the NMJ. This novel target is usually highly expressed in motor neurons and muscles, protecting against toxic signals. In ALS models, it is decreased. We suggest that elevation of miR126 levels will restore motor neuron axons, muscle contraction and prevent paralysis in ALS. To test this hypothesis, we will over-express miR126 both in ALS mice and unique patients NMJ cellular models and track neuron function and survival. We will also evaluate the specific effects of miR126 on ALS-related gene expression. If successful, these studies will not only deepen our understanding of ALS; they will also greatly facilitate the development of RNA-based therapies for ALS and related conditions.
Grantee: Eran Perlson, Ph.D
Grant type: Research Grant
Award total: $299,000.00
Institution: Tel Aviv University
Country: Israel
Understanding how VCP mutations cause Amyotrophic Lateral Sclerosis
ALS is a devastating neuromuscular disorder for which there is no current cure. Mutation in a number of genes are known to cause ALS, one of which is valosin containing protein (VCP). VCP is an important enzyme that regulates the destruction of many proteins within the cell and as such, its mutation perturbs many different cellular pathways. Most studies related to VCP mutation have been performed in cell lines not directly impacted in human disease. These two aspects have hindered our ability to understand how VCP mutations cause ALS. Our group has developed motor neurons and skeletal myocytes that have VCP mutations seen in individuals with ALS using induced pluripotent stem cells. We will investigate how VCP mutation impacts these two cell types. These studies will lay the foundation for our understanding of how VCP mutations cause the pathophysiology observed in ALS.
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Grantee: Malavika Raman, Ph.D
Grant type: Research Grant
Award total: $299,864.00
Institution: Trustees of Tufts College, Boston,MA
Country: United States
Disrupted nuclear pore complex surveillance as an initiating event in ALS
Maintenance of the protein complexes called nuclear pore complexes (NPCs) that control communication between the nuclear and cytoplasmic compartments of cells is essential for proper neuronal function and survival. Recent work has demonstrated that defects in a nuclear surveillance pathway initiate damage to these cellular communication channels as an early and significant event in sporadic and familial forms of Lou Gehrig’s disease or Amyotrophic Lateral Sclerosis (ALS). Critically, this damage cascade contributes to common pathological hallmarks of ALS such as altered function and mislocalization of specific proteins. Cumulatively, this NPC injury cascade can lead to impaired neuronal survival in ALS pathogenesis. This proposal will examine the contribution of proteins that comprise the fundamental nuclear surveillance pathway to these NPC injury cascades and therefore illuminate potential therapeutic targets and strategies for ALS and perhaps related neurodegenerative diseases.
Grantee: Alyssa Coyne, PhD
Grant type: Research Grant
Award total: $300,000.00
Institution: Johns Hopkins University School of Medicine
Country: United States
Nucleocytoplasmic GU-RNA gradients and TDP-43 mislocalization in ALS
Amyotrophic lateral sclerosis (ALS) is a fatal degenerative disease of motor neurons for which there is no curative therapies. Despite significant genetic and phenotypic variability, postmortem evaluation in 97% of ALS patients shows disruption of the essential RNA binding protein, TDP-43. TDP-43 critically regulates RNA processing within the nucleus of the cell, and its cytoplasmic mislocalization and aggregation in disease causes widespread RNA splicing defects and aggregate-mediated disruption of cellular homeostasis. TDP-43 is therefore an important therapeutic target, although the upstream causes that initiate the TDP-43 pathogenic cascade in ALS remain unknown. A major goal of our laboratory is to investigate the molecular regulation of TDP-43 trafficking in healthy cells and its disruption in disease. Our recent studies show a major role for TDP-43's normal, nuclear RNA binding partners in regulating TDP-43 localization. Surprisingly, we have also observed that a prolonged disruption of the cellular gradient of TDP-43 RNA targets can initiate aberrant TDP-43 cytoplasmic aggregation. Here, we will perform a detailed biochemical and molecular characterization of RNA-induced TDP-43 cytoplasmic aggregation in cell lines and human neurons, to advance our understanding of the beneficial versus deleterious interactions of TDP-43 with RNA.
https://doi.org/10.55762/pc.gr.157034
Grantee: Lindsey Hayes, M.D., Ph.D.
Grant type: Research Grant
Award total: $300,000
Institution: Johns Hopkins University School of Medicine
Country: Maryland, United States
Clinical Research in ALS (CRiALS)
There is an enormous need for a better understanding of the clinical, demographic, and genetic features that underlie the phenotypic variability of ALS. Indeed, it may be more accurate to define ALS as a “syndrome” defined by the commonality of clinical features and progression. The syndrome of ALS may encompass a number disease mechanisms that will require different approaches for therapeutic intervention, and one could hypothesize that our failures in clinical trials for ALS are due to the inclusion of multiple disease types, some of which are not responsive to the experimental drug under investigation. Thus, we need to better understand whether multiple mechanisms of ALS truly exist, and to do that we need to better define the disease by documenting phenotypes along with genetic, serologic, and physiological features of disease. This improved categorization of disease will result in the definition of specific disease features that will allow for clinical trials targeting specific disease mechanisms. The CRiALS project, supported by MDA funding, has generated a world-class clinical database and biobank for use locally, nationally, and internationally for discovery research focused on better defining the mechanisms of ALS, which will lead to drug targets and directed therapeutics.
https://doi.org/10.55762/pc.gr.154583
Grantee: Jonathan Glass, PhD
Grant type: Restricted Research Grant
Award total: $16,255
Institution: Emory University
Country: Georgia, United States
Unraveling the contribution of local translation to ALS pathogenesis
Despite identification of ALS-associated RNA binding proteins (RBPs) including TDP-43 and FUS (which also cause the second most frequent dementia, frontotemporal dementia or FTD), the disease mechanism(s) are unknown. The effort proposed here seeks to uncover this mechanism to support therapy development in familial ALS forms and beyond. Key questions to be tackled will be to understand the emerging critical functions of TDP-43 and FUS within motor neuron projections called axons and at their synapses, where the mutant forms are known to accumulate. We will thus investigate how mutations cause axonal degeneration and loss of their neuromuscular junctions (NMJs), which are the earliest hallmarks of ALS pathogenesis. In particular we will identify the FUS/TDP-43 mRNA targets along axons and NMJs and unravel the mechanisms underlying their local protein synthesis in health and ALS pathogenesis.
https://doi.org/10.55762/pc.gr.157008
Grantee: Sandrine Da Cruz, Ph.D.
Grant type: Research Grant
Award total: $300,000
Institution: VIBvzw
Country: Belgium
Investigating a link between ER stress and nucleocytoplasmic transport in ALS
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons, leading to paralysis and death within 2-5 years for most patients. There is a growing consensus that disruption of the nuclear pore complex (NPC) which shuttles proteins and RNAs in and out of the nucleus, contributes to the disease, but both the cause and consequences of this impairment remain unclear. A key finding in motor neurons in ALS is that they have protein aggregation and upregulation of endoplasmic reticulum (ER) stress pathways. While the ER stress pathway may initially protect motor neurons against accumulating toxic protein aggregates, chronic ER stress is believed to contribute to toxicity and cell death in ALS. Indeed, the Amylyx drug AMX0035 being reviewed by the FDA for treatment of ALS, is believed to protect neurons by inhibiting ER stress. ER stress induces activation of the “unfolded protein response” (UPR), which relies on the communication between the nucleus and cytoplasm (NCT). Our proposal aims to study how NCT impairment—a state of incommunicado between the nucleus and cytoplasm—affects ER stress and UPR in ALS models. Furthermore, ER is an important organelle that helps assemble the NPC, and we will also examine how ER stress affects NCT. Establishing how NCT and ER stress interact in ALS have the potential to identify new therapeutic target for ALS.
https://doi.org/10.55762/pc.gr.157027
Grantee: Chang Geon Chung, Ph.D.
Grant type: Development Grant
Award total: $210,000
Institution: Johns Hopkins University School of Medicine
Country: Maryland, United States
Identification of genetic modifiers for C9ORF72-ALS/FTD
A hexanucleotide repeat expansion in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two adult-onset progressive neurodegenerative diseases. One of the major hypotheses for toxicity is the accumulation of dipeptide repeat (DPR) proteins produced by RNA repeats. There were many studies unraveling the toxicities by different DPRs. In particular, poly-GR is one of the most toxic DPRs and is found to correlate with neurodegeneration in C9ORF72-related ALS, implicating the contribution of poly-GR to the disease etiology. Therefore, we performed a genetic screening in human neurons to identify modifiers that regulate the poly-GR mediated toxicity. I identified and validated one candidate modifier, knockdown of which strongly improved the survival of the poly-GR expressing neurons. I now propose to further decipher the neuroprotection mechanism, and validate the rescue efficacy in both C9ORF72-ALS patient-derived neurons and the mouse model. This study will provide novel insights on disease mechanisms and potential therapeutic target.
https://doi.org/10.55762/pc.gr.157004
Grantee: Zhe Zhang, Ph.D
Grant type: Development Grant
Award total: $210,000
Institution: Johns Hopkins University School of Medicine
Country: Maryland, United States
Contribution of variable number tandem repeats to Amyotrophic Lateral Sclerosis
The number of people in our world over 60 years old is estimated to more than double by 2050. As life expectancy increases, so will the prevalence of age-related neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS). The genetic contributions that lead to ALS are still not fully clear despite intensive sequencing efforts, necessitating further studies into genes that cause or modify ALS. We hypothesize that a significant genetic contribution to disease comes from regions of the human genome that are still challenging to characterize using standard sequencing technology. Some of these regions contain repetitive stretches of DNA can expand in patient populations and often can manifest in different neurodegenerative disorders. We have established techniques to characterize these genetic regions in a multiplexed high-throughput manner. We propose to use our approaches to determine the contributions of these repeats to ALS, determine how they aggregate in cells and what additional factors they can bring into these aggregates. Our proposed work will provide insight into novel mechanisms of ALS and help bridge genes associated with disease for the purpose of devising novel therapeutics.
https://doi.org/10.55762/pc.gr.157016
Grantee: Paul Valdmanis, Ph.D
Grant type: Research Grant
Award total: $300,000
Institution: University of Washington
Country: Washington, United States
Leveraging microglia states to understand ALS disease
Although most therapeutic avenues for Amyotrophic lateral sclerosis (ALS) have focused on neurons, recent studies suggest that microglia, the immune cells of the brain, are key players in pathogenesis, pointing toward alternative approaches to therapeutic development. Many genetic risk factors for ALS are expressed in microglia and recently, a distinct subpopulation, or “state”, has been identified in ALS patients. Interestingly, microglia have also been involved in other neurodegenerative diseases like Alzheimer’s disease. In this study, we used human cell culture models and single-cell-resolution analyses to identify how ALS genetics affect microglia states and functions and understand how microglia affect motor neuron health. This project will identify pathways of neurodegeneration specific to ALS and open the door for new therapeutic avenues.
https://doi.org/10.55762/pc.gr.156998
Grantee: Martine Therrien, Ph.D
Grant type: Development Grant
Award total: $208,027
Institution: Broad Institute (Eli and Edythe L. Broad Institute of MIT and Harvard)
Country: Massachusetts, United States
2021 - ALS - Jeffrey Rothstein, MD, PhD
"Our unbiased transcriptomics and metabolomics profiles with ALS-specific spinal motor neurons derived from induced pluripotent stem cells (iPSCs) revealed dysregulation in lipid metabolism and its related gene expression. Importantly, pharmacological modulation of one of the disrupted lipid pathways is sufficient to reverse ALS-related phenotypes in ALS iPSC motor neurons, fly and mouse models."
Jeffrey Rothstein, M.D., Ph.D., director of the Robert Packard Center for ALS Research at Johns Hopkins University School of Medicine, has been awarded an MDA restricted research grant of $31,113 for one year for investigator Gabsang Lee, PhD, Associate Professor in the Department of Neurology and Neuroscience, to develop unbiased screening of lipid pathways and lipid metabolites that can reverse ALS-related phenotypes.
Research in Dr. Lee's lab analyzes small molecule substrates left behind by chemical processes and collects a snapshot of the total transcripts in the cell at a given time to examine changes of lipid-related metabolism pathways in ALS spinal motor neurons. Their study aims to understand the connection between mis-regulated metabolism and ALS, which could potentially lead to new therapies.
Grantee: Unbiased lipid screening to reverse ALS Phenotypes in vitro and in vivo - Jeffrey Rothstein, MD, PhD
Grant type: Restricted Research Grant
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2021 - ALS - Hiroshi Mitsumoto, MD, DSci
"ALS begins rarely with only upper motor neuron. We have no scientific data as to how the patient whose disease begins only with upper motor neuron impairment."
Hiroshi Mitsumoto, M.D., Wesley J. Howe Professor of Neurology at Columbia University Medical Center, has been awarded an MDA restricted research grant of $31,112.95 for one year to support continuation of three National Institutes for Health and Centers for Disease Control and Prevention-funded studies, for which MDA has already provided supplemental funding.
Studying the epidemiology associated with ALS is critical for developing a better understanding of the disease. Dr. Mitsumoto will continue to analyze large cohorts of ALS patients to identify potential environmental risk factors in ALS.
Grantee: Upper Motor Neuron Onset ALS: Natural History Study - Hiroshi Mitsumoto, MD, DSci
Grant type: Restricted Research Grant
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2021 - ALS - Jonathan Glass, MD
"There is an enormous need for a better understanding of the clinical, demographic, and genetic features that underlie the phenotypic variability of ALS."
Jonathan Glass, M.D., Ph.D., Professor of Neurology at Emory University, has been awarded an MDA restricted research grant of $75,517 for one year to continue to provide the ALS research community with data, biofluids, and tissues from deeply phenotyped ALS patients and people without ALS who participate in Emory's Clinical Research in ALS (CRiALS) project.
There is significant phenotypic and genetic heterogeneity observed among persons with ALS, which may partly explain some of the failures in clinical trials. The CRiALS database is considered one of the most valuable resources for ALS research with a large and extremely well characterized patient population. Dr. Glass' work could pave the way for better defined disease features and ultimately clinical trials targeting specific patient populations.
Grantee: Clinical Research in ALS (CRiALS): A clinical database and specimen biobank - Jonathan Glass, MD
Grant type: Restricted Research Grant
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2021 - ALS - Andrew Geronimo, PhD
"Amyotrophic lateral sclerosis (ALS) affects multiple parts of the body including the muscles that control breathing. Early signs of breathing difficulty can appear during sleep, where they often go unrecognized by patients and physicians alike. Identifying early breathing changes in ALS may improve access to life-sustaining therapies."
Andrew Geronimo, M.Sc., Ph.D., is an Assistant Professor at The Pennsylvania State University College of Medicine in Hershey, PA, has been awarded an MDA Idea Grant totaling $25,000 for one year to measure changes in carbon dioxide (CO2) levels using a medical device that is attached to the skin.
ALS is a progressive neuromuscular disorder that weakens the muscles of respiration, eventually leading to chronic respiratory failure with abnormally high concentration of CO2 in the blood. In ALS clinics, they collect respiratory measurements during the day, but not during the nighttime. Dr. Geronimo's project hopes to show that the use of a medical device that will sense CO2 on the skin during sleep can help identify breathing problems and detect any breathing challenges at an earlier stage. Their study has the potential to inform how early respiratory therapies can improve the quality of life and survival of ALS patients.
https://doi.org/10.55762/pc.gr.147564
Grantee: Assessment of Nocturnal Hypoventilation in Amyotrophic Lateral Sclerosis – Andrew Geronimo, PhD
Grant type: Idea Award
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2021 - ALS - Frederick Arnold, PhD
"Altered RNA metabolism is a common theme in ALS. Indeed, RNA binding proteins (RBPs) are among the most commonly mutated proteins in inherited forms of ALS. These mutations alter gene expression and change the function of RNA-RBP condensates in the cell."
Frederick Arnold, Ph.D., is a Postdoctoral Scholar at The Regents of the University of California in Irvine, CA has been awarded an MDA Development Grant totaling $220,000 for three years to identify central regulators of RNA metabolism in human motor neurons and understand how it changes in ALS.
The RNA exosome complex is found in all cells and known to be important for the survival of motor neurons. The subunits of the exosome complex interact directly with RBPs implicated in ALS. Dr. Arnold's project will help discover RNA substrates and RBP cofactors of the exosome complex in healthy and ALS human motor neurons which could have broad therapeutic impact in ALS treatment.
https://doi.org/10.55762/pc.gr.147555
Grantee: The RNA exosome complex in ALS disease pathogenesis – Frederick Arnold, PhD
Grant type: Development Grant
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2021 - ALS - Xin Jiang, PhD
"ASO-based approaches have shown promising results in different neurodegenerative diseases and I will test whether the method is efficient in blocking aberrant translation in C9ORF72 ALS/FTD. Overall, this project will not only help us understand the contribution of DPRs in ALS/FTD but will also shed light on a potential therapeutic strategy for C9ORF72-disease."
Xin Jiang, Ph.D., is a Postdoctoral Research fellow at Massachusetts General Hospital in Charlestown, MA, has been awarded an MDA Development Grant totaling $220,000 for three years to investigate the effects of genome editing and antisense oligonucleotides (ASOs) in blocking the synthesis of dipeptide repeats (DPRs).
Accumulation of abnormal proteins called dipeptide repeats (DPRs) are the most common cause for inherited ALS and FTD (Frontotemporal dementia). These DPRs are easy to form protein aggregates in the brain and are toxic to the brain cells. Findings from Dr. Jiang's project will help us understand the effects of DPRs in ALS and Frontotemporal Dementia (FTD).
https://doi.org/10.55762/pc.gr.147548
Grantee: Blocking RAN translation to rescue C9ORF72-related ALS/FTD phenotypes – Xin Jiang, PhD
Grant type: Development Grant
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