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.

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.

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.

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.

MDA and the nonprofit biotech ALS Therapy Development Institute (ALS TDI) have extended their strategic research partnership through 2013. With the extension comes a $3.2 million MDA grant to help support the nonprofit biotech's continued progress toward developing treatments for amyotrophic lateral sclerosis (ALS).

ALS TDI, located in Cambridge, Mass., screens at least 25 potential ALS therapeutics every year.

“MDA has been, and continues to be a key partner in providing us the resources needed to move more ideas and projects forward faster than before,” said Steve Perrin, ALS TDI CEO and chief scientific officer. “MDA support has enabled many discoveries and advancements which hold great potential for people diagnosed with ALS.” 

MDA launched its innovative Bridge-to-Industry (B2I) program with a $180,000 grant over three years to postdoctoral fellow Archi Joardar at the University of Arizona in Tucson, to develop two promising drug candidates for the treatment of amyotrophic lateral sclerosis (ALS).

MDA’s Bridge-to-Industry, or B2I, is a pilot project that trains promising researchers in translational research by providing experience both in academia and the biopharmaceutical industry.    

Through the B2I program, MDA is able to fund investigators to conduct drug development research under the guidance of two mentors: one experienced in academic research and the other experienced in the industrial side of drug development.

Daniela Zarnescu, associate professor in neuroscience and molecular & cellular biology at the College of Science, University of Arizona (UA), will provide academic mentoring to Joardar. Zarnescu currently has an active MDA research grant for her work on gene and drug discovery research in a fruit fly model that carries a mutation in the ALS-associated TDP43 gene.

Joardar will receive mentoring on the industry side from Chris Hulme, co-director of the BIO5 Institute in Oro Valley, Ariz. Hulme is an expert in small-molecule drug design and the development of chemical-based methods to hasten the drug discovery process.

Mentorship under Zarnescu and Hulme will provide Joardar with a unique environment in which to train while furthering the development of two promising ALS drug candidates identified in Zarnescu's work. Joardar will evaluate the ability of each drug to reduce neurotoxicity caused by ALS-associated mutations in the TDP43 gene..

The Muscular Dystrophy Association has committed $750,000 to help support a phase 2 clinical trial assessing the ability of the NeuRx Diaphragm Pacing System (DPS) to improve respiratory function and quality of life in people with amyotrophic lateral sclerosis (ALS).

Developed by Synapse Biomedical in Oberlin, Ohio, the DPS received approval from the U.S. Food and Drug Administration (FDA) on Sept. 29, 2011, as a “humanitarian use device” (HUD) for the treatment of chronic hypoventilation (inadequate breathing) in ALS. The surgically implanted device stimulates the movement of the diaphragm, the main muscle used in breathing.

In people with ALS who have chronic breathing problems and whose diaphragms are still able to respond to electrical stimulation, the DPS may forestall or negate the need for invasive ventilation.

Investigators will compare respiratory function and quality of life in people with ALS who use the DPS and those who receive the current standard treatment.

MDA has awarded $400,000 to National Institutes of Health (NIH) Laboratory of Neurogenetics researchers to perform exome sequencing on samples taken from 1,000 people with sporadic amyotrophic lateral sclerosis (ALS). The project will be led by neurologist Bryan Traynor, head of the Neuromuscular Diseases Research Group at the NIH in Bethesda, Md.

Data generated by the first-of-its-kind project will be made publicly available online and are expected to accelerate the pace of ALS research by helping scientists identify genes associated with the disease.

The exome-sequencing project, which is expected to be completed within 12 months, will produce genetic information for:

• 360 deceased individuals who had the sporadic (without any family history of the disease) form of ALS, for whom postmortem tissue samples are available; and
• 640 samples stored at the Coriell ALS Repository from people (both living and deceased) with sporadic ALS.

Exome sequencing data from a large number of people unaffected by ALS will be used for comparison in analysis.

Iron Horse Diagnostics in Scottsdale, Ariz., was awarded an MDA Venture Philanthropy (MVP) grant totaling $233,200 to support development of a prognostic (predictive) test for ALS (amyotrophic lateral sclerosis). Iron Horse Diagnostics Chief Scientific Officer Andreas Jeromin will serve as the principal investigator on the project.

The prognostic test will measure specific protein-based biomarkers in blood and cerebrospinal fluid that indicate the presence of neurodegenerative disease.

Such a test could help physicians predict the likely course of disease — for example, fast versus slow progression — in individuals with ALS, which could improve and accelerate clinical trials and speed the development of life-saving ALS drugs.

In addition to its usefulness in planning and conducting clinical trials, Iron Horse’s prognostic test could provide important information for individuals and families affected by ALS, informing discussion on, for example, how soon to shop for a power wheelchair; when a feeding tube or breathing assistance might be needed; and timing for everything from home modifications to assistive communication devices, to financial and end-of-life plans and decision-making.

About Iron Horse Diagnostics

Iron Horse Diagnostics is an early-stage biotech company focused on developing diagnostic and prognostic tests for neurological conditions with high unmet medical need. Founded in 2012 by Dr. Robert Bowser, Iron Horse has developed assays for ALS, traumatic brain injury/concussion and for multiple sclerosis relapse. Its European licensee, Euroimmun, launched Iron Horse’s ALS diagnostic test in Europe in June 2017. The U.S. launch for the ALS diagnostic test is set for late 2017.

Samuel Alworth, MS, MBA, CEO and founder of AcuraStem, was awarded an MDA Venture Philanthropy (MVP) grant totaling $300,000 over two years to support preclinical development of a novel small molecule therapeutic for amyotrophic lateral sclerosis (ALS). MVP grants are awarded to researchers developing therapeutics for neuromuscular diseases to help lower the barriers and bridge the high-risk stages of drug development.

A team led by Justin Ichida, PhD, co-founder and chief scientific officer of AcuraStem and head of the Ichida Lab at the Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at the University of Southern California, published research in Nature Medicine in 2018 in which they discovered that inhibiting the action of a specific protein in ALS patient-derived motor neurons helped prevent their death in vitro (in a petri dish). While the target was discovered in cells from a patient with C9-ALS (or, C9ORF72 ALS; mutations in the C9ORF72 gene are the most common genetic cause of ALS), it may also be applicable to other forms of ALS, including the more common sporadic forms of the disease.

The MVP grant will allow AcuraStem to undertake proof-of-concept studies in mouse models of ALS, as well as develop biomarkers for its orally delivered, blood-brain-penetrating, preclinical development candidate, AS2015.

Stanley Appel, MD, co-director of Houston Methodist Neurological Institute, chair of the Stanley H. Appel Department of Neurology and the Peggy and Gary Edwards Distinguished Chair in ALS at Houston Methodist Hospital, and professor of Neurology at Weill Cornell Medical College, was awarded an MDA human clinical trial grant totaling $558,800 over two-and-a-half years to expand the first-in-human study that demonstrated promising results leveraging patients’ own immune cells to treat amyotrophic lateral sclerosis (ALS). In ALS, muscle-controlling nerve cells called motor neurons are progressively lost, eventually causing muscles to become nonfunctional.

The award is part of a larger grant from The ALS Association, ALS Finding a Cure (ALSFAC), and MDA, which jointly awarded a clinical trial grant totaling more than $2.5 million over two-and-a-half years to leading investigators at the Houston Methodist Neurological Institute and Massachusetts General Hospital. The clinical trial grant is a collaborative study between the ALS team at Houston Methodist Hospital led by principal investigator Dr. Appel and the ALS team at Mass General Hospital led by Merit Cudkowicz, MD, chief of Neurology at Mass General Hospital and the Julieanne Dorn Professor of Neurology at Harvard Medical School.

Regulatory T-lymphocytes (Tregs) are a type of T-lymphocyte (a white blood cell that plays a central role in the immune response) that reduces immune system activation. Tregs are decreased in both numbers and function in the blood of people with ALS. Building on positive preclinical results showing that it was possible to restore Treg function outside the body, the first clinical trial in humans demonstrated that Tregs could be extracted from people living with ALS, expanded in vitro, and then safely infused back into the same patients, with three treated patients showing improved Treg suppressive function and slowed disease progression. The phase 2a clinical trial led by Dr. Appel will expand on the results of the first trial with participants receiving infusions of expanded regulatory (EPAR) T-cells followed by an ascending-dose, open-label extension trial.

MDA awarded a research grant totaling $330,000 to Stanley H. Appel, chair of the department of neurology at the Methodist Neurological Institute (MNI) in Houston, to study the protective effects of a specific class of immune system cells in ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

Appel, a longtime MDA adviser and director of the MDA/ALS center at MNI, will look at T cells, observed in people with ALS as well as in mouse models of the disease, and known to be involved in protecting motor neurons (nerve cells that activate muscles).

Appel's lab previously has documented that T cells can protect neurons in a mouse model of ALS, at least in part by enhancing the neuroprotective functions of another type of immune system cell called microglia. When activated, these cells can produce helpful proteins, but they also can cause dangerous inflammation.

Finding ways to protect motor neurons is a key goal in the development of ALS therapeutics, and Appel's group is working to understand the interaction among other cells in the immune system responsible for prompting T cells to protect neurons.

Project plans include the transplantation of various T-cell types into ALS research mouse models in order to determine which of the cells are most helpful to neurons. A greater understanding of this T-cell population and its associated molecular signals may lead to therapeutics based on increasing the numbers and effectiveness of these cells to help protect neurons in people with ALS.

"MDA has been a critical source of support throughout the development of our immunological studies in ALS," Appel said. "It's permitted us to assemble a team of scientists focused on the neuroinflammatory processes in ALS, and to substantiate the importance of protective immunomodulation in ALS."

Funding for this MDA grant began August 1, 2010.

Stanley Appel, a professor of neurology at Methodist Neurological Institute in Houston, was awarded an MDA research grant totaling $253,800 over three years to study immune mechanisms in amyotrophic lateral sclerosis (ALS). Experiments previously conducted by Appel and colleagues in mice with an ALS-like disorder have shown that the immune system acts to protect nerve cells during the early stages of the disease but that it damages nerve cells in the disorder’s later stages. The mouse studies suggest that manipulating aspects of the immune system could improve ALS outcomes. With the new funding, Appel will investigate whether the same immunologic changes seen in the mice occur in ALS patients and whether they follow the same time course. If so, these “immune hallmarks,” Appel says, have the potential to be used as biological indicators of the effectiveness of therapies that alter the immune system.

Funding for this MDA grant began May 1, 2014.

Gary Armstrong, a senior post-doctoral researcher at Université de Montréal in Quebec, Canada, was awarded a development grant totaling $177,670 over three years to further understanding of the synaptic defects that occur in ALS (amyotrophic lateral sclerosis). Abnormalities arising at the neuromuscular junction occur early in animal models of the disease and very little is known about the role central synaptic defects play in disrupting neuronal communication with the muscular system. A greater understanding of these abnormalities will facilitate the development of the next generation of therapeutics that target early functional defects and slow or stop the progression of ALS.

Funding for this MDA development grant began Aug. 1, 2015.

"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.

“One of the main roadblocks for ALS drug development is the lack of markers that tell us about drug efficacy in patients,” Nazem Atassi says. “With the recent science explosion and the exciting potential ALS treatment targets, we now need efficient tools that will allow us to quickly test many treatments.” 

MDA has awarded a human clinical trial grant totaling $750,000 to ALS ONE to explore the potential for a type of imaging called positron emission tomography (PET) to measure inflammation in the brain that could serve as a biomarker for ALS.

ALS ONE is an alliance between four institutional leaders in ALS treatment development: Massachusetts General Hospital (MGH), ALS Therapy Development Institute (ALS TDI), University of Massachusetts Medical School, and Compassionate Care ALS (CCALS). The partnership was formed with the goal of speeding the discovery of treatments for ALS and developing new approaches to improve care for individuals living with the disease.

The new project, led by Nazem Atassi, M.D., MSSc, will use PET imaging to track inflammation in healthy people who carry a known ALS gene and in symptomatic people with early-stage ALS. Atassi is a member of the ALS ONE science team, associate director for the Neurological Clinical Research Institute at Massachusetts General Hospital and associate professor of neurology at Harvard Medical School. 

Early data from previous studies conducted by Atassi and colleagues have shown significantly increased inflammation in the motor regions in people with ALS. The team also found that ALS patients who have more inflammation tend to have more advanced disease and worse functional status. Implementing PET technology potentially could reduce both the duration of future trials as well as the number of participants required to enroll. This would add enormous efficiency to ALS drug development. 

“This project is poised to change the paradigm of ALS drug development and have a direct impact on the design of future treatment trials for both familial and sporadic ALS,” Atassi says. 

Paul August, at Sanofi, was awarded an MDA research grant totaling $298,500 over a period of three years to develop a neuron-muscle contraction unit on a chip. On the chip, developed using cells derived from people with amyotrophic lateral sclerosis (ALS), motor neurons will cause muscle cells to contract. The development of this innovative tool provides for a complete muscle-nerve unit, which could be used to test drugs and better understand the mechanisms behind motor neuron death in ALS. 

Funding for this MDA research grant began Feb. 1, 2016.

Ellen Barrett, professor of physiology and biophysics at the University of Miami (Florida) Miller School of Medicine was awarded an MDA grant totaling $297,102 over three years. The funds will support Barrett's study of the disease process and potential therapies in familial, or inherited, ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

It has been observed in some cases of ALS that motor nerve terminals (the part of the motor neuron, or nerve cell that conveys signals from the brain to muscles) deteriorate prior to the death of the motor neuron cell body.

In previous studies, Barrett and colleagues have demonstrated that motor nerve terminal health relies heavily on the proper function of cellular "energy factories" called mitochondria. The team also has found that mitochondrial function in motor nerve terminals is impaired in presymptomatic mice with an ALS-like disease, and that it worsens as the mice age and begin to show symptoms.

In her new work, Barrett will test various mitochondria-protective drugs in a research mouse model of ALS and then observe whether more motor terminals remain intact and functional in mice that receive treatment versus mice that do not.

Results from this work may point the way toward a therapeutic strategy involving a combination of treatments: some designed to protect mitochondria and preserve motor nerve terminals, and others targeted toward preservation of motor neuron cell bodies.

"MDA funding has been critical to research progress in our laboratory," Barrett said. "We have especially appreciated MDA’s (1) willingness to support basic as well as clinical research with relevance to neuromuscular diseases; (2) support for pilot projects investigating new research directions; and (3) excellent reviewers, who have always read our grant applications carefully and offered valuable suggestions."

Funding for this MDA grant began February 1, 2011.

Asim Beg, assistant professor at University of Michigan in Ann Arbor, was awarded an MDA research grant totaling $300,000 over a period of three years to study the role of a protein, EphA4, in amyotrophic lateral sclerosis (ALS). High levels of EphA4 correlate with rapid disease progression in ALS patients. Beg and colleagues will work on the development of a strategy to reduce EphA4 levels. This work will provide insight into the molecular mechanisms of motor neuron degeneration and will facilitate new strategies to slow ALS disease onset and progression.

Funding for this MDA research grant began Feb. 1, 2016.

Michael Benatar, at the University of Miami Miller School of Medicine in Florida, and Jonathan Katz, at California Pacific Medical Center in San Francisco, were awarded a clinical research network grant to support their work on the Clinical Procedures To Support Research (CAPTURE) project, which aims to implement the “ALS Toolkit” within the Epic Electronic Health Record System. The ALS Toolkit provides a mechanism to systematize the collection of clinical data so that it can also be used for ALS (amyotrophic lateral sclerosis) research. The two-year award totaling $300,000 will support work conducted through Clinical Research in ALS and Related Disorders for Therapy Development (CReATe) aimed at lessening the burden on people with ALS to attend both clinical and research appointments. CReATe, a rare diseases clinical research consortium, is a member of the National Institutes of Health’s Rare Diseases Clinical Research Network.

Throughout the course of the disease, people with ALS require input and assistance from multiple health care professionals and, as a result, multidisciplinary clinics such as MDA ALS Care Centers are a key resource for ongoing medical management and care. Visits to care centers take several hours, and a substantial amount of clinical data (such as neurological examination results, quantification of respiratory muscle strength and motor function assessments) are routinely collected — much of it identical to the assessments performed at specialized research visits. However, data from these two types of visits are typically captured separately, necessitating separate appointments for people who, depending on the stage of their disease, may experience profound weakness, disability and difficulty associated with travel.

It has therefore been a longstanding goal of many ALS clinician-investigators to find ways to reduce the burden on patients by finding a way to regularly collect a standard data set at clinical appointments that can be used for research purposes as well.

With increasing penetration of the electronic medical record into academic medical centers, and the recently established collaboration between Benatar and Katz with Epic, a team will now develop and implement a novel ALS Toolkit (set of “smart forms”) within the electronic medical record system that will enable clinicians to collect standardized data that can serve both clinical and research purposes.

If successful, the work will support a fundamental change in practice that will provide people with ALS a simple and straightforward way to contribute to research that can accelerate progress towards treatments and cures. 

Michael Benatar, associate professor of neurology and epidemiology at Emory University in Atlanta, received an MDA grant totaling $525,000 to continue research into the early stage of FALS — familial, or inherited, ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease) — prior to symptom onset.

With funding from MDA, Benatar began his "pre-FALS" study in 2007, tracking a group of 30 people at risk for developing ALS because they harbor a mutation in the SOD1 gene, known to cause some forms of the disease. His team collected a series of physical, functional and neurological data over time in an effort to discern early biological markers ("biomarkers") of the disease process, and established a repository of biological samples collected from the study participants.

In Benatar's new follow-up study, the original group of 30 participants will expand to include presymptomatic individuals with mutations in other ALS susceptibility genes such as TDP43 and FUS.

Study aims include better definition of the presymptomatic stage of familial ALS, identification of environmental factors that might modify the age of disease onset among genetically susceptible individuals, continued development of biomarkers of early disease, and expansion of the existing collection of biological specimens.

Benatar's exploration into the presymptomatic phase of ALS could facilitate earlier recognition and diagnosis of both the familial and sporadic forms of the disease, which in turn could point the way toward therapeutics aimed at prevention or delay of ALS onset, as well as attempts to stop or slow the disease before it causes irreversible damage.

"MDA has shown great foresight in recognizing the importance of this study and the kind of long-term contribution that it can make to our understanding of the disease," Benatar said.

Funding for this MDA grant began August 1, 2010.

"A holy-grail of physician-investigators engaged in both ALS patient care and research has been the efficient and effective use of clinically-derived data for research purposes. To address this critically unmet need, we have partnered with Epic (the maker of the most widely used electronic health record [EHR] system) to build the ALS Toolkit. This resource will permit broad sharing of de-identified clinical data in a regulatory-compliant manner."

Michael Benatar, Professor of Neurology at the Miller School of Medicine of the University of Miami, was awarded an MDA Clinical Research Network Grant totaling $916,261 over three years to support the multicenter deployment of the ALS toolkit, a module built into the Epic EHR that aims to facilitate structured data collection for research and improve quality of care.

Clinics are critical to ALS patient care, leading to improved quality of life and prolonged survival. Clinic visits can take several hours with substantial clinical data collected; however, these data have limited utility for research purposes because of the unstructured way in which the data are collected. The ALS toolkit will provide a platform for standardized data collection across clinical sites, which could obviate the need for separate research visits and reduce the burden on patients and physicians.

MDA has awarded a clinical research training grant totaling $180,000 to clinical research fellow James Berry at Massachusetts General Hospital (MGH) in Boston. The grant will support completion of a two-year fellowship during which Berry plans to study the effects of a drug called ISIS-333611 in familial, or inherited, ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease).

Familial ALS accounts for 5 to 10 percent of all ALS cases. About 20 percent of those (1 to 2 percent of all ALS cases) are caused by a mutation in the SOD1 gene, which leads to production of abnormal SOD1 protein.

Berry is a member of the study team currently planning a phase 2 clinical trial of intrathecal (into the spinal canal) administration of the experimental drug ISIS-333611 (made by Isis Pharmaceuticals of Carlsbad, Calif.) in people with familial ALS. The trial will be a follow-on study to a phase 1 trial of the drug, currently under way, if results from that trial are favorable.

Previous studies of the drug in rats have shown that it is safe and tolerable, that it reduces mutant SOD1 RNA (the chemical step between DNA and protein synthesis) and protein levels, and slowed progression of the disease. It's thought that decreasing mutant SOD1 levels in humans may confer similar therapeutic benefits.

The planned phase 2 study will test ISIS-333611 over an extended period of time to assess its safety and tolerability. If the phase 2 trial is successful, a phase 3 trial may be planned to test efficacy of the drug.

"MDA funding is critical to my career development and my ability to begin my career as a clinical researcher in ALS," Berry said. "I am incredibly excited to have received this award, and I am looking forward to getting started on the project."

Funding for this MDA grant began February 1, 2011.

MDA has awarded a grant totaling $347,094 over three years to François Berthod, a professor in the department of surgery at Laval University in Quebec City, Quebec, Canada. The funds will help support Berthod's study of the underlying molecular mechanisms and disease process in ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

ALS is characterized by the degeneration of motor neurons (nerve cells that control muscle movement) in the spinal cord and brain.

Berthod, who has a background in tissue engineering, previously has shown that human motor neurons can differentiate (mature) from a population of stem cells obtained from human skin.

Now, Berthod plans to develop a three-dimensional model of the human spinal cord using neural (nervous system) cells obtained from the tissues of people with ALS. The human tissue-engineered spinal cord (TESC) model is expected to mimic the human disease "in vitro," or in a laboratory setting. Its design will permit testing of the interactions of various neural cell types, including motor neurons and neuroprotective cells such as astrocytes, microglia and Schwann cells, as a means of determining the conditions that induce or aid motor neuron death in ALS.

Findings from Berthod's work are expected to improve understanding of the causes and progression of sporadic ALS.

"MDA funding over the years has been the only source of support for our research on amyotrophic lateral sclerosis," Berthod said, adding that it's been "the strongest encouragement to continue developing innovative in vitro models of this disease."

Funding for this MDA grant began February 1, 2011.

Martha Bhattacharya, a postdoctoral research scholar in developmental biology at Washington University School of Medicine in St. Louis, Mo., was awarded an MDA development grant totaling $180,000 over a period of three years to study how and why axons degenerate.

Axons are the long extensions of motor neurons (muscle-controlling nerve cells) that link up with muscles. Signals are sent down the axon to cause the muscle to contract. When an axon degenerates, it can no longer carry those signals, leading to weakness.

“In neuromuscular diseases where motor neuron dysfunction is the primary cause of disability, such as amyotrophic lateral sclerosis (ALS) and Charcot-Marie-Tooth (CMT) disease, axonal degeneration is a unifying pathological hallmark of disease progression,” Bhattacharya says.

To study axonal degeneration, she and her colleagues developed a fruit fly research model that allows the identification of necessary components of the axonal degeneration cascade. Using this system, she has identified several key steps in the process, including one involving a protein called G-protein coupled receptor (GPCR), and another called protein kinase.

“These receptors are highly desirable drug targets,” Bhattacharya says, and pharmaceutical companies have a great deal of experience designing drugs to influence their behavior. “For the GPCR, we will determine its signaling mechanism in mammalian neurons and test its ability to protect neuromuscular synapses after injury. For the kinase, we will examine the effects of loss of this protein on mouse axons and synapses,” the sites of information exchange between nerve and muscle.

Learning more about the details of axonal degeneration also will help researchers understand more about the entire disease process, potentially leading to other targets for therapeutic intervention.

Funding for this MDA grant began Feb. 1, 2013.

Izumi Biosciences in Lexington, Mass., was awarded an MDA Venture Philanthropy (MVP) grant totaling $96,360 to fund early-stage development of a type of IZ10023, a type of drug called a “pharmacokinetic (PK) enhancer,” for use in people with ALS (amyotrophic lateral sclerosis) who are taking riluzole. (Riluzole, marketed under the brand name Rilutek, was developed based on MDA-supported research on the neurotransmitter glutamate, and is the only drug approved by the U.S. Food and Drug Administration to treat ALS.)

IZ10023 targets and blocks two proteins in the brain and spinal cord that work to protect the central nervous system (CNS) by acting as pumps that remove foreign or toxic substances. In mouse studies it’s been shown that these pumps remove drugs such as riluzole, reducing levels of the drug in the CNS and thereby limiting its effectiveness.

President and CEO of Izumi Biosciences Antonius Bunt will serve as the principal investigator on the project.

“Blockade of these pumps maintains effective levels of riluzole in the diseased tissues and leads to improved outcomes in animal models of ALS and other brain diseases where multi-drug resistance is a key clinical bottleneck,” Bunt explained.

Confirmation that the pumps’ activity is increased in most ALS patients and demonstration that sufficient blood levels of IZ10023 can be achieved to block their activity are important milestones that must be achieved before moving IZ10023 into clinical trials in patients with ALS, Bunt noted. If the work is successful, Izumi Biosciences intends to open an Investigational New Drug Application and move into clinical trials — possibly as early as 2019.

MDA has awarded a research grant totaling $429,983 over three years to Don Cleveland, departmental chair of cellular and molecular medicine; professor of medicine, neurosciences, and cellular and molecular medicine; and member of the Ludwig Institute for Cancer Research in La Jolla, Calif. The funds will help support Cleveland’s research into the connection between mitochondria and ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

Mitochondria, the intracellular compartments that consume oxygen to produce chemical fuel that supports the cell, have been implicated as targets for toxicity in the inherited, SOD1-associated forms of ALS.

It is not known, however, in which cell types of the nervous system mitochondrial damage occurs, whether the ensuing mitochondrial dysfunctions are a cause or a consequence of neuronal degeneration during the disease and if the effects are the same in SOD1-associated ALS caused by different SOD1 mutations.

Using mice that are genetic mimics of inherited, SOD1-related ALS, Cleveland intends to determine at what disease stage and in which cell types of the central nervous system mitochondrial dysfunction occurs, and whether rescue of individual mitochondrial functions or an increase in mitochondrial activity may alter the ALS disease course.

“This comparative analysis will, in principle, provide a test for whether mitochondria are a common target of toxicity,” Cleveland said.

Funding for this MDA grant began August 1, 2011.

Don Cleveland, distinguished professor and chair in the department of cellular and molecular medicine at the University of California, San Diego, in La Jolla, was awarded an MDA research grant totaling $300,000 over three years to elucidate the mechanisms of ALS (amyotrophic lateral sclerosis)caused by mutations in the Fused in Sarcoma (FUS) gene. Cleveland and colleagues will be using newly developed mouse models to investigate whether alterations in the FUS gene cause ALS by a loss of the normal function of the FUS protein or through adoption of a new, toxic function of the protein. A better appreciation of how FUS alterations cause motor neuron death will aid in determining what type of treatment approach may work best for this type of ALS.

Funding for this ALS research grant began Aug. 1, 2015. 

Benoit Coulombe, director of the Proteomics and Gene Transcription Laboratory at the University of Montréal in Quebec, Canada, was awarded an MDA research grant totaling $377,067 over a period of three years to study the regulation of a protein whose gene, when mutated, can cause amyotrophic lateral sclerosis (ALS) and inclusion-body myositis (IBM).

Valosin Containing Protein (VCP) helps clear misfolded proteins so that they do not cause damage within cells. Mutations in the VCP gene that interfere with this function are one cause of both ALS and IBM.

VCP is a type of protein called a molecular chaperone. “Building a detailed understanding of the mechanisms by which molecular chaperones play a role in the onset and development of neuromuscular disorders is important for the design of new tools to better diagnose and treat some of these conditions,” Coulombe says.

Recently, his group discovered that a set of proteins called methyltransferases regulates the activity of VCP, raising the possibility that this regulatory system may go awry when VCP is mutated. By studying the activity of methyltransferases and VCP in both healthy and diseased cells, Coulombe hopes to learn more about the regulation of chaperones and how it is affected by disease-causing mutations.

The goal is to examine the full range of changes brought about by methyltransferase activity, using state-of-the-art tools to capture and characterize the set of protein modifications in cells. Coulombe also will explore whether changes in VCP and the proteins with which it interacts can serve as a “biomarker,” helping to identify diseased cells and following their response to treatment.

“Characterizing these newly discovered enzymes will help us understand the molecular bases of these disorders and accelerate the development of diagnosis and therapeutic tools relevant to their treatment,” he says.

Funding for this MDA grant began Feb. 1, 2013.

“This work will provide critical insight for elucidating the mechanisms regulating protein aggregation and cell-to-cell spreading of protein aggregates, as well as [for] establishing safety and applicability of an antisense oligonucleotide (ASO) strategy as a therapy for fused in sarcoma (FUS) proteinopathies.”

Sandrine Da Cruz, PhD, assistant investigator of Neurobiology at the San Diego Branch of the Ludwig Institute for Cancer Research, was awarded an MDA research grant totaling $300,000 over three years to investigate the mechanisms underlying amyotrophic lateral sclerosis (ALS) caused by mutations in the fused in sarcoma (FUS) protein and potential therapies to treat the disease.

Despite having identified ALS-associated proteins, including FUS and TDP-43, the disease mechanism behind these proteins in ALS has yet to be discovered. Previously, Dr. Da Cruz used a mouse model to determine that if mutant FUS is delivered to the cytoplasm of a cell, then FUS aggregates there and spreads to adjacent cells in the central nervous system (CNS), worsening behavior in the mice associated with mutant FUS expression.

Dr. Da Cruz will use this funding to study both familial and sporadic ALS (and frontotemporal dementia, a related disease) in both an FUS mouse model and in cell culture. She will aim to determine the role of FUS aggregation and its cell-to-cell transmission in the CNS in the pathology of ALS. Dr. Da Cruz hopes to test the feasibility of lowering FUS levels using an antisense oligonucleotide as a first step in the development of a therapy, which may act to delay onset and slow progression of ALS.

Heather Durham, professor at the Montreal Neurological Institute of McGill University in Quebec, Canada, was awarded an MDA research grant totaling $355,936 over a period of three years to study the consequences of mutations in the FUS gene for muscle-controlling nerve cells called motor neurons.

Mutations in FUS are known to be a cause of amyotrophic lateral sclerosis (ALS), a disease that involves the death of motor neurons. The FUS protein binds to RNA, which cells use to bring protein-making instructions from the nucleus to other parts of the cell. FUS joins up with other proteins to do this. FUS mutations can disrupt the protein's ability to move through the cell and bind properly to other cell components to make these transport complexes.

“In neurons, the distribution of these RNA-containing complexes is particularly important for maintaining connections with other neurons, and for responding to the level of neuronal activity and stress,” Durham says. Her research will study the details of how mutations affect trafficking of FUS and its partners, including RNA, and how these abnormalities relate to or affect cellular adaptive responses. Understanding these important changes may shed light on how these and other ALS-causing gene mutations lead to the death of motor neurons.

“This is a very exciting time in ALS research,” she says. “The recent discoveries of new genes associated with ALS point us toward the commonalities and differences in the multiple disorders we call ALS. Those commonalities will not only help us to identify targets for therapy, but will establish the best preclinical models in which to evaluate their efficacy.”

Funding for this MDA grant began Feb. 1, 2013.

Heather Durham, professor in the department of neurology and neurosurgery at Montreal Neurological Institute, McGill University, Quebec, Canada, was awarded an MDA research grant totaling $299,017 over a period of three years to evaluate strategies that could prolong function of motor neurons, the nerve cells that lose function and die in amyotrophic lateral sclerosis (ALS).

ALS is a complex disease that involves widespread disruption of cellular functions. With colleagues, Durham has determined that the Neuronal Brg1/Brm Associated Factor (nBAF) protein complex is disrupted in the disease. nBAF regulates the expression of neuronal-specific genes that help neurons extend processes to connect to other neurons in the network. Key proteins in nBAF are lost in motor neurons in familial and sporadic ALS which could disrupt motor neuron connectivity and ultimately, result in motor neuron dysfunction.

Durham will examine the mechanisms involved in nBAF activity and function, and work to determine whether interventions in the pathway could have a protective effect on motor neurons.

An understanding of the key elements and processes associated with nBAF could pave the way toward new therapies for ALS that could help motor neurons function longer and stay connected in the network.

Funding for this MDA research grant began Aug. 1, 2016.

“I expect to determine how stathmin-2 provides a crucial role in the maintenance and regeneration of the neuromuscular junctions that connect motor neurons and skeletal muscles. With this, I hope to uncover insights for the development of ALS treatments that will halt the progression of the disease from its early phases.”

Jone Lopez Erauskin, PhD, postdoctoral fellow in Cellular and Molecular Medicine at the San Diego Branch of the Ludwig Institute for Cancer Research, was awarded an MDA development grant totaling $210,000 over three years to study the mechanisms of maintenance and regeneration of the neuromuscular junction (NMJ) in amyotrophic lateral sclerosis (ALS).

Normally, nerve cells communicate with muscle cells by sending electrical signals across the NMJ. Frequently, disruption of this communication happens early in the course of ALS. Recently, Dr. Lopez Erauskin discovered that the loss of stathmin-2, a neuronal growth-associated protein, is universally found in sporadic and familial (inherited) ALS, and that stathmin-2 is essential for axonal (nerve fiber) regeneration.

In this project, Dr. Lopez Erauskin seeks to identify the mechanisms that underlie disruption of nerve-muscle connections in ALS through the loss of stathmin-2. These studies may enable the design of therapeutic strategies to maintain or restore nerve-muscle connections, thereby delaying or halting disease progression in ALS.

Mohamed Farah, assistant professor of neurology at Johns Hopkins University School of Medicine in Baltimore, Md., was awarded an MDA research grant totaling $375,000 over a period of three years to test drugs in models of amyotrophic lateral sclerosis (ALS).

In ALS, muscle-controlling nerve cells called motor neurons become dysfunctional before they die, and that period of dysfunction may represent an important window in which new therapies could rescue them. “The overall goal of this grant is to investigate whether the capacity of motor nerves to regenerate after insult or disease can be enhanced to a degree that results in functional recovery,” Farah says.

He will be testing whether drugs originally designed for Alzheimer’s disease can offer benefit in animal models of ALS by increasing neuronal regeneration and restoring neuromuscular function when given in the early stages of disease.

Funding for this MDA grant began Feb. 1, 2013.

Mohamed Farah, assistant professor of neurology and neuroscience at Johns Hopkins School of Medicine in Baltimore, was awarded an MDA research grant totaling $300,000 over three years to investigate whether a drug currently in development for Alzheimer’s disease can improve function in ALS (amyotrophic lateral sclerosis).

It’s thought that repair and regrowth of motor nerve endings might result in restoration of function for motor neuron diseases such as ALS — particularly slowly progressing forms.

In previous work, Farah and colleagues discovered that manipulating the amount of BACE1, an enzyme whose job it is to cut other proteins into pieces, enhances peripheral nerve regeneration in mice. Those studies prompted the team to explore the possibility that using a drug to reduce BACE1 might be an effective means to encourage motor axon regrowth at an early stage of motor neuron disease in mice.

Because BACE1 inhibitors currently are being developed and tested as potential therapies for Alzheimer’s disease, Farah’s work could lead to rapid development and clinical evaluation of BACE1 inhibitors in motor neuron diseases. If successful, the approach could enhance the quality of life of people with ALS or other motor neuron diseases.

Funding for this MDA research grant began Feb. 1, 2017.

MDA awarded $180,000 to research scientist Brian Freibaum at St. Jude Children's Research Hospital in Memphis, Tenn., for research into the mechanism by which toxic TDP43 protein leads to the development and progression of some forms of ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

Prior research has suggested that mutant (flawed) TDP43 protein is a critical component in the development of some forms of ALS, although the mechanism by which it works remains unknown. Freibaum has planned a three-tiered approach to uncover the protein's role in the disease.

First, Freibaum's team will test for toxicity in various tissues of fruit flies engineered to carry the human TDP43 gene. Using different mutant (flawed) and shortened forms of the protein is expected to help pinpoint what parts of the TDP43 protein are required for disease progression.

Next, the team will use human cell lines and mouse motor neurons (nerve cells that control muscle) to explore how TDP43 interacts with other proteins, where it normally localizes in the cell, and whether these locations are altered with mutant forms of the protein. Further experiments will be used to determine what other proteins interact with normal and flawed TDP43 protein.

Finally, the group will use the fruit fly model to perform genetic screens designed to explore how other proteins cooperate with mutant TDP43 to induce toxicity in motor neurons.

Greater understanding of the role TDP43 plays in ALS will help provide a more targeted approach to the development of new therapies.

"I am honored to be funded by such a prestigious organization that has a strong history in the advancement of neuromuscular disease research," Freibaum said. "This funding will be of great significance to our lab’s ALS research."

Funding for this MDA grant began August 1, 2010.

"We’re in the middle of a scientific revolution that’s seeing the development of increasingly precise and effective tools for correcting many different kinds of genetic defects. Our lab and many others are committed to using these and other emerging technologies to treat a range of neuromuscular diseases."

Thomas Gaj, PhD, assistant professor of Bioengineering at the University of Illinois at Urbana-Champaign, was awarded an MDA research grant totaling $300,000 over three years to evaluate whether gene editing could be applied as a potential treatment for amyotrophic lateral sclerosis (ALS) caused by mutations in the superoxide dismutase 1 (SOD1) gene. Mutations in SOD1 are estimated to cause about 2 percent of all ALS cases.

It is believed that mutations in the SOD1 gene cause the SOD1 protein to adopt abnormal toxic functions, leading to the loss of motor neurons that causes ALS. Gene editing allows researchers to change or correct DNA. A new kind of gene-editing technique called single base editing is modeled on the CRISPR-Cas9 system but with additional enzymes that modify DNA by converting one base in the DNA code to another.

Unlike traditional gene-editing tools, single base editors can alter a gene sequence without breaking the DNA. In this project, Dr. Gaj will use single base editing to reduce the amount of toxic SOD1 protein in the spinal cord of mice by either causing the mutated SOD1 gene to become inactive or by directly correcting a specific gene mutation. If successful, this work could pave the way for the development of a gene therapy for ALS based on single base editing technology as well as the discovery of how gene-editing technology can be used to treat other neuromuscular diseases.

Fen-Biao Gao, professor at the University of Massachusetts Medical School in Worcester, was awarded an MDA research grant totaling $300,000 over three years to identify new drug targets for ALS (amyotrophic lateral sclerosis).

C9ORF72 repeat expansion is the most common genetic mutation known to cause ALS. In this and several other forms of the disease, damage to DNA has been identified as a common, downstream pathway that can contribute to the death of nerve cells called motor neurons.

To understand how the C9 mutation drives the disease, Gao and colleagues have generated induced pluripotent stem cells (iPSCs) from C9 ALS patients and developed them into motor neurons and cortical neurons that recapitulate some key features observed in diseased cells, such as abnormal accumulation of RNA “clumps” and production of unusual toxic proteins. The team will use the iPSC-derived motor neurons as well as fruit fly models of ALS to investigate what causes DNA damage, and will perform a screen to identify new drug targets based on the findings.

Gao’s work will greatly enhance understanding of ALS disease mechanisms and may lead to the identification of key components in the DNA damage pathway that may serve as targets for therapy development.

Funding for this MDA research grant began Feb. 1, 2017.

“I believe that understanding the initial event that provokes TDP-43 abnormalities and TDP-43 spread within the nervous system will guide directions for therapeutic development in ALS,” Fatima Gasset-Rosa said.  

Fatima Gasset-Rosa, postdoctoral fellow at the Ludwig Institute for Cancer Research, University of California – San Diego in La Jolla, Calif., was awarded an MDA development grant totaling $180,000 over three years to study the role of abnormal TDP-43 protein in ALS (amyotrophic lateral sclerosis).

A common feature of the majority of ALS cases is the aggregation of TDP-43 protein in the tissues of the brain and spinal cord. Using neuronal cells and mouse models, Gasset-Rosa and colleagues are working to uncover the mechanisms that cause TDP-43 protein to assemble into these aggregates. In addition, they aim to determine whether the spread of these clumps of abnormal TDP-43 occurs anatomically — from cell to cell — to neighboring regions of the brain and spinal cord, leading to the spreading of disease and progression of ALS. 

If successful, Gasset-Rosa’s work could help inform the development of drugs aimed at blocking the formation and propagation of TDP-43 aggregates in ALS.

Tania Gendron, assistant professor of neuroscience at the Mayo Clinic in Jacksonville, Fla., was awarded an MDA research grant totaling $285,000 over a period of three years to investigate the c9RAN protein as a potential biomarker to measure the effectiveness of promising treatments for C9ORF72 amyotrophic lateral sclerosis (C9ALS) and serve as a prognostic biomarker to predict disease progression.

With therapies in development for C9ALS, the most common form of ALS known to date, it is crucial to have biomarkers in place that can inform clinical studies. It’s been found that in C9ALS, there is an expanded piece of RNA (an intermediate step between the genetic instructions in DNA and the manufacturing of proteins). RNA from this expansion codes for the production of potentially harmful c9RAN proteins. Evidence that these c9RAN proteins are toxic has spurred the field to investigate therapeutic approaches to counteract it.

Gendron and colleagues previously have reported that poly(GP), one of the c9RAN proteins produced in C9ORF72 ALS, is present in cerebrospinal fluid (CSF) and in white blood cells. The team will study CSF and blood collected from C9ALS patients and investigate whether measurements of the protein can be associated with clinical features of the disease. In addition, the team will work with C9ALS patient cell lines and CSF from mice engineered to model the disease to probe the effectiveness of poly(GP) in predicting treatment response.

Funding for this MDA research grant began Aug. 1, 2016.

"We hope that the biomarkers of cognitive impairment identified through this work will prove useful in the clinical assessment and care of patients, and in the design of clinical trials. Moreover, because biomarkers for cognitive dysfunction are likely to reflect biochemical changes that precede its clinical manifestation, they may permit the earlier diagnosis of such dysfunction — information important for the effective timing of potential medical interventions."

Tania Gendron, PhD, assistant professor of Neuroscience at the Mayo Clinic in Jacksonville, Fla., was awarded an MDA research grant totaling $285,000 over three years to identify biomarkers to predict cognitive impairment in amyotrophic lateral sclerosis (ALS), which could be useful in patient care as well as for stratification of clinical trials.

As many as half of all ALS patients will show signs of impaired cognition during the course of the disease. Recognizing symptoms of cognitive impairment is important considering the effect they have on disease progression (patients with ALS who also have cognitive impairment have a shorter survival time), quality of life, and disease management and treatment of symptoms. To date, there are no validated biomarkers for cognitive impairment in patients with ALS.

The goal of this project is to deliver a panel of biomarkers that can detect emerging cognitive impairment in ALS patients. Dr. Gendron will use mass spectrometry-based proteomics to identify protein biomarkers of cognitive impairment in patients’ spinal fluid, and then determine whether these biomarkers correlate with the severity of cognitive impairment and if they can be used to determine the rate of disease progression and survival.

If successful, identifying biomarkers for cognitive impairment in ALS patients would help to improve patient stratification in clinical trials, as well as provide insight into the discovery of drug targets for treating cognitive impairment in not only ALS but also a variety of other neurological diseases.

"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.

Aaron Gitler, an associate professor of genetics at Stanford University in Stanford, Calif., was awarded an MDA research grant totaling $253,800 over three years to investigate how mutations in the gene for a protein called profilin 1 cause amyotrophic lateral sclerosis (ALS).

In experiments conducted in cells, Gitler and colleagues have found that the profilin 1 protein may be a regulator of "stress granules" — tiny cellular factories that stores and process RNA molecules — and that further understanding this function may provide insights that lead to ALS therapy development.

Funding for this MDA grant began May 1, 2014.

"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.

"Research into ALS cannot move forward without the participation of patients, who provide the needed clinical information, biosamples, and involvement in clinical trials. Our NEALS organization is the largest academic organization focused on promoting clinical trials in ALS and educating both investigators and patients/families on the science of clinical trials."

Jonathan Glass, MD, professor of Neurology and Pathology at Emory University in Atlanta and director of the Emory ALS Center, was awarded an MDA research infrastructure grant totaling $151,592 over three years to further develop the member services and activities of the Northeast ALS (NEALS) Consortium for the amyotrophic lateral sclerosis (ALS) research community. It builds upon a previous grant awarded to Dr. Glass from 2015 to 2018 for the development and support of the consortium.

The NEALS Consortium is an international organization of 125 research sites that collaborate to support and conduct clinical research in ALS and other motor neuron diseases. The mission of the NEALS Consortium is to translate scientific advances as rapidly as possible into new treatments for people with ALS and motor neuron disease.

This grant will help support the NEALS Consortium’s biorepository, which contains tissues and fluids that are widely used by the community — including MDA-funded researchers — to advance ALS research. The grant will also support the annual NEALS Consortium meeting, which is an opportunity for the sites to come together to share advances and receive training.

"There is an enormous need for a better understanding of the clinical, demographic, and genetic features that underlie the clinical variability seen in patients suffering from ALS."

Jonathan Glass, M.D., Ph.D., Professor of Neurology at Emory University, has been awarded an MDA restricted research grant of $137,228 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.

MDA has awarded a research grant totaling $202,508 over a period of three years to Raymond Grill, assistant professor in the department of integrative biology and pharmacology at the University of Texas Health Science Center, Houston. The funds will support testing in the SOD1 mouse model of an experimental combination drug treatment in ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

One process suspected to be heavily involved in ALS disease progression is inflammation, which can create a toxic environment and kill motor neurons.

Using the SOD1 ALS research mouse model, Grill's research team will test the hypothesis that a drug called Licofelone, which has completed phase 3 testing in humans, will enhance the ability of riluzole (Rilutek) to better penetrate the nervous system. (Rilutek is the only drug approved by the U.S. Food and Drug Administration for treatment of ALS.)

The researchers expect the combination treatment will reduce inflammation, protect motor function, rescue motor neurons and prolong survival in the SOD1 mice, and if favorable results are obtained, the group will attempt to "fast-track" the "two-part" treatment into clinical development.

"The support provided by the Muscular Dystrophy Association provides an invaluable opportunity for laboratories such as ours to enter this important field and both test and translate new ideas."

Funding for this MDA grant began August 1, 2011.

Maurizio  Grimaldi, leader of the Neuropharmacology/Neuroscience Laboratory at Southern Research Institute in Birmingham, Ala., was awarded an MDA research grant totaling $253,800 over three years to study the development of molecules that have neuroprotective effects and have the potential to be used as therapies for the treatment of amyotrophic lateral sclerosis (ALS).

Grimaldi and colleagues have found that two molecules — SR22818 an SR22819 — increase levels of a potentially neuroprotective protein called SOD2 in brain cells. These two molecules were safe and well-tolerated in mice, and they increased life expectancy and improved neurologic symptoms in mice with an ALS-like disease.

Grimaldi plans to improve on these molecules and pursue their development as potential therapies for ALS.

Funding for this MDA grant began May 1, 2014.

"The pathophysiological mechanisms underlying ALS and other neuromuscular diseases are still poorly understood. Only through systematic and mechanistic investigations of disease-relevant pathways can more novel therapeutic targets be discovered. More diverse therapeutic strategies will most likely accelerate the development of treatments."

Junjie Guo, PhD, assistant professor of Neuroscience at Yale University, was awarded an MDA research grant totaling $297,678 over three years to learn more about the process by which RNA from the C9ORF72 gene mutation in amyotrophic lateral sclerosis (ALS) forms complexes with proteins inside the cell and whether specific complexes are detrimental to the health of the motor neuron.

Although most cases of ALS are sporadic, meaning there is no family history of the disease, about 10 percent of cases are familial, meaning the disease runs in the family. Recently, it was discovered that a mutation in the C9ORF72 gene where one segment of the gene is repeated too many times — also known as a repeat expansion — is the most common cause of the familial form of ALS (this form is referred to as C9-ALS) and is found in some sporadic cases as well. It’s uncertain, however, if the disease is caused by reduced levels of normal C9ORF72 protein and/or by toxic RNA and proteins manufactured using instructions from the extra DNA.

Defects in cellular RNA metabolism have been shown to play important roles in a variety of sporadic and familial neuromuscular diseases, including familial ALS. In C9-ALS, RNA from the repeat expansion forms RNA foci (clump-like structures) inside the cell. Previous studies have shown that these RNA foci can alter the function of RNA-binding proteins, thereby affecting the function of cells. In this project, Dr. Guo will study how RNA foci are formed, what factors regulate their formation, and how these foci affect RNA metabolism in a C9-ALS motor neuron model. He aims to better understand the molecular mechanisms and pathophysiological roles of RNA foci in not only ALS but also other neuromuscular diseases associated with repeat expansions.

Amanda Haidet-Phillips, a postdoctoral student at Johns Hopkins University School of Medicine in Baltimore, was awarded an MDA research development grant totaling $150,717 over three years to investigate how cells known as upper motor neurons, located in the top part of the brain, degenerate in amyotrophic lateral sclerosis (ALS). Recently, nervous system support cells called astrocytes were found to cause the death of lower motor neurons, located in the brainstem and spinal cord, and Haidet-Phillips will study whether astrocytes also kill upper motor neurons. By conducting experiments in cells, she hopes to find clues to upper motor neuron loss in ALS and uncover leads to therapy development.

Funding for this MDA grant began May 1, 2014.