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.

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.

“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, 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.

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. 

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.

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. 

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.

“It surprises me that we don’t have better drugs to treat ALS patients. I think we need better models of ALS to test whether drugs are effective.”

Todd J. Cohen, assistant professor at the UNC School of Medicine at the University of North Carolina at Chapel Hill,was awarded an MDA Research Grant totaling $300,000 over 3 years to study a novel mouse model of sporadic ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating disease resulting from loss of motor neurons, leading to paralysis and eventually death. The major disease hallmark found in most patients with ALS is called TDP-43, a protein that accumulates in the brain and spinal cord and is implicated in the death of neurons. Dr. Cohen’s goal is to generate better ALS models that faithfully mirror the human disease and will allow better testing for the effectiveness and clinical potential of emerging ALS drugs.

Dr. Cohen’s laboratory generated a first-of-its-kind ALS model that displays many of the hallmarks of human ALS, including the toxic accumulation of TDP-43 as well as motor impairments that resemble those seen ALS patients. The team plans to establish these TDP-43 mutant mice as a next-generation ALS model that could dramatically accelerate the testing of potentially effective therapies for eventual translation to human patients.

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.

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.

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.

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.

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.

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.

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.

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.

Samantha Harris, an associate professor in the department of neurobiology, physiology and behavior at the University of California, Davis, has been awarded an MDA grant totaling $244,024 over two years. The funding will help Harris in her quest to determine the properties of a skeletal-muscle protein called myosin binding protein C.

Mutations in the gene for myosin binding protein C affect muscle contraction and could play a role in a number of muscle diseases.

"MDA support of this work comes at a pivotal time," Harris said, "not only for the opportunity it provides for making rapid inroads into our understanding of [muscle contraction abnormalities], but also for the opportunity it provides in opening up new research directions for my lab by fostering new collaborations. I am eager to get started!"

Funding for this MDA grant began August 1, 2011.

Muralidhar Hegde, a professor at the Houston (Texas) Methodist Research Institute, was awarded an MDA research grant totaling $253,800 over three years to study whether deficient repair of DNA strand breaks by a protein called TDP43 is involved in amyotrophic lateral sclerosis (ALS) causation. Hegde will conduct experiments in mouse and human cells and says the result could lead to a “major paradigm shift in our understanding of ALS pathology” and “open up new avenues for therapeutic interventions.”

Funding for this MDA grant began May 1, 2014.

MDA awarded a research grant totaling $330,000 over a period of three years to Terry Heiman-Patterson, section chief of neuromuscular disorders at Drexel University College of Medicine in Philadelphia. Heiman-Patterson also is medical director of the MDA/ALS Center of Hope at that institution.

The newly awarded funds will help support Heiman-Patterson's work to identify "modifier" genes in mouse models of amyotrophic lateral sclerosis (ALS).

A great deal is known about one of the most commonly used mouse models of ALS — the SOD1 mouse. This model carries mutations in the SOD1 gene and develops some of the same signs and symptoms exhibited by people with SOD1-related ALS.

"Our lab, along with others, have shown that disease severity in these transgenic mice depends on their genetic background," Heiman-Patterson said. 

With colleagues, Heiman-Patterson plans to compare a number of mouse models and identify genes that are able to modify disease.

It's already suspected that a region on chromosome 17 modifies disease severity in mice with certain backgrounds. Heiman-Patterson's team intends to validate that the region of chromosome 17 does modify disease, to identify the responsible gene within the region, and to test whether the gene also can affect severity in other models of motor neuron disease.

The identification of modifier genes will provide new targets for therapy development.

MDA awarded a research grant totaling $328,153 over a period of three years to Kenneth Hensley, associate professor in the departments of pathology and neuroscience, and research director in the department of pathology at the University of Toledo Medical Center in Ohio. The funds will help support Hensley’s study of a potential new target and treatment strategy for amyotrophic lateral sclerosis (ALS).

Recent findings from Hensley’s laboratory and from other groups, Hensley said, suggest that ALS actually begins near the junction of nerve and muscle (the neuromuscular junction, or NMJ).

“We hypothesize that molecules called semaphorins acting inappropriately near the NMJ signal axons, the long fibers that extend and carry information away from the bodies of motor neurons (nerve cells). The semaphorins’ signals cause the axons to move away from the muscle and ‘collapse’ backward toward the spinal cord.”

Research conducted by Hensley and colleagues implicates a protein calledcollapsing response mediator protein-2, or CRMP2, in this process of axon degeneration. The group will now test three distinct pharmacological (drug-based) approaches to interrupting CRMP2-dependent axon degeneration in the SOD1 research mouse model of ALS.

“We have invented and patented small molecule compounds calledlanthionines that bind CRMP2 and inhibit or reverse CRMP2-dependent axonal degeneration,” Hensley said.

The investigators also are researching antibodies that could be administered to people with ALS, where they would block semaphorin binding to neural receptors and prevent the inappropriate activation of CRMP2 pathways.

Claudio Hetz, full professor at the Institute of Biomedical Sciences, Faculty of Medicine at the University of Chile in Santiago, was awarded an MDA research grant totaling $217,500 over a period of three years. The funds will help support Hetz’ study of protein misfolding and mislocation in amyotrophic lateral sclerosis (ALS).

The primary mechanism underlying nerve cell (motor neuron) death in ALS remains unknown. One hypothesis suggests that alterations in protein folding functions in a cellular compartment called the endoplasmic reticulum(ER) determine the aggregation and neurotoxicity of ALS-linked mutant SOD1 protein.

Hetz and colleagues have preliminary data that shows specific ER folding mediators called foldases are involved in cellular protection both in models of ALS and in human sporadic ALS spinal cord samples.

The team has demonstrated that induction of ER stress in motor neurons triggers a dramatic misfolding of normal SOD1 protein, resembling recent observations described in sporadic ALS-affected tissue. The investigators uncovered components of the stress pathway that mediate the abnormal misfolding of SOD1 and identified three foldases that can cause normal SOD1 to misfold.

In his new work, Hetz aims to define the impact of specific foldases on motor neuron dysfunction, and assess the possible therapeutic benefits of manipulating them in ALS.

“Since protein folding stress is a common event observed in familial and sporadic cases, our research may open novel possibilities for disease intervention in the near future,” Hetz said.

Claudio Hetz, a professor in the Faculty of Medicine at the University of Chile, was awarded an MDA research grant totaling $294,000 over a period of three years to study a potential new therapy aimed at rescuing motor neurons in amyotrophic lateral sclerosis (ALS). In ALS, some proteins do not fold into their required shape correctly, triggering stress-response pathways which can be detrimental to neurons. Hetz aims to use a gene therapy approach to target one of these stress response pathways, known as the “Unfolded Protein Response” (UPR). If successful, the work could point the way to a new therapeutic target at which to aim treatments for this fatal disease. 

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

MDA awarded $374,511 to Oliver Hobert, professor of biochemistry and molecular biophysics at Columbia University, New York, to study the function of the TDP43 gene, mutations in which can cause ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

"In order to diagnose and treat ALS, it is important to understand the molecular events that underlie this disease," Hobert said. The TDP43 gene, known to cause ALS in humans, "works in a manner that is not understood. Our goal is to better understand the function of this gene."

Using the invertebrate C. elegans (nematode, or roundworm) model, Hobert's team will study the TDP43 gene in order to determine its function and possible interaction with other genes.

"Funding by the MDA means a great deal to us — not just because of the financial support but also because it motivates us to direct our basic research toward questions that are medically relevant," Hobert said.

Funding for this MDA grant began August 1, 2010.

Fenghua Hu, research scientist at Cornell University in Ithaca, N.Y., was awarded an MDA research grant totaling $360,000 over a period of three years to study the effects of TDP43 gene mutations in a model of amyotrophic lateral sclerosis (ALS).

Mutations in the TDP43 gene have been shown to cause ALS in some instances. Even in individuals with ALS who do not have TDP43 mutations, the TDP43 protein usually clumps together abnormally, forming aggregates within muscle-controlling nerve cells called motor neurons. “This suggests that the misbehavior of TDP43 protein could cause neurodegeneration,” Hu says.

The TDP43 protein found in the aggregates is often just a piece of the whole protein, indicating it has been cleaved. It is also often “tagged” with a smaller protein, called ubiquitin, used by the cell to mark a protein for destruction and recycling. “However, the role of TDP43 fragments and ubiquitination in disease progression is still not clear,” Hu says.

She plans to develop a model of ALS using zebrafish, a small and fast-growing fish used as a lab model for the study of many diseases. In the fish, she will study how TDP43 protein fragments induce toxicity and cause neurodegeneration, which should help researchers develop better targets for therapy in ALS.

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

MDA awarded a grant totaling $412,500 over a period of three years to Eric Huang, professor of neuropathology at the University of California in San Francisco. The funds will help support Huang’s work to create cellular and mouse models of amyotrophic lateral sclerosis (ALS) that is caused by mutations in the fused in sarcoma (FUS) gene.

Genetic data have shown that mutations in the FUS gene can be identified in more than 5 percent of people with familial (inherited) ALS.

Huang and colleagues hypothesize that these FUS mutations interfere with the normal production of proteins, ultimately leading to the degeneration and death of the nerve cells called motor neurons.

The team’s goal is to create cellular and transgenic mouse models of FUS-related ALS that can be used to determine the ways in which mutant FUS proteins cause motor neuron degeneration.

Studies in the new FUS transgenic mice are expected to provide novel insights into the disease process and therapeutic targets for ALS, Huang said.

Justin Ichida, assistant professor in the department of stem cell biology and regenerative medicine at the University of Southern California in Los Angeles, was awarded an MDA research grant to elucidate the mechanisms underlying ALS (amyotrophic lateral sclerosis) caused by mutations in the C9ORF72 gene. Ichida will investigate whether mutations in the C9ORF72 gene lead to a loss of the protein’s normal function or a gain of a toxic new function, and how this could affect motor neuron health in ALS. Knowledge gained from this research will help inform scientists about whether future therapy development should aim to increase the protein’s normal function or reduce toxic downstream effects of altered C9ORF72 protein.

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

Update (April 1, 2015): Adrian Israelson is now at Ben-Gurion University of the Negev in Beer Sheva, Israel.

MDA has awarded a research development grant totaling $180,000 over three years to Adrian Israelson, a postdoctoral researcher at the University of California, San Diego in La Jolla, Calif. The funds will help support Israelson’s study of the underlying mechanisms governing motor neuron (nerve cell) death in SOD1-related familial ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

Israelson noted that mutant SOD1 has been shown to inappropriately associate with the cellular "energy factories," called mitochondria that are responsible for generating the power to run all cellular processes — but only in nervous system cells.

He previously has demonstrated in cell culture and in an ALS rat research model that mutant SOD1 binds directly to a key protein channel called VDAC1, which controls the import and export of chemicals required by mitochondria for power production. He also has shown that the misfolded portion of mutant SOD1 that is present in spinal cord mitochondria binds to the VDAC1 channel, inhibiting its conductance and compromising the energy supply for motor neurons.

Israelson's new work will focus on the ways in which mutant SOD1 protein associates with mitochondria, and whether and how that interaction affects the energy factories' function, possibly leading to motor neuron death. In addition the data may shed light on how modification of mutant SOD1 misfolding and the protein's association with mitochondria might affect mutant SOD1 toxicity.

Findings from these studies may provide valuable insight needed for development of therapies that either slow or prevent the degenerative process in ALS.

"Generous funding from MDA is very important," because of the Association's commitment to stopping rare diseases, Israelson said. "Thanks to the support of MDA, we’re able to keep investigating neuromuscular diseases that otherwise might go underfunded and unstudied."

Funding for this MDA grant began February 1, 2011.

Research scientist Dena Jacob at Thomas Jefferson University in Philadelphia, received an MDA grant totaling $180,000 for research into decreasing cells' resistance to therapeutic medications in ALS (amyotrophic lateral sclerosis, or Lou Gehrig’s disease).

Jacob plans to study a "transporter" protein called P-glycoprotein, or P-gp, which belongs to a class of "transporter" proteins that pump drugs out of cells. P-gp recognizes a broad range of drugs and normally is found in cells of the blood brain and blood spinal cord barriers and also in some affected brain tissue, limiting drug penetration.

"P-gp expression in the spinal cord itself may impart overt pharmacoresistance (drug resistance) to ALS-affected cells and account for the poor therapeutic effect observed in [a number of previous] ALS clinical trials," Jacob said.

Jacob's findings could lead to re-examination of many previously unsuccessful clinical drug trials and encourage the development of new, combined therapeutic strategies for ALS.

"I am extremely honored and excited to be a Development Grant recipient of the MDA, an organization whose efforts and support are essential for advancing our understanding of neuromuscular diseases," Jacob said. "This funding will enable me to complete important experiments that will help us identify improved therapeutic strategies to target the mouse model of ALS and, ultimately, humans with this disease."

Funding for this MDA grant began August 1, 2010.

MDA awarded $294,183 over three years to Vasanthi Jayaraman, an associate professor in the department of biochemistry and molecular biology at the University of Texas Health Science Center in Houston. The funds will help support Jayaraman’s study of the molecular mechanisms underlying motor neuron death in ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

Jayaraman is particularly interested in a type of glutamate receptor known as calcium-permeable AMPA receptors. These cause toxicity and are thought to be a major trigger for selective motor neuron death and the resulting loss of muscle control in ALS.

Although AMPA receptor inhibitors have been shown to consistently decrease neuronal death in experimental models and increase survival time in a mouse model of ALS, they’ve not been tried in the clinic.

The challenge her research team has taken on, Jayaraman said, is to develop AMPA receptor antagonists that prevent activation of the calcium-permeable AMPA receptors without causing harmful side effects or affecting the function of other subtypes of glutamate receptors.

“With the funds provided by the Muscular Dystrophy Association,” Jayaraman said, “we are in a position to show the feasibility of these projects, which we believe will have high rewards in terms of being able to develop therapeutic agents toward ALS.”

Funding for this MDA grant began August 1, 2011.

Jie Jiang, 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 improve understanding of the disease mechanisms underlying the most common inherited form of ALS (amyotrophic lateral sclerosis).

Expanded repeated sections of DNA (GGGGCC hexanucleotide repeats) in a non-coding region of the C9ORF72 gene have been identified as the most common genetic cause of ALS and frontotemporal dementia (FTD), another neurological disease characterized by behavioral and language changes. It’s uncertain, however, if disease is caused by reduced levels of normal C9ORF72 protein and/or by toxic RNA and proteins manufactured using instructions encoded in the extra DNA.

Jiang and colleagues will work to determine whether the loss of normal C9ORF72 protein synergizes with toxic RNA and proteins to exacerbate disease in research mouse models.

Jiang’s work may guide direction of therapy development for C9ORF72 ALS/FTD.

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

MDA awarded a grant totaling $345,000 to Jean-Pierre Julien, professor at Laval University, Canada, for research into genetic variations in a protein called chromogranin B (CHGB) that has been shown to modify disease risk and hasten onset in a type of familial ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).

In previous studies, Julien's group discovered that CHGB interacts with mutant, or flawed, forms of the superoxide dismutase 1 (SOD1) protein associated with SOD1-mediated familial, or inherited, ALS.

The team studied variations in the chromogranin B gene, which carries the instructions for the CHGB protein, in a large group of people with and without ALS. Results showed that people with ALS were twice as likely to have a common CHGB variant called P413L than those without the disease. The P413L CHGB variant also correlated with a 2.2-fold greater relative risk for development of ALS, and among those with the disease, onset of symptoms occurred an average 10 years earlier for those with the variant than for those without it.

In its new work, Julien's group will conduct experiments in cultured nerve cells and in a strain of mice engineered to carry the human CHGB variant to test the hypothesis that P413L increases vulnerability of motor neurons. The investigators also aim to determine whether the variant affects CHGB's interaction with mutant SOD1 and uncover the exact mechanism by which it increases risk of ALS and modifies disease onset.

"MDA funding is timely and needed," Julien said, "to determine how this particular genetic variant increases risk of ALS and hastens disease onset."

Funding for this MDA grant began August 1, 2010.

Hong Joo Kim, a postdoctoral fellow at St. Jude Children’s Research Hospital in Memphis, Tenn., was awarded an MDA development grant totaling $180,000 over a period of three years to study new genes for a newly recognized disorder called multisystem proteinopathy (MSP).

MSP causes symptoms that are seen frontotemporal dementia (FTD) and Paget’s disease of bone (PDB), and in two diseases covered by MDA — amyotrophic lateral sclerosis (ALS) and inclusion-body myositis (IBM). “Patients with this rare, inherited multisystem disease may experience isolated IBM, FTD, ALS or PDB, which can be indistinguishable from other familial and sporadic cases of these disorders, or the disease may manifest in multiple tissues in the same patient,” Kim says.

While a gene has been discovered that causes MSP, this gene is not responsible for the disease in other families. That led Kim and colleagues to use modern gene-hunting techniques to search for other potential candidates.

They found two such genes, called heterogeneous nuclear ribonucleoproteins (hnRNPA2B1 andhnRNPA1), which bind to a cellular messenger called RNA. Alterations in binding and transport are increasingly seen as likely causes of multiple diseases in the nervous system. “Studying the genes that cause this rare multisystem syndrome represents a unique opportunity to identify a fundamental molecular defect that underlies multiple common age-related diseases,” Kim says.

The disease-causing mutations they have found appear to increase the likelihood that individual units of protein will clump together, a feature of many other neurodegenerative diseases. Kim plans to generate fly and mouse research models that contain either the normal or mutant forms of hnRNPA2B1 and A1, in order to study their effects. “We seek to recapitulate the full spectrum of MSP, to elucidate the molecular mechanism of pathogenesis, and to identify target genes that are misregulated in hnRNPA2B1- and A1-associated diseases,” she says, which may lead to new strategies for treating MSP and other diseases.

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