Nine New MDA Grants Focus on Stopping ALS

by Amy Madsen on Thu, 2011-09-01 10:50
 
 
Article Highlights:
  • MDA has awarded funding to help support nine new ALS research projects.
  • The ALS grants are part of 40 new grants awarded by MDA, funding worldwide research in 22 of the more than 40-plus diseases in MDA's program.

In its latest round of funding this July, MDA awarded nine grants totaling more than $2.5 million to research projects focused on uncovering the causes of, and developing therapies for, amyotrophic lateral sclerosis (ALS).

The new grants were awarded to investigators at labs in the United States and Canada.

Five are research grants, awarded to independent investigators who direct their own research and that of others.

The other four are development grants that support research conducted by scientists who are members of a research team and who study under the guidance of a principal investigator.

How does MDA decide which projects to fund?

MDA’s Board of Directors approves all new grants based on recommendations from the Association’s Scientific and Medical Advisory Committees (SAC and MAC). Grant applications are scored and recommended for approval based on the capabilities of the applicant, the scientific merit of the project, and the proposal’s relevance to developing treatments for the diseases in MDA’s program.

 


 

Vasanthi Jayaraman in her lab
“With the funds provided by the Muscular Dystrophy Association,” Jayaraman said, “we are in a position to show the feasibility of high-risk, high-impact projects that we believe will have high rewards in terms of being able to develop therapies for ALS.”

MDA awarded a research grant totaling $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 are helping support Jayaraman’s study of a type of glutamate receptor known as a calcium-permeable AMPA receptor.

AMPA receptors 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.

Jayaraman and colleagues plan 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.

 

a bioluminescent mouse
Noninvasive, 3-dimensional images reveal early neuronal stress in live bioluminescent “reporter” mice. Signals imaged from these animals can be used as valid biomarkers to isolate distinct elements of the ALS disease process, Kriz said, including indications representative of presymptomatic stages of the disease.

Jasna Kriz, associate professor in the department of psychiatry and neuroscience at Laval University, Quebec City, Canada, was awarded an MDA research grant totaling $445,086 over three years to help generate ALS imaging reporter mice.

Previously, Kriz and colleagues developed mouse models with bioluminescent and fluorescent genes (from fireflies) that allow researchers to visualize ALS-related events such as neuroinflammation and neuronal damage in the brains and spinal cords of living mice. They even were able to detect distinct and disease-specific signals linked to presymptomatic stages of the disease.

Now Kriz plans to use the previously generated models to create the ALS imaging reporter mice, which will enable scientists to visualize, in live mice, different elements of the ALS disease process such as neuroinflammation and neuronal damage in the brain and spinal cord, as well as real-time response to experimental therapies.

The 3-dimensional representations will make it possible for scientists to make assessments over a period of time and in a noninvasive manner.

 

microscope scan of microglial cells
A high-magnification, high-resolution confocal microscope scan of microglial cells, which provide support to nerve cells, taken from the mouse lumbar (lower back) spinal cord. “We have a strong interest in the role of microglia in terms of their ability to enhance inflammatory conditions found in ALS,” Grill said.

MDA awarded a research grant totaling $202,508 over three years to Raymond Grill, assistant professor in the department of integrative biology and pharmacology at the University of Texas Health Science Center in Houston.

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 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, and slightly extends survival time. Licofelone has completed phase 3 testing in humans for osteoarthritis, but is not yet FDA approved.

The researchers expect the combination treatment will reduce inflammation, protect motor function, rescue motor neurons and prolong survival in the SOD1 mice.

If favorable results are obtained, the group plans to attempt to “fast-track” the two-part treatment into clinical development.

 

Clotilde Lagier-Tourenne
“It is our hope that understanding of TDP43 and FUS normal functions and disease-associated properties will serve as the foundation for development of potential therapeutic approaches for the vast majority of ALS patients,” Lagier-Tourenne said.

Clotilde Lagier-Tourenne, a postdoctoral fellow at the University of California, San Diego, in La Jolla, was awarded an MDA development grant totaling $180,000 over a period of three years. The funds are helping support Lagier-Tourenne’s study of the effects of ALS-causing mutations in two RNA binding proteins, TDP43 and FUS.

Abnormal function of these proteins appears to disrupt the processing of RNA (the chemical step that directs protein synthesis). Lagier-Tourenne and colleagues’ proposed set of studies aims to identify clinically useful biomarkers associated with TDP43 and FUS mutations.

A biomarker is a biological indicator that scientists can use to measure phenomena such as the onset of disease or progression of a disease, how a disease is responding to a treatment or how a drug is behaving in the body.

Those that Lagier-Tourenne’s team is working to find are expected to describe the set or sets of characteristics present in TDP43- or FUS-associated ALS, and may indicate potential targets for the development of therapies in ALS.

 

Alfred Goldberg
“My laboratory has received generous support from the Muscular Dystrophy Association over the years,” Goldberg (right, above) said, noting that this has made possible a number of important findings about protein metabolism in muscle and the mechanisms of muscle atrophy.

Alfred Goldberg, professor of cell biology at Harvard Medical School in Boston, received an MDA research grant totaling $410,777 over three years to support his ongoing research into the mechanisms underlying muscle atrophy.

In his previous work, Goldberg helped clarify the general mechanisms of muscle atrophy resulting from motor neuron disease, inactivity, various systemic diseases and myopathies.

Goldberg and his research team will focus now on mechanisms that normally inhibit a protein called FoxO, which has been implicated in stimulating muscle protein breakdown.

Of particular interest to the team are two proteins, PGC1-alpha and SIRT1, both of which previously have been shown to inhibit FoxO function.

 

Don Cleveland
Don Cleveland is working to refine current knowledge of the role of mitochondrial dysfunction in ALS.

MDA awarded a research grant totaling $429,983 over three years to Don Cleveland at the Ludwig Institute for Cancer Research in La Jolla, Calif. The funds are helping support Cleveland’s research into mitochondrial dysfunction and toxicity in the inherited SOD1-associated forms of ALS.

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 is working to determine at what disease stage and in which nervous system cell types mitochondrial damage occurs; whether the ensuing mitochondrial dysfunction is a cause or a consequence of neuronal degeneration; and whether rescue of individual mitochondrial functions or an increase in mitochondrial activity may alter the ALS disease course.

 

Youngjin Lee
Lee and colleagues hypothesize that altered activity of the transporter protein MCT-1 in ALS results in insufficient metabolic support for motor neurons from glial (support) cells including oligodendrocytes, astrocytes and Schwann cells. Pictured: Lee examines magnified images of primary oligodendrocytes.

 

Youngjin Lee, postdoctoral associate in the department of neurology at Johns Hopkins University School of Medicine in Baltimore, was awarded an MDA development grant totaling $179,997 over three years. The funds are helping support Lee’s study of a type of transporter protein called MCT-1.

Lee’s research team has generated mice specifically designed to help elucidate the activity, regulation and function of MCTs and, specifically, MCT-1’s role in neurodegeneration in ALS.

Lee and colleagues are testing the hypothesis that the death of motor neurons in ALS may be caused by the failure of glial cells to provide enough necessary energy components called substrates — particularly one called lactate, which is delivered by MCT-1.

 

 

astrocytes in the central nervous system
Astrocytes in the central nervous system, magnified 100 times. Neurons appear round and red. The astrocytes (motor neuron support cells) are yellow and activated, signifying an inflammatory response in the nervous system. Following nerve-cell injury, moderate inflammation is helpful for motor neuron regeneration, but uncontrolled inflammation may result in the death of nerve cell body instead.

 

MDA awarded a development grant totaling $180,000 over three years to Junping Xin, research associate at the Neuroscience Institute, Loyola University Medical Center in Chicago, and Edward Hines Jr. Veterans Administration Hospital in Hines, Ill.

The funds are helping support Xin’s research into the effects of immune system dysfunction, particularly with regard to CD4+ T cells, which, when dysregulated, may cause an increase in disease-related inflammation in people with ALS.

In addition to their contribution to immune system dysfunction, however, it’s known that CD4+ T cells also play an important role in supporting motor neuron survival. Xin and colleagues plan to describe the mechanisms of the CD4+ T cell-mediated neuroprotection, as well as the effects that result when the cells become dysfunctional.

A better understanding of both the normal and dysfunctional roles of CD4+ T cells should provide a better understanding of their possible use in new experimental therapies to treat ALS.

 

 

 

Muscle fibers

Pictured: (A) Normal muscle fibers; (B,C) Muscle fibers with perturbed mitochondria. Dashes indicate muscle diameter, and asterisks illustrate the space between individual muscle fibers. Normal muscle fibers adjoin each other and are longer in diameter than muscle fibers with perturbed mitochondria. In contrast, muscle fibers with disruption in mitochondrial function separate from each other and appear either split (B) or angulated (C).

MDA awarded a development grant totaling $180,000 over three years to Edward Owusu-Ansah, a postdoctoral fellow in the department of genetics at Harvard Medical School in Boston. The funds are helping support Owusu-Ansah’s research into the molecular mechanisms underlying normal and abnormal function in the cellular power factories known as mitochondria.

A system consisting of five large protein complexes, known as the functional oxidative phosphorylation system, or OXPHOS, plays a crucial role in the generation of energy (ATP) in the mitochondria.

In a fruit fly research model, Owusu-Ansah plans to examine the intracellular signaling that contributes to disruption of mitochondrial functioning, which, in turn, leads to compromise of a range of biochemical and metabolic activities in cells and resulting muscle degeneration.


For more information

Visit MDA's Grants at a Glance, an online showcase highlighting new MDA research projects, to learn more about all of the 40 new grants recently approved by MDA for neuromuscular diseases in its program.

For a comprehensive list of the approximately 300 research projects currently receiving support from MDA, download the Active Research Grants PDF.

Amy Madsen
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