MDA Awards $2 Million in ALS Grants

Six new MDA grants totaling $2 million have been awarded to research projects seeking to uncover the basic mechanisms that drive ALS (amyotrophic lateral sclerosis), with an eye toward the development of future therapies. The grants took effect Feb. 1.

"It's exciting to see that recent scientific advances in ALS have spurred the funding of promising new areas of research," said MDA Vice President of Research Sanjay Bidichandani. "That's what happens when researchers let science lead the way."

ALS a multisystem disorder

Not long ago, it was thought that ALS affected only the motor neurons (nerve cells) that control muscles. Involvement of other "non-motor" systems was thought to be rare. But recent research has shown that ALS is a multisystem disorder that involves:

  • cell types other than motor neurons, such as central nervous system astrocytes and oligodendrocytes;
  • parts of cells, such as the mitochondria (cellular "energy factory") and the endoplasmic reticulum (membrane surrounding a cell);
  • body systems besides the central nervous system, such as the immune system; and
  • various genetic modifiers and biological pathways.

Each of the six new grants awarded by MDA approaches the ALS puzzle from a different angle, building on new scientific insights into the disease.

ALS 'modifier' genes

Previous research has shown that disease severity in transgenic mice (such as the SOD1 ALS research mouse model) depends on the genetic backgrounds of the mice. It's suspected that differences in the disease process in these mice are the result of modifier genes (genes that affect other genes).

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; pinpoint the responsible gene within the region; and test whether the gene also affects severity in other models of motor neuron disease.

Heiman-Patterson, who did the previous research upon which this grant is based, is section chief of neuromuscular disorders at Drexel University College of Medicine in Philadelphia, and medical director of the MDA/ALS Center of Hope at Drexel University College of Medicine.

Semaphorin signaling

The role of molecules called semaphorins in motor neuron degeneration is the subject of MDA’s $328,153 grant 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.

Hensley's group hypothesizes that semaphorins signal axons (the long fibers that extend and carry information away from motor neuron cell bodies) to move away from muscle and "collapse" backward toward the spinal cord. The investigators say their research implicates a protein called collapsing response mediator protein-2 (CRMP2) in this process of motor neuron axon degeneration.

Hensley and his team have invented and patented small-molecule compounds called lanthionines that bind CRMP2 and inhibit or reverse CRMP2-dependent axonal degeneration. Now the group will test whether treatment with lanthionines has any effect on axon degeneration in the SOD1 research mouse.

The team also will test the Ac-rER peptide (peptides are similar, but smaller than, proteins) to see whether it slows ALS progression in the SOD1 mouse. A third part of the project involves the deployment of antibodies that could be administered to people with ALS to block semaphorins from binding to neural receptors and prevent the inappropriate activation of CRMP2 pathways.

It’s hoped this research will lead to investigational new drug applications and clinical trials in people with ALS.

Protein misfolding

One hypothesis for motor neuron death in ALS is that alterations in protein-folding functions in a part of the cell called the endoplasmic reticulum (ER) cause protein clumps called aggregates and neurotoxicity.

MDA has awarded $217,500 to Claudio Hetz, full professor at the Institute of Biomedical Sciences, Faculty of Medicine at the University of Chile in Santiago, to help support his study of protein misfolding and mislocation in ALS.

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

The team has demonstrated that inducing 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.

Because protein folding stress is a common event in familial and sporadic cases, this research may open novel possibilities for disease intervention, Hetz said.

FUS mutations

Mutations in the fused in sarcoma (FUS) gene have been identified in more than 5 percent of people with familial (inherited) ALS. It’s hypothesized that FUS mutations interfere with the normal production of proteins, ultimately leading to motor neuron degeneration and death.

MDA has awarded $412,500 to Eric Huang, professor of neuropathology at the University of California in San Francisco, to help support the creation of cellular and mouse models of ALS caused by mutations in the FUS gene.

These research tools will be used to pinpoint the various ways in which mutant FUS proteins cause nerve cells to die, and uncover targets for therapy development.

TDP43 phosphorylation

Abnormal TDP43 protein has been observed in the brain cells and spinal cord nerve cells of people with ALS, and mutations in the gene for TDP43 have been shown to cause inherited ALS in some families. However, the way in which abnormalities in the TDP43 protein cause motor neurons to die remains unclear.

Brian Kraemer, a research biologist in the Geriatrics Research Education and Clinical Center at the Veterans Affairs Puget Sound Health Care System in Seattle, received a $316,557 grant from MDA to study the connection between mutated TDP43 protein and motor neuron degeneration.

Kraemer noted that phosphorylation (the addition of chemicals called phosphates) to TDP43 at abnormal positions "is the most constant hallmark of ALS-related nerve cell destruction seen in post-mortem examination of the nervous systems of affected patients."

Kraemer and colleagues plan to identify the proteins responsible for TDP43 phosphorylation and then test in mice whether inhibition of the abnormal addition of phosphates to TDP43 could lead to a valid neuroprotective strategy in ALS.

Autophagy

One hallmark of a number of neuromuscular diseases is the presence in affected tissues of protein clumps called aggregates or inclusions. It’s unknown whether facilitating the clearance or degradation of these inclusions is beneficial.

To help determine the answer, MDA awarded $397,064 to Chris Weihl, assistant professor of neurology at theWashington University School of Medicine in St. Louis. The grant supports Weihl's research into a process called autophagy in skeletal muscle.

Autophagy, which means "self-digestion," is a cellular cleanup and garbage-disposal system. Cells use it to degrade and destroy abnormal cellular or protein components that otherwise could lead to toxicity and cell death.

Weihl and colleagues plan to test FDA-approved drugs reported to enhance autophagy to determine whether protein degradation via autophagy is neuroprotective. The group will test the drugs in a newly developed mouse model of myofibrillar myopathy.

In addition to its applicability to ALS, data gleaned from Weihl's studies may inform research in other disease areas, including the muscular dystrophies.

Therapy development requires multiple approaches

It's likely that a combination, or "cocktail," of therapies will be needed to exert a significant effect on the ALS disease process. Funding the study of multiple biological pathways and various targets is certain to help speed the therapy development process.

For more information about these new grants and others awarded by MDA, see Grants at a Glance, a slideshow feature with photos and information on the new MDA grantees and their research.


Video: MDA Vice President of Research Sanjay I. Bidichandani discusses the excitement behind certain new grants.

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