MDA has awarded 10 grants totaling nearly $3.5 million to fund research projects focused on uncovering the causes of, and developing therapies for, ALS.
The new grants went to investigators at labs in the United States, Canada and Israel.
Newly funded projects include research into the role of the immune system in the disease; early-stage (presymptomatic) biological markers ("biomarkers"); gene therapy; the molecular causes of degeneration of motor neurons (muscle-controlling nerve cells); combined-drug therapy; the function of the TDP43 gene and its interactions with other genes; and risk factors and modifiers of disease onset in SOD1-related genetic ALS.
MDA's Board of Directors met in Los Angeles July 16, where it reviewed and approved these new grants and 28 others based on recommendations from the Association's Scientific and Medical Advisory Committees. Grants were 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 ALS. The effective start date for the grants was July 1, 2010.
These new grants are in addition to some 330 grants currently being funded by MDA, 82 of which focus on ALS. MDA conducts two grant-funding cycles annually, and most awards are for projects lasting over several years.
Below is a list of ALS grants approved by MDA’s Board. For more detailed information about each of these, see the new online feature Grants at a Glance.
Studying pre-symptomatic familial ALS: Michael Benatar, associate professor of neurology and epidemiology at Emory University in Atlanta and co-director of the MDA clinic at that institution, received $525,000 to continue research into early-stage FALS (familial ALS). Benatar's group will study pre-symptomatic individuals with mutations in SOD1 and other ALS susceptibility genes, such as TDP43 and FUS. The team aims to better define the pre-symptomatic stage of familial ALS and identify environmental factors that might modify the age of disease onset among genetically susceptible individuals.
Genes that interact with TDP43: Daniela Zarnescu, assistant professor in neuroscience at the University of Arizona in Tucson, received $375,000 to conduct gene and drug discovery research in a drosophila fruit fly model that carries a mutation in the TDP43 gene. Mutations in this gene are associated with a genetic form of human ALS. Zarnescu's group will conduct genetic screening tests on a TDP43 fruit fly model of ALS in order to identify genes that interact with TDP43, some of which may be involved in disease causation or progression. The group also will screen drugs in search of one or more that can repair the defects in the fruit fly model.
Studying function of TDP43 gene: Oliver Hobert, professor of biochemistry and molecular biophysics at Columbia University in New York City, was awarded $374,511 to study the TDP43 gene, mutations in which can cause a genetic form of ALS. Using the invertebrate C. elegans (nematode, a type of worm) model, Hobert's team will study the TDP43 gene in order to determine its function and possible interaction with other genes.
Combined cell/gene therapy in ALS: Daniel Offen, head of the neurology laboratory at Tel-Aviv University in Israel, received $359,700 for research into a combined cell and gene therapy approach for ALS. Offen's research team will engineer progenitor cells (a type of immature cell that forms muscle), to express various combinations of proteins supporting motor neuron health. The investigators will observe the cells' effects on disease in an ALS research mouse model and in human muscle cells.
TDP43’s effect on motor neurons: Wilfried Rossoll, assistant professor at Emory University in Atlanta, received $358,653 for research into the effects on motor neurons of TDP43 protein, which has been implicated in ALS. Preliminary data generated by Rossoll's team suggests that TDP43 plays a role in mRNA processing (one of the steps in the cell's protein-making process) in the long axons (fibers) that conduct electrical impulses from nerve cells to muscle cells. The team will test the hypothesis that decreased levels of TDP43 in mRNA-protein complexes in these axons may contribute to the degeneration of motor neurons in ALS.
Studying motor neuron degeneration: Shanthini Sockanathan, associate professor of neuroscience at the Johns Hopkins University School of Medicine in Baltimore, was awarded $347,832 for research into the molecular causes of motor neuron degeneration in diseases including ALS. Sockanathan's team will study the physical and biological characteristics of the GDE2 research mouse model (which lacks the GDE2 protein) and monitor the progression of motor neuron degeneration in older animals. The investigators plan to remove the protein in mice at different times during development to determine at which stage or stages GDE2 loss causes degeneration.
Identifying a possible ALS risk factor: MDA awarded $345,000 to Jean-Pierre Julien, professor at Laval University in Quebec, Canada, to study variants of a protein called chromogranin B in ALS. In previous work, Julien's group discovered that chromogranins interact specifically with mutant (flawed) forms of SOD1. (SOD1 mutations are known to be a cause of ALS.) The aim of the current project is to describe the exact mechanism by which a chromogranin B variation called P413L may act as a risk factor for ALS and as a modifier of disease onset.
T cells' effect on motor neurons: MDA awarded $330,000 to Stanley H. Appel, chair of the department of neurology at the Methodist Neurological Institute in Houston, to study the ability of immune-system T cells to protect the nerve cells (motor neurons) in ALS. 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 could lead to therapeutics based on increasing the numbers and effectiveness of these cells to help protect neurons in people with ALS. Appel is a member of MDA’s Board of Directors, chairs the MDA Medical Advisory Committee and co-directs the MDA Neuromuscular Clinic in Houston.
Role of toxic TDP43 in ALS development/progression: Brian Freibaum at St. Jude Children's Research Hospital in Memphis, Tenn., was awarded $180,000 for research into the mechanism by which toxic TDP43 protein leads to the development and progression of some forms of ALS. Freibaum has planned a three-tiered approach to uncover the protein's role in the disease using various tissues of fruit flies engineered to carry the human TDP43 gene; human cell lines and mouse motor neurons; and a fruit fly research model.
Clearing excess glutamate in ALS: Research scientist Dena Jacob at Thomas Jefferson University in Philadelphia was awarded $180,000 for research into increasing the effectiveness of drugs designed to clear excess buildup of the neurotransmitter glutamate in ALS. Jacob plans to test the hypothesis that a protein called P-gp may make ALS-affected cells resistant to medications designed to reduce glutamate levels and possibly to other drug therapies.