May 12, 2008 

A Diverse Research Portfolio: The ALS Association Research Program Takes a Multi-pronged Approach to Speed Therapy Development

By Richard Robinson

The ALS Association hopes to make promising new therapies available to ALS patients by leveraging novel technologies and fostering collaboration across complementary fields.  In its role as a leader in ALS research, The Association manages a diverse project portfolio through several different granting processes.  All grants are peer-reviewed and are of the highest scientific relevance to ALS.

Investigator-initiated grants. Each year, The Association selects the best from over 300 proposals from scientists working in the area of ALS and motor neuron biology. This program has already funded studies that have led to a better understanding of the mechanisms thought to underlie the ALS disease process.

Association-initiated grants. The Association also identifies gaps in our understanding of ALS and actively seeks top researchers to undertake studies to fill these in. These grants have funded international collaborations to identify new ALS genes, biomarker studies to diagnose ALS earlier, and development of new animal models, among other projects. 

Translational Research Contracts. To enable important lab findings to be translated quickly into potential treatments, The Association created a new initiative, TREAT ALS (Translational Research Advancing Therapies for ALS). This contract-based program forges relationships between academic institutions and industry to support the development of novel treatments, generate preclinical data, and support pilot clinic trials. The Association has also established the TREAT ALS/NEALS clinical trials network to improve access to clinical trials for patients throughout the United States.

For a sample of this diverse research portfolio, with short descriptions of representative projects, please see below.

To search through a database of all funded studies, Click here.

SOD1-Related Investigations

Gene mutations in Cu/Zn Superoxide Dismutase (SOD1) account for 2% of ALS. Several projects examine the role of the SOD1 protein in ALS and the potential therapeutic benefit of altering its properties.

Identification of protein modifiers of SOD1 aggregation: New Targets for ALS

A key feature of the mutated protein is that it aggregates, or clumps together, which may be toxic. Researchers will seek ways to prevent aggregation.

Role of Chromogranin-mediated secretion of superoxide dismutase mutants in ALS pathogenesis

Proteins called chromogranins promote movement of mutant SOD1 from inside to outside the cell, where it can trigger immune system reaction that worsens the disease. By further characterizing this interaction, researchers hope to determine whether blocking it may be beneficial.

Post-translational modification of SOD1 WT as a potential factor in sporadic ALS

Like many proteins, normal (non-mutated) SOD1 is modified after it is made. Some evidence suggests that certain modifications may cause non-mutated SOD1 to behave like the mutant version, which may help explain the many cases of ALS that are not due to inheritance of the mutated gene. This study will examine these modifications and determine if the provide targets for therapy.

Downregulation of SOD1 in the CSF of SOD1 G93A rats using antisense oligonucleotides

An antisense oligonucleotide is a short bit of nucleic acid (similar to the genetic material) that binds to and inactivates a target gene. This study seeks to develop a way to measure the effect of antisense treatment against mutant SOD1, the gene that causes about 2% of ALS cases. This will be needed in any clinical trial using antisense to target mutant SOD1.

Other Disease Mechanisms

Does selective Shh expression in mature motor neurons identify motor neuron subtypes of distinct vulnerabilities in the G93A SOD1 model of familial ALS?

Researchers will investigate whether Shh, a signaling molecule important in development, increases vulnerability of adult motor neurons, the cells affected in ALS.

Function of VAP-B in early secretory pathway and protein clearance system

Mutations in the VAP-B gene have been associated with ALS. The protein helps move other proteins through the cell, and the mutation causes protein clumping, which may be toxic. Understanding more about this protein and the behavior of the mutant may lead to new ideas for therapy.

Alterations in retrograde signaling lead to motor neuron degeneration

Motor neurons require movement in both directions along their very long extensions, called axons. A mutation that causes ALS impairs transport from the axon tip back to the cell body. Researchers hope to better understand this impairment in order to design therapies to mitigate its effects.

The role of tau neurotoxic fragment in ALS

Tau is a protein that helps maintain cell one of the cell transport systems, called microtubules. Tau fragments have been found in brains of ALS patients, but the significance of this is unknown. Researchers will characterize the distribution of tau throughout the brain in order to better understand its role in ALS.

Motor neurons die from too much stimulation. Motor neurons receive much of their stimulation from interneurons, and in ALS models, these cells appear to be overactive. Researchers will investigate this further and examine drugs that may control interneuron overactivity.

Improving Animal Models

ALS Model Development

Two strains of mice with the same SOD1 mutation have different times to onset of disease. Researchers have found the gene region than accounts for this difference and will further investigate it, perhaps revealing factors that influence onset in human disease.

Construction of Mouse Spinal Cord Gene Expression Atlas

Gene “expression” means using a gene to make a protein. Within the spinal cord, motor neurons and other cells have unique patterns of gene expression that influence their resistance and susceptibility to damage, among many other properties. But researchers have a very incomplete picture of expression in all these cells. This project will map gene expression in the spinal cord, providing a deeper understanding of cell function.

Transgenic zebrafish carrying mutant sod1: Characterization and a pilot modifier screen

The tiny zebrafish is widely used in many areas of biology, where its short life cycle and ease of care make it ideal for genetic and developmental studies. By creating an SOD1 model of ALS in zebrafish, researchers will be able to test hypotheses about ALS and the genes that increase risk or offer protection.

Risk factors for ALS

Role of Neuregulin-1 in promoting motor neuron survival

Neuregulin is a key factor in maintaining the connection between motor neurons and the cells around them, including cells that provide “insulation” and the muscle cells that motor neurons control. Understanding how neuregulin performs these functions should provide insight into how motor neurons lose contact with these cells in ALS.

HFE Polymorphisms and ALS

Mutations in the HFE gene cause a blood disease called hemochromatosis. A variant in the HFE gene has recently been linked to ALS. Researchers will investigate further to determine if this variant, or some other nearby gene, is responsible in these cases.

Amyotrophic lateral sclerosis, sport, physical activity and trauma. An international case-control study on genetic and environmental risk factors

Soccer players in Italy appear to be at increased risk for ALS. By examining in detail the history of sports participation, drug use, and other factors, investigators will shed light on which factors may be truly involved in this association.

New Therapeutic Strategies

Using iPS cells to generate ALS patient specific stem cell lines

This project will use cells from individual ALS patients to develop stem cells. Each new stem cell line created in this way may offer insights into commonalities and differences in the ALS disease process between individuals. The project also provides initial experience with developing individualized stem cell lines for future therapeutic applications.

Astrocytes support motor neurons and are also affected in ALS. Researchers will investigate whether an astrocyte protective factor, Nrf2, can be used to protect both astrocytes and motor neurons.

Clinical Trials

EAAT2 biomarker for clinical trial of ceftriaxone in ALS

Ceftriaxone is undergoing clinical trials in ALS. One effect of the drug is to increase EAAT2, which helps reduce the amount of potentially toxic glutamate in the environment of motor neurons. This study will develop means to monitor EAAT2 production during ceftriaxone treatment.

Identification and quantitation of protein biomarkers for ALS in the CSF and blood plasma

Biomarkers are identifiable compounds that allow researchers to track disease and response to treatment. In this study, researchers will identify and further characterize potential biomarkers from ALS patients, which may lead to better ability to monitor the disease, as well as deeper understanding of the disease process.

Glutamate Transporter Positron Emission Tomography (PET) imaging agents to monitor ALS therapy and disease

PET imaging is used to take pictures of the brain, but requires specific markers to show changes for different diseases and therapies. Researchers plan to develop a marker for the glutamate transporter, which helps reduce the amount of potentially toxic glutamate in the environment of motor neurons. This will allow better understanding of the transporter’s role in the brain of ALS patients, and whether its function can be improved therapeutically.

TREAT ALS/ NEALS Clinical Trials Network

This grant supports the ongoing collaboration between the Association’s TREAT-ALS initiative and the NEALS (Northeast ALS) clinical trials network, in order to facilitate more comprehensive analysis of data collected during clinical trials of ALS treatments.