National ALS Biorepository Current Research

Studies approved for the use of National ALS Biorepository samples.

This list will be updated as new research proposals are approved by ATSDR.

BioRepositoryStudies
No Study Name Institution Investigator Sample Type Date
1 New!
Histologic investigation of extracellular innate checkpoint molecule CD47 in ALS motor neurons
University of Pittsburgh Medical Center Lauren Kokai, MD Brain and Spinal Cord Ongoing
2 New!
Development and validation of assays to determine target engagement in ALS clinical studies
QuArlis Daniel Elbuam, PhD CSF Ongoing
3 New!
The Influence of Inflammation in the Progression of ALS
University of Vancouver Honglin Luo, PhD Plasma Ongoing
4 New!
LBT-3627: A Novel Immunomodulatory Disease-Modifying Approach to ALS Treatment
Longevity Biotech Inc. Sarah Bertrand, PhD PBMC’s Ongoing
5 RNA-Sequencing based drug discovery in ALS Cerevance, Inc. Dr. Mark Carlton Serum, brain, spinal cord Ongoing
6 Assessment of Unbound Free Fatty Acids in ALS Plasma Center for Neurologic Study Richard Smith, MD Plasma Ongoing
7 Biomarkers in neuronal exosomes for assessment of ALS progression University of California Los Angeles (UCLA) Gal Bitan, PhD Serum Ongoing
8 Novel extracellular vesicle and molecular biomarkers of environmental exposure and disease progression in ALS Columbia University Medical Center Neil Shneider, MD, PhD Brain tissue, whole blood, hair Ongoing
9 Metals analysis Centers for Disease Control and Prevention (CDC) National ALS Registry Whole blood, serum, urine, urine hg Ongoing
10 Genomic Analysis National Institutes of Health Bryan Traynor, MD, PhD, MMSc, MRCPI DNA Ongoing
11 Mitochondrial DNA and Micro RNAs in Amyotrophic Lateral Sclerosis Columbia School of Public Health Pam Factor-Litvak, PhD Whole blood, plasma, brain and spinal cord Ongoing
12 Role of FUS protein in inflammation and neurodegeneration, as potentially applied to understanding the development of ALS Icahn School of Medicine at Mount Sinai Ivan Marazzi, PhD Human primary cells, Whole blood Ongoing
13 ALS risk, exposure sources, and effects on the unfolded protein response pathway Dartmouth College Elijah Stommel, MD PhD Fingernails Ongoing
14 Identification and characterization of potential environmental risk factors for ALS using the ATSDR ALS Registry cases and a control population. University of Pittsburgh Evelyn Talbott, DrPH DNA Ongoing
15 Targeting Ataxin-2 in Amyotrophic lateral sclerosis (ALS) University of Utah Stefan M. Pulst, MD Human primary cells Ongoing

Study Description:

1. Histologic investigation of extracellular innate checkpoint molecule CD47 in ALS motor neurons
In Amyotrophic Lateral Sclerosis (ALS), the underlying trigger of the catastrophic cascade of neuron functional decline, activation of immune cells, inflammation, tissue damage spread and hardening of the corticospinal tracts is unknown. CD47 is an extracellular protein used to self-identify all cells and functions by turning off the innate immune system (innate checkpoint). In this study, we will explore CD47 expression levels and location to determine if loss of surface CD47 or change in cell surface localization occurs with neural cellular dysfunction, possibly linking neural damage to innate immunity activation.

2. Development and validation of assays to determine target engagement in ALS clinical studies
Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig’s disease) leads to changes in and ultimately the death of nerves that control muscles. As these nerves decay they undergo a number of changes. Our work is focused on developing tests that can be used to determine the effectiveness of experimental therapies for the treatment of amyotrophic lateral sclerosis by demonstrating whether or not a particular therapy reverses the disease induced changes.

3. The Influence of Inflammation in the Progression of ALS
This research aims to understand how inflammatory responses, especially those aided by external stimulations such as virus infection, propel the progression of ALS. To further validate their hypothesis, they hope to obtain biological information from the blood of ALS patients with specific genetic mutations.

4. LBT-3627: A Novel Immunomodulatory Disease-Modifying Approach to ALS Treatment
Longevity Biotech is measuring the immune function in patients with amyotrophic lateral sclerosis (ALS). De-identified patient immune cell samples will be obtained and cultured in a dish where samples will be treated with the experimental compound LBT-3627. Function will be measured using a standard suppression of proliferation assay.

5. RNA-Sequencing based drug discovery in ALS
The study approach combines the detailed examination of gene expression in sections from human brain using immunohistochemistry (IHC) and in situ hybridization (ISH). On identification of proteins or mRNAs expressed in and restricted to motor neurons, our discovery process moves to sub-dissection of frozen human CNS, isolation of nuclei, fluorescence activating cell sorting (FACS) and RNA sequencing with bioinformatic analysis [Xu et al, in press].
In applying this approach in the context of amyotrophic lateral sclerosis (ALS), the aim is to identify genes expressed in distinct populations of motor neurons (upper or lower) dysregulated in disease. Ideally, the targets we identify through bioinformatic analysis of sequencing data should offer the potential for therapeutic intervention through both neuroprotective mechanisms or through stimulation of key receptors. Use of high-quality human CNS samples from normal and diseased donors is therefore key to their research. The primary aim is to isolate nuclei from upper and lower motor neurons by FACs and compare gene expression by RNA sequencing between neurons and glia from healthy donors and donors with ALS

6. Assessment of Unbound Free Fatty Acids in ALS Plasma
Measure profiles of unbound free fatty acids in the plasma of ALS patients to determine whether these may serve as a biomarker for the disease. Unbound FFAs were measured using fluorescently labeled mutated fatty acid binding proteins (probes). Nine FFAs comprise more than 96% of the long-chain FF in plasma. Using 20 different probes with complementary specificities for the 9 FFA we determined the concentrations of each of the 9 unbound FFA (profiles) in plasma and CSF samples obtained from the NEALS biorepository. We are requesting plasma samples from 100 ALS subjects. To the degree possible, we would like demographic information including: e.g., age, gender, race, limb vs. bulbar onset, disease duration, and drug usage.

7. Biomarkers in neuronal exosomes for assessment of ALS progression
To conduct a pilot, feasibility study measuring biomarkers longitudinally in neuronal exosomes isolated from the serum of a small cohort of patients with ALS. Exosomes will be isolated from the serum using the ExoQuick ULTRA kit (Systems Bioscience) followed by immunoprecipitation of neuronal exosomes as described previously (Yan et al., ACS Sensors, 2019). Following extensive washing the exosomes will be lysed and candidate biomarkers will be measured using ELISA (for protein biomarkers) or qPCR for RNA biomarkers). Patients with ALS (n = 30) from whom serum samples are available at two different time points 6-12 months apart.

8. Novel extracellular vesicle and molecular biomarkers of environmental exposure and disease progression in ALS
The study from the Columbia University Health Sciences will test new non-invasive ways for identifying possible toxic exposures to the brains of ALS patients. The study will explain which processes link exposures and progression of disease. The study will be the first to test whether extracellular vesicles from the central nervous system can be used as new biomarkers. These biomarkers will be measures of environmental exposures and disease progression in ALS. The researchers will test samples from persons with ALS for metals and pesticides. They will then match the exposure and patient specific transcriptomic signatures to ALS signaling pathways.

9. Metals analysis
There have been limited studies that measured environmental chemicals in specimens from persons with ALS. We will first focus on metals and metalloids, including mercury, cadmium, lead, manganese, arsenic, chromium, selenium, copper, and possibly others. We will examine the hypothesis that exposure to metals is associated with the getting ALS. We will use specimens that were collected as part of the ALS biorepository. We expect the sample size will be between 300 and 600. The biorepository does not include a control group. Therefore, we will use the NHANES data to obtain estimates of the distribution of metal levels for the US Population.

10. Genomic Analysis
DNA samples are evaluated for mutations in known ALS genes. The NeuroChip genotyping array is used. It is a low-cost, custom-designed array. It contains a tagging variant backbone of about 306,670 variants. 179,467 variants have been added. These added variants have been linked to diverse neurological diseases. These diseases include Alzheimer’s disease, Parkinson’s disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy.

11. Mitochondrial DNA and Micro RNAs in Amyotrophic Lateral Sclerosis
Recent advances in the molecular genetics have increased understanding of many of the genetic/familial forms of ALS and other motor neuron diseases. Nevertheless, most ALS cases cannot be attributable to genes alone. There is much to be learned from studying environmental factors in the etiology and progression of ALS and other motor neuron diseases. Recent evidence points to a role of oxidative stress in the etiology of ALS. Recent developments in molecular epidemiology suggest that changes in mitochondrial DNA (mtDNA) and microRNAs (miRNAs) are associated with oxidative stress. The best biological specimens to measure these novel biomarkers would be the motor cortex of the brain and the spinal cord. However, these tissues are not available until after death. In this project we will compare measures of mtDNA and miRNAs in the motor cortex, spinal cord, and blood. This will help us see whether blood adequately reflects their amounts in target tissues.

12. Role of FUS protein in inflammation and neurodegeneration, as potentially applied to understanding the development of ALS
Several pathogenic mutations have been identified in the genome of ALS patients. Each mutation is associated with varied phenotypes. The researcher’s lab studies the function of the protein FUS. FUS has numerous variants associated with ALS. To address the cause-effect relationship between inflammation and neurodegeneration the researcher aims to study the function of FUS along with other ALS implicated proteins in the context of susceptibility to infection.

13. ALS risk, exposure sources, and effects on the unfolded protein response pathway
The first phase of the proposed study will focus on comparing exposures to environmental pollutants (lead, mercury, and other heavy metals) in nails. Samples from ALS patients will come from the National ALS Biorepository. They will compare with those of controls from a large, nationally representative prospective cohort. This cohort is funded by the National Institute of Environmental Health Sciences.

14. Identification and Characterization of Potential Environmental Risk Factors for ALS using the ATSDR ALS Registry Cases and a Control Population
This research will study self-reported environmental/occupational exposure to metals, pesticides, and solvents for persons with ALS and controls. It will also study life-time air pollution exposure based on where people lived. The first aim will look at a variety of air pollution data. The second aim will verify self-reported exposures to solvents and pesticides using blood measures of persistent pollutants. In aim three we will study the relationship between environmental toxicants in human samples and key biological pathways and common genes associated with developing ALS.

15. Targeting Ataxin-2 in Amyotrophic lateral sclerosis (ALS)
In 1996 we discovered a gene that is mutated in a rare disorder known as spinocerebellar ataxia type 2, or SCA2. The mutated gene that causes SCA2 is called ATXN2. When mutated ATXN2 gains abnormal and toxic functions. For diseases caused by such “gain of function disease genes,” it is believed that treatments that lower or eliminate their function may be therapeutic. Recent studies have shown that lowering the amount of ATXN2 also improves the survival of mice with the same abnormalities causing ALS in humans. The underlying reason for that is related to the abundance of yet another protein called staufen. Staufen is overabundant when ATXN2 is mutated. We have shown that lowering staufen works essentially as well as lowering ATXN2 for treating SCA2 mice. We also shown that staufen is overabundant in cells that are abnormal in ALS. Our hypothesis is that therapeutics that target the abundance of staufen will be as effective for treating ALS as therapeutics that target ATXN2. Moreover, targeting staufen may be an effective therapeutic approach for the treatment of other progressive neurological disorders. This research will support future work on the producing a drug that targets staufen for the treatment of ALS and potentially other neurological diseases.

Page last reviewed: October 22, 2020