- ALS Stem Cell Trial
- ALS Biorepository
- Understanding Environmental Risk Factors of ALS
- ALS Stem Cell Research Projects
- The Immune Response in ALS
- Studying the Head and Neck Manifestations of ALS
ALS STEM CELL TRIAL
Eva L. Feldman, M.D., Ph.D., is the principal investigator of the first FDA-approved human clinical trial in which millions of stem cells are injected directly into the spinal cords of ALS participants. After extensive and careful study of neural stem cell properties and their effectiveness in animal disease models, the approach progressed into two human clinical trials. Phase 1 results from 15 ALS participants showed that stem cells could be safely injected into their lumbar (lower) and cervical (upper) spinal cords. Phase 2 then confirmed the safety of transplantation of increasing numbers of stem cells in 15 additional participants. Comparison of these results to historical control subjects further demonstrated that the approach shows promise and warrants further research.
- Long‐term Phase 1/2 intraspinal stem cell transplantation outcomes in ALS (Annals of Clinical and Translational Neurology; May 2, 2018)
All patients seen at the Multidisciplinary ALS Clinic at Michigan Medicine are invited to participate in ongoing research projects that will aid in the understanding of disease mechanisms and provide insight into potential therapeutic options.
One important resource, the University of Michigan ALS Biorepository, collects detailed clinical histories, residential and occupational histories, as well as blood, urine, skin, and other biospecimens from ALS patients and healthy control subjects for use in laboratory research projects. This resource includes samples from more than 600 participants, including longitudinal samples. This unique resource is utilized to advance our understanding of ALS, which is illustrated below.
UNDERSTANDING ENVIRONMENTAL RISK FACTORS OF ALS
PNR&D researchers are interested in understanding how environmental exposures contribute to the susceptibility and progression of ALS. While studies to date have focused on the state of Michigan, we believe these findings hold importance for all ALS community members. This research is accomplished by understanding specific environmental risk factors (such as occupational hazards), measuring pollutants in biosamples of participants, and understanding modifications that environmental exposures have on genetics.
Residential and occupational risk factors: An area of focus is understanding whether certain occupations, hobbies, or chemical exposures increase one’s risk of developing ALS. One of our findings indicates that reported exposure to pesticides increases the risk of having ALS, a finding consistent with other studies. We continue to review these detailed occupational and residential histories to identify other risk factors.
Pollutant measurements: Persistent organic pollutants (POPs) are classes of chemicals that have been used as pesticides, flame retardants, and coolants. These chemicals are known to be toxic to the nervous system and as a result, many have been banned. However, they survive for decades in the environment resulting in ongoing exposures. We have found that these chemicals are more likely to be measured in participants with ALS, specifically the organochlorine pesticides. We believe that further investigation into how these chemicals affect the nervous system can help us better understand causes of ALS.
- Association of environmental toxins with amyotrophic lateral sclerosis (JAMA Neurology; July 1, 2016)
Genetic modifications: Environmental exposures are able to alter the way that genes are expressed, or turned on/off, via mechanisms such as epigenetic modifications and DNA methylation. These alterations in gene expression could be an explanation for why persons with no known gene abnormalities develop ALS.
Current PNR&D research focuses on studying DNA methylation and microRNA differences in blood and postmortem spinal cord samples from ALS and control participants to identify these critical modifications which may in turn lead to better mechanistic understandings and druggable disease targets. Further, by understanding the role of small vesicles (exosomes) in development and progression of ALS we may be able to understand how ALS spreads. Typically, these exosomes gather and transport molecules, including those involved in epigenetic mechanisms, from cell to cell to enable cell communication. In collaboration with the University of Michigan Department of Biomedical Engineering, we are using a new technology called the ExoChip to isolate and study the contents of these small vesicles from blood, brain, and spinal cord samples from participants with ALS.
- Expression of microRNAs in human post-mortem amyotrophic lateral sclerosis spinal cords provides insight into disease mechanisms (Molecular Cellular Neuroscience, March 2016)
- Amyotrophic lateral sclerosis: mechanisms and therapeutics in the epigenomic era (Nature Reviews Neurology, May 2015)
- Identification of epigenetically altered genes in sporadic amyotrophic lateral sclerosis (PLoS One, December 2012)
To model ALS, examine disease mechanisms, and screen for novel ALS therapies using stem cell technology, the PNR&D is generating cellular models of both familial ALS and sporadic ALS using induced pluripotent stem cell (iPS) technology. iPS cell lines are established from ALS participant skin samples, which are collected through the University of Michigan ALS Biorepository, by introducing transcription factors that revert the cells to a pluripotent, or stem cell-like, state. These pluripotent cells can then be grown in the laboratory and induced to form large numbers of nervous system cells that can be used in numerous types of investigations. While previous cellular and animal models are based on the less common forms of ALS that are associated with a known genetic mutation, these cellular models will provide more broadly applicable insights into the molecular and cellular mechanisms that underlie both familial and sporadic ALS.
Using iPS cells, PNR&D investigators are collaborating with Dr. Sami Barmada, a University of Michigan neurologist, to study how alterations in specific RNA- and DNA-binding proteins like TDP43 and Matrin 3, which are involved in both familial and sporadic ALS cases, contribute to the disease. Recent work has shown that these proteins contribute to RNA destabilization and neurodegeneration, providing much-needed insight into the mechanisms of ALS onset and progression. The resulting insight may facilitate the development of new therapeutic approaches for ALS.
Overall, the stem cell research program in the PNR&D has the possibility to revolutionize our scientific and clinical approach to ALS by providing new insights into disease pathogenesis and identifying innovative approaches to treat ALS.
- Abnormal RNA stability in amyotrophic lateral sclerosis (Nature Communications, July 2018)
- Matrin 3-dependent neurotoxicity is modified by nucleic acid binding and nucleocytoplasmic localization (eLife, July 2018)
In addition to studying how genetic and environmental factors contribute to impaired motor neuron survival in ALS, PNR&D researchers are also interested in understanding how alterations in the immune response drive disease. Previous studies have demonstrated that the immune system contributes to the chain of events leading to ALS; however, most immune studies have utilized mouse models of familial ALS to identify key cellular contributors.
Using the University of Michigan ALS Biorepository, PNR&D investigators are evaluating the role of innate and adaptive immune cells in human subjects with both familial and sporadic ALS who have provided blood and tissues samples. With the University of Michigan School of Public Health, PNR&D scientists have identified specific immune cell populations that may play a role in ALS, including CD4 T cells, neutrophils, and natural killer (NK) cells. These observations in turn have led to multiple interlocking projects in both human patients and mouse models of ALS that are identifying several potential therapeutic targets.
Current work is now characterizing how NK cells contribute to disease and determining how immune cell populations change throughout the disease course using monthly patient samples. In addition, ALS animal models are being used to study how targeting specific immune cell populations, like NK cells, may represent a means to eventually treat ALS. Overall, these projects are supporting improved approaches to diagnose and assess progression of the disease, and will ultimately expand our understanding of ALS pathogenesis.
- Correlation of peripheral immunity with rapid amyotrophic lateral sclerosis progression (JAMA Neurology, December 2017)
ALS causes not only loss of motor neurons in the spinal cord, but also in a critical area of the brain called the brainstem that control facial and neck muscles. About one quarter of ALS patients develop motor neuron loss in the brainstem first, call bulbar ALS. However, almost all people with ALS will exhibit bulbar symptoms at later disease stages. Loss of bulbar motor neurons results in symptoms that impact the patient’s ability to speak, swallow and breathe. PNR&D investigators are using an animal model of ALS to study these head and neck manifestations of ALS. The goals of these studies are to determine the causes of these problems and help develop better treatments to improve the quality of life for patients with ALS.