Neurologists say it’s time for a moonshot for their patients with ALS, the neurodegenerative disease that is always deadly, often in just a few years or less.

ALS, also known as Lou Gehrig’s disease, hijacks people’s ability to move, and ultimately, to breathe. Clinicians know there’s some combination of genetic susceptibility and environmental factors, but they can’t usually tell a patient what specifically sparked their disease. They can’t slow it down, either.

Now, a $3.6 million project funded by the National Institutes of Health will allow a team of experts to intensely explore the intersection of environmental exposures, genetics, inflammation and other factors, in order to better determine what makes someone more likely to develop ALS.

Dr. Stuart Batterman

Co-principal investigator Stuart Batterman, Ph.D., from the U-M School of Public Health, said a bold design is needed that pushes environmental exposures to the forefront — things like pesticides, metals, industrial chemicals, and air pollution and other toxicants found in air, water, furnishings or food.

“There are so many potential environmental toxins that it would be extremely difficult to pinpoint which are important without a broad approach,” said Batterman, a U-M professor of environmental health sciences, global public health and civil and environmental engineering.

Dr. Stephen Goutman

“We need to understand the mechanisms by which these exposures cause disease so that we can begin to develop treatments that are personalized to an individual’s previous exposure,” said co-PI Stephen Goutman, M.D., M.S., an associate professor of neurology and the director of U-M’sPranger ALS Clinic. “In addition, once we know more about the environmental mechanisms that cause ALS, there is real hope that we can prevent people from getting ALS in the future by reducing exposure to these triggers.”

Goutman said a combination of new therapeutic targets and public health preventative strategies is the ultimate goal of the four-year project.

“Given that we are seeing more and more individuals with ALS every year, there is no better time than now to initiate these important investigations,” said co-PI Eva Feldman, M.D., Ph.D., the Russell N. DeJong Professor of Neurology, director of the U-M ALS Center of Excellence(link is external) and director of U-M’s NeuroNetwork for Emerging Therapies.

Researchers will compare blood samples from 400 patients with ALS who have contributed to the U-M ALS Biorepository, housed in the Feldman laboratory, to a control group of 200 blood samples from research participants without ALS. The team will also analyze individual environmental exposures and polygenic risk scores to build new computer models for ALS risk and prediction.

“The time is ripe for undertaking this work, given the recent advances in sequencing and computational approaches to integrate large sets of heterogeneous multi omics data,” said co-principal investigator Maureen Sartor, professor of computational medicine and bioinformatics and of biostatistics at the School of Public Health. “We believe this is a unique opportunity to really take the field in a new direction.”

Dr. Eva Feldman

“ALS is a devastating disease for our patients and for their loved ones,” Feldman said. “We need a better answer to the common question, ‘Why did I get ALS?’ Precision health will help us get there.”

This project is one of four ALS initiatives just funded by the National Institutes of Health to “dramatically advance the understanding of what triggers and drives the rapid progression of ALS” as part of the NIH Common Fund’s High-Risk, High-Reward program. It’s one of the NIH director’s Transformative Research Awards.

“The science put forward by this cohort is exceptionally novel and creative and is sure to push at the boundaries of what is known,” NIH Director Francis S. Collins, M.D., Ph.D., said about the program. “These visionary investigators come from a wide breadth of career stages and show that groundbreaking science can happen at any career level given the right opportunity.”

Co-investigators, all from U-M, include Kelly Bakulski, Ph.D., an assistant professor of epidemiology; Alla Karnovsky, Ph.D., an associate professor of computational medicine and biology; Bhramar Mukherjee, Ph.D., a professor and the chair of biostatistics, a professor of epidemiology and a professor of global public health; and Lili Zhao, Ph.D., an associate professor of biostatistics.

This research will be conducted under grant number 1 R01 NS127188-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

The World Health Organization (WHO) estimates that 4.2 million people die annually as a result of outdoor air pollution.  It has been causally linked to multiple neurodegenerative diseases, leading it to be identified as one of the 12 modifiable risk factors for Alzheimer’s disease by the Lancet Commission.  A University of Michigan multidisciplinary consortium believes the same is true for amyotrophic lateral sclerosis (ALS).

ALS is a progressive neurodegenerative disease that hijacks people’s ability to eat, speak, move and eventually breathe.  It is almost always deadly, usually in just two to four years.  There is no cure for ALS and currently nothing to slow its progression.  There is an urgent need for new insights to identify modifiable risk factors.

Environmental factors represent novel sources of risk for ALS, which are both prevalent and controllable. The Centers for Disease Control (CDC) has awarded what is expected to amount to more than $1 million over three years to study the premise that air pollution is a likely, but understudied, ALS environmental risk factor, which could be controlled to minimize the burden of ALS in the population.

Dr. Sara Adar

“Even though air pollution is a likely risk factor for ALS, there has been relatively little research to date on this question,” explains Dr. Sara Adar, Associate Chair of Epidemiology. “Our research project is exciting because it newly investigates this question here in Michigan. If we find associations between long-term exposures to air pollutants and ALS, it suggests that environmental policies or local actions targeting emission sources could be an effective way to reduce the number of people living with ALS.”

Drs. Eva Feldman and Stephen Goutman will lead a research collaborative that includes Dr. Adar from the School of Public Health and Lili Zhao from the Department of Biostatistics. They will first identify how air pollution exposure associates with both ALS risk and progression.  Then, they will employ the current knowledge that air pollution is linked to inflammation in the immune system and our own research tying inflammation in the immune system to ALS progression and survival to understand a possible connection between air pollution and inflammation in the disease.

Dr. Eva Feldman & Stephen Goutman

What does this mean for those affected by ALS? Pranger ALS Clinic Director and Co-PI Dr. Stephen Goutman explains: “We will take what we learn about the association between air pollution, the immune system and ALS to identify therapeutic targets using immunomodulatory drugs or identify existing FDA approved drugs that can be repurposed.  This really provides new hope in our fight against ALS.”

The proposed studies have potentially broad utility for future biomedical research and bedside treatment, as well as public health and personal interventions.

“Patterns of air pollution and immune profiles can be applied to neurodegenerative diseases other than ALS,” explains Co-PI Dr. Eva Feldman, Director of the NeuroNetwork for Emerging Therapies and ALS Center of Excellence.  “Our proposed study examines hundreds of ALS subjects and controls, and the associations found here can then be applied to therapeutic development in a multitude of diseases.”