Barrow Receives Over $2.1M in DoD Grants for ALS Research

Barrow Neurological Institute recently received three grants, totaling more than $2.1 million, from the United States Department of Defense (DoD) for amyotrophic lateral sclerosis (ALS) research.

Two of the grant-funded projects will explore potential neuroprotective therapies for ALS. One will examine a promising drug already prescribed to lower cholesterol, while the other aims to develop a new gene therapy to activate a specific cell signaling pathway linked to ALS. The third project will evaluate blood vessel changes as a possible indicator of disease progression—and potentially a therapeutic target—by comparing neuroimaging scans, biofluid specimens, and clinical measures of people with and without ALS over time.

“Barrow has a longstanding commitment to ALS research and drug development,” said Robert Bowser, PhD, Chief Scientific Officer at Barrow. “It is quite rare for an institution to receive three Department of Defense grants for ALS research in a single year. This accomplishment highlights both the impactful research performed at Barrow and our mission of translational research.”

Often referred to as Lou Gehrig’s disease, ALS involves the deterioration and death of the nerve cells responsible for voluntary muscle movements. This causes the muscles to gradually weaken and waste away, affecting vital functions like movement, speech, eating, and breathing. An estimated 5,600 people in the United States are diagnosed with ALS each year.

“Our research scientists at Barrow are showing how translational medicine should occur,” said Shafeeq Ladha, MD, division director of the Gregory W. Fulton ALS and Neuromuscular Disease Center at Barrow. “Translational science aims to make a real difference by streamlining the path of new therapies from the lab to the bedside and speeding up the development of new therapies for neurological disease.”

A New Use for Lovastatin? Cholesterol-Lowering Drug Shows Promise for ALS

A team of researchers led by Brad A. Racette, MD, Senior Vice President and Chair of Neurology at Barrow, mined de-identified U.S. Medicare data in hopes of discovering associations between existing medications and a lower risk of ALS. Through their large case-controlled study, they narrowed in on three drug candidates.

Dr. Racette partnered with Tim Miller, MD, PhD, at the Washington University School of Medicine in St. Louis to test those drugs in the most widely used mouse model of ALS: the SOD1 model. The SOD1 gene mutation is the most common cause of familial ALS. Most cases of ALS, however, are considered sporadic—meaning they occur in people with no known family history of the disease. Dr. Miller and his team noted encouraging observations in the mice that received the drug lovastatin: a preservation of motor neurons, reduced protein aggregates associated with SOD1, delayed symptom onset, and prolonged survival.

“Our study provided compelling evidence that lovastatin exerted a true disease-modifying effect,” Dr. Racette said. “However, our Medicare data includes both sporadic ALS patients and genetic ALS patients, which suggests that lovastatin has the potential to slow progression in both forms of ALS. We will follow up on these findings in our grant.”

The two laboratories published the results in Annals of Neurology, presenting the preliminary data that earned them nearly $667,000 from the DoD.

The two-year grant will support the Racette Laboratory as they work to validate these findings in a more recent and larger Medicare dataset. Not only will this data increase the sample size, but it will also allow Dr. Racette and his team to investigate newer cholesterol-lowering drugs. Additionally, the lab will probe de-identified electronic health records from CommonSpirit Health, a partner of Barrow. These records will offer more detailed information than Medicare claims data, like clinical lab results, that can be accessed if needed.

The Miller Laboratory will test lovastatin and other statins in two additional mouse models of ALS—the TDP43 and Profilin1 models—to determine if the results align with those in the SOD1 model.

“We want to be able to identify which cholesterol-lowering medications may be best suited for a human trial,” Dr. Racette said. “You could argue that because cholesterol-lowering drugs are safe and already available that you could just go to human trials, but so many studies like that just fail. We’re trying to leverage this DoD grant to come up with the drug and dose that’s most likely to be effective.”

Dr. Racette said statins offer an additional benefit to their safety and availability: They’re often free with insurance coverage.

“If this drug slowed progression by, let’s say, 10 or 15 percent and doesn’t cost anything, that would be pretty remarkable—even if it’s not a cure,” he explained.

Moreover, this research could provide valuable information about neuroprotective mechanisms in ALS. In other words, it may offer insights into the ways a therapy can prevent the death of motor neurons.

“If we demonstrate that lovastatin is truly effective in humans,” Dr. Racette posited, “then the question becomes: Why is it effective? What can we do to make it more effective?”

“Ultimately,” he continued, “we may be able to tease out the pathways by which this is working and create even better targeted therapies to slow disease progression.”

Going Viral: Developing a Retinoid-Activating Gene Therapy for ALS

David Medina, PhD, an assistant professor in the Department of Translational Neuroscience at Barrow, is exploring a non-pharmaceutical approach to protecting motor neurons in ALS. His grant from the DoD culminates nearly a decade of work involving the retinoid signaling pathway.

Dr. Bowser and Rachael Sirianni, PhD, received a grant to target this cellular signaling pathway in ALS while Dr. Medina was a postdoctoral fellow in Dr. Bowser’s lab. Retinoids are chemically derived from vitamin A and often used for skin care. By binding to specific cell surface receptors, these chemical compounds can regulate gene expression.

Multiple preclinical studies have suggested benefits of retinoids for neurological diseases, but these therapies have failed in clinical trials.

“The thing is, with most retinoids, you can’t deliver them very well for systemic use,” Dr. Medina said.

Drs. Bowser and Sirianni tasked Dr. Medina with creating nanoparticle formulations as a method for delivering retinoids, particularly adapalene. They hoped that encapsulating the drug within these tiny containers—too small to even be seen with an ordinary light microscope—would help it cross the blood-brain barrier more effectively.

Dr. Medina then tested the nanoparticles in a mouse model of ALS. His findings supported previous data that activating the retinoic acid signaling pathway may be neuroprotective. However, the nanoparticles still encountered the common challenges of retinoid delivery—namely off-target effects and rapid clearance from the body.

While continuing to pursue this project as junior faculty at Barrow, Dr. Medina sought out a collaboration with Fredric Manfredsson, PhD, to shift from a pharmaceutical approach to one involving gene therapy. Dr. Manfredsson joined Barrow as an associate professor in 2019 and specializes in developing viral vectors to deliver therapeutic genes into the body. Although these adeno-associated viruses work by infecting cells, they are modified so as not to cause disease.

“Projects like this really represent one of my roles at Barrow: to establish collaborations and enable other investigators a mean to deliver genetic therapeutics,” Dr. Manfredsson said. “This project truly embodies the type of synergy that we are working hard to build within the Department of Translational Neuroscience at Barrow.”

The viral vectors will deliver short hairpin RNA to cells, instructing them to reduce the activity of CYP26 enzymes. The therapy will specifically target these retinoic acid-degrading enzymes in the sites most affected by ALS progression: the spinal cord and motor cortex. This work seeks to validate the use of the retinoid signaling pathway and of adeno-associated virus technology for delivering new ALS therapies.

The pivot to a gene therapy approach appealed to the DoD, who granted Dr. Medina close to $782,000 to develop the project over two years.

“When we hit a funding lull, Barrow Neurological Foundation was there to support it so that we could keep collecting preliminary data and improve our application,” Dr. Medina said. “I think it’s a very interesting pathway, and I just didn’t want to let it go.”

Simultaneously, Dr. Medina obtained funding from the Arizona Alzheimer’s Consortium to apply this gene therapy to a mouse model of Alzheimer’s disease. So far, he and Dr. Manfredsson have developed a working version of the viral vector in a dish and are beginning to test it in a mouse model.

“Being at Barrow, having the collaborators that are here, I think we’re in a perfect position to apply this to different degenerative diseases,” Dr. Medina said. “At Barrow, it’s very easy to go down the hallway and ask anybody for a collaboration.”

Teaming Up to Illustrate Blood Vessel Changes in ALS

Nadine Bakkar, PhD, an assistant professor in the Department of Translational Neuroscience at Barrow, also enlisted the help of her colleagues at Barrow to delve into blood vessel changes in the brain associated with ALS. These cerebrovascular changes have emerged in scientific literature as a feature of many neurodegenerative diseases and, based on evidence from mouse models, researchers suspect these changes precede nerve cell death in ALS.

Dr. Bakkar’s two-year DoD grant of about $707,000 builds upon collaborative research with Dr. Bowser and the Translational Genomics Research Institute (TGen).

“Looking at postmortem tissue, we did extensive studies with sequencing and histological staining to characterize how the blood vessels in the brain and the surrounding cells are disrupted in ALS,” Dr. Bakkar said. “We found that the blood-brain barrier becomes leaky.”

Seeking a way to validate this finding in living patients, Dr. Bakkar approached Dr. Bowser about the clinical study infrastructure he had already built with the Target ALS Foundation. Barrow is a site for the Target ALS Study, which collects longitudinal biofluid samples—blood, CSF, and urine—and clinical measurements of speech and respiratory function from volunteers with and without ALS to make them available for the international research community. She proposed expanding the clinical research study to include magnetic resonance imaging scans of the blood-brain barrier, with the help of Barrow neuroimaging scientist Ashley Stokes, PhD, and a molecular-level analysis of the biofluid samples.

“The Target ALS study is very extensive in terms of collecting biofluids and functional assessments,” Dr. Bakkar said. “Linking this to neuroimaging and the biomarkers of vascular health gets these different areas of research to talk together. It also gives us the most information possible in the least amount of steps for the patients.”

Dr. Stokes uses an advanced MRI method known as spin- and gradient-echo (SAGE) to study blood vessel changes, because it can provide information from both large and small blood vessel networks at once.

“The approach of our team to investigate complementary cerebrovascular biomarkers is critical to understand how these changes contribute to disease progression,” Dr. Stokes said. “Combining our advanced neuroimaging biomarkers with molecular biomarkers may reveal underlying factors that contribute to ALS. I am grateful for the opportunity to work with Dr. Bakkar and this team of dedicated researchers to further our understanding of this devastating disease.”

Dr. Bakkar hopes the knowledge garnered with this grant will lay the groundwork for a therapeutic target to prevent or delay ALS progression. Additionally, it could provide valuable insight into how brain barrier function and dysfunction affect drug delivery.

“That’s not only important for ALS,” she said, “but for all of neuroscience.”