NIH Funds Barrow Research of Imaging-Based ALS Biomarkers
Chad Quarles, PhD, director of the Neuroimaging Innovation Center at Barrow Neurological Institute, has received a $2.5 million grant from the National Institutes of Health to develop imaging-based biomarkers for amyotrophic lateral sclerosis. These new measures of disease progression and treatment effect could help accelerate clinical trials for ALS drugs.
ALS is a progressive neurodegenerative disease, meaning it causes the gradual deterioration and death of nerve cells. It specifically attacks motor neurons, which control voluntary muscle movements. Over time, people with ALS lose their ability to move, speak, eat, and breathe.
Although the rate of progression varies, ALS is a fatal disease with no known cure. The U.S. Food and Drug Administration (FDA) has approved a medication that prolongs survival. However, the benefit is modest at about three months.
Lack of ALS Biomarkers: A Bottleneck in Clinical Trials
Clinical trials abound for ALS, but many are impeded by the same roadblock: a lack of biological measures that can quickly and objectively show whether a drug is successful.
Although functional rating scales are validated instruments for measuring ALS progression, they are variable and subjective based on who is performing the assessment. It can also take several months or even years to see noticeable changes in a patient’s function.
“There needs to be a way to establish more quickly if drugs work, because if it takes a year or two years to figure out if a drug is a success or failure, it slows the whole pipeline down,” Dr. Quarles explained.
Biomarkers, such as blood sugar levels in diabetes or white blood cell counts in infections, provide researchers and clinicians with measurable indicators of the presence or progress of a disease. They can also show whether a person’s disease is responding to treatment.
To meet the need for biomarkers in ALS trials, Dr. Quarles and his team are working to develop a noninvasive imaging approach known as relaxivity contrast imaging, or RCI.
This magnetic resonance imaging, or MRI, approach is uniquely sensitive to changes in muscle fibers, such as decreases in diameter and density.
“Within MRI, there are ways to adjust the type of information you can gather,” Dr. Quarles said. “Most commonly we use MRI to evaluate anatomy. But you can tune MRI to be sensitive to specific biological properties, and that’s what we’re doing here.”
Thinking Outside the Brain: From Cancer to… Tongues?
Dr. Quarles and his team began exploring the mostly uncharted waters of RCI in the context of brain cancer.
When cancerous cells weaken the blood-brain barrier, contrast dye injected into the bloodstream can successfully permeate the brain. Once there, the dye enables the MRI image to highlight properties of the cells, such as their density, size, and shape.
But when that protective barrier isn’t broken down, the dye doesn’t get through—limiting the use of RCI for brain imaging. That led Dr. Quarles to wonder: Where else in the body and to what other diseases could he apply this new contrast-enhanced MRI approach?
Dr. Quarles homed in on muscle degeneration and applied for a grant from the Flinn Foundation to explore the idea further. The $100,000, two-year grant enabled him and his team to gather early data showing the sensitivity of RCI to muscle fibers in the legs.
Equipped with this promising new data, Dr. Quarles applied for an R61/R33 grant specifically created by the NIH to unearth entirely new biomarkers for rare neurodegenerative disorders.
The five-year grant will support the discovery and validation of new imaging-based biomarkers in preclinical models. It will also allow Dr. Quarles to show proof-of-concept in human patients.
The discovery phase of the project will consist of computer simulations. Dr. Quarles and team will use the state-of-the-art computational laboratory in the Neuroimaging Innovation Center and the approach they’ve developed over the past decade.
“This is where we answer questions like: How do we interpret the information we get? How should we acquire the data? How should it be used in a trial setting?” Dr. Quarles explained.
In the preclinical validation phase, Dr. Quarles will test a drug in a rat model of ALS to mimic a clinical trial. The drug was identified by Robert Bowser, PhD, the director of the Department of Translational Neuroscience whose own research focuses on ALS biomarkers.
“The final phase is optimizing the protocols in healthy controls and then doing a study in ALS patients,” Dr. Quarles said. “In a clinical trial, you want to know: Are there changes before and after you give the drug? We want to image every few months with this approach to see whether we can detect changes in the underlying muscle biology that precede whatever functional deficits you might see a year later.”
And this time, Dr. Quarles and his team won’t only be looking at muscles in the legs.
“While our early work only involved leg muscles we know that ALS can impact other muscle groups,” Dr. Quarles said. “So we’re establishing the same measures in the muscles of the arm and the muscles of the tongue, which is the onset site for some patients with ALS. Ultimately, we want to develop a whole-body muscle imaging approach so we can better characterize each patient’s condition and their response to therapy.”
The Barrow Difference: From the Computer to the Patient
Dr. Quarles hopes RCI will not only be useful in ALS but in other diseases as well, such as Duchenne muscular dystrophy and cardiomyopathies.
Along with Dr. Bowser, Dr. Quarles is collaborating with neurologist Shafeeq Ladha, MD, director of the Gregory W. Fulton ALS and Neuromuscular Disease Center at Barrow.
“What makes these kinds of studies unique to Barrow is the strong partnership and integration of basic scientists with clinicians,” Dr. Quarles said. “As a translational research group, we want to take discoveries from computer simulations and preclinical studies and advance these technologies into patient care and clinical trials.”