Researchers at Houston Methodist have identified two biomarkers with the potential to track ALS disease progression and assess the efficacy of novel treatments, a promising finding in the elusive hunt for objective measures of the deadly neurological disease.

Dr. Stanley Appel and David Beers, Ph.D., uncovered the biomarker candidates for amyotrophic lateral sclerosis — LOX-1 and oxidized LDL, both measures of peripheral oxidative stress — in a small Phase II A clinical trial investigating a new immunotherapy treatment for the disease. They then confirmed the association in a serum analysis.

"We didn't set out to find biomarkers — it was more of a happy accident," says Dr. Appel, director of the Johnson Center for Cellular Therapeutics at Houston Methodist. "We noticed that the trajectory of the patient's condition was closely mirrored in the levels of these two markers of oxidative stress."

If validated, the proteins would constitute the first clinically relevant blood test available to inform management of the disease. Researchers have been searching for meaningful biomarkers for ALS for several decades.

Launching a successful spin-off

The biomarker study, published in Annals of Neurology, followed up on an open-label clinical trial on regulatory T cells, or Tregs, immune cells that help protect against harmful inflammation that accelerates the progression of ALS.

Participants in the clinical trial, published in Neurology, reported that they felt much better as they went on Treg therapy and much worse as they went off it. LOX-1 and ox-LDL levels reflected the stabilization and deterioration of the subject's clinical status, plummeting after the initiation of infusions and skyrocketing after the cessation of therapy.

"This indicated to us that oxidative stress was a) an important part of the progression of this disease; b) suppressed by the administration of Treg therapy; and c) powerfully expressed in these two biomarkers, LOX-1 and ox-LDL, so much so that it merited a study of its own," explains Dr. Appel, an early pioneer in Treg therapy for neurodegenerative disease.

In the Annals of Neurology study, the researchers went back and looked at preserved blood samples from a previous Phase I clinical trial to see if a similar pattern emerged.

"Not only did the numbers align beautifully with overall burden of disease, we also found that ox-LDL levels, in particular, were indicative of a rapid escalation of the disease, something we have been looking for better ways to predict," Dr. Appel says.

Trust but verify

Currently, the only tool available for clinicians to monitor the severity and pace of disease progression is the amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) — a questionnaire which relies on patient self-report.

"When a kidney patient goes to see the nephrologist, we don't ask the kidneys how they're doing," Dr. Appel says. "But when a patient with a brain disorder goes to see the neurologist, what do we do? We ask the brain to essentially report on itself."

Given that half of all patients with ALS experience neurocognitive decline during the course of their disease, there are some obvious limitations to this approach. Even if there are no processing errors to speak of, patients may feel obligated to be positive, particularly when they're trying a new therapy.

"Patients want to get better, their families want them to get better, their clinicians want them to get better," Dr. Appel says. "It would be nice, and, frankly, a lot more scientific, if we had an independent way to verify that they are, in fact, doing better on this or that therapy. That's how it is with kidneys or cancer or almost any other field."

Next generation ALS research

The ability to compare different clinical trials using common, clinically validated biomarkers to measure response could push research on the disease to a new level.

"Amyotrophic lateral sclerosis is a complex disorder with a very diverse disease pathway," says Dr. Appel. "A more standardized way to test treatments would enable smaller, more meaningful clinical trials, which could help focus the direction of research and encourage more industry support."

Likewise, for clinicians trying to keep up with the latest research in order to figure out which experimental therapy might be right for their patient, biomarkers would help ensure they're comparing apples to apples, not apples to oranges to grapes.

"Unfortunately, we're still in early days when it comes to monitoring therapeutic benefits in ALS," Dr. Appel acknowledges. "Biomarkers represent a collective leap forward. We'll still have a long way to go, but it will bring us closer together and give us a common dialect."