Astonishing Effects of Compound on ALS in Mice Intensifies Search for Human Therapy

Preventing the TDP-43 protein from entering mitochondria may be a treatment option for amyotrophic lateral sclerosis (ALS), according to a new report.

But while blocking the abnormal process is possible in mice, the compound used is not suitable for humans. To overcome this, researchers are using multiple approaches in their search for a drug candidate that mimics the actions of the experimental compound, but can be used in humans.

The study, “Motor-Coordinative and Cognitive Dysfunction Caused by Mutant TDP-43 Could Be Reversed by Inhibiting Its Mitochondrial Localization,” was published in the journal Molecular Therapy. It showed that mice with severe movement disability and dementia improved drastically when treated with the experimental compound called PM1.

“The result astonished everyone in my lab,” Xinglong Wang, PhD, assistant professor of pathology at Case Western Reserve University School of Medicine, said in a press release.

“Even mice with severe motor and cognitive impairment showed a rapid improvement in disease symptoms following the infusion of the peptide, PM1,” Wang said. “Previously demented mice were able to learn mazes again and those with severe motor impairment were soon able to walk normally. It seemed to be miraculous. We were stunned.”

In an earlier study, published in the journal Nature Medicine last year, the team discovered that TDP-43 — a protein often associated with ALS — can cause disease by accumulating in mitochondria. These cell structures have the key task of producing energy, but when TDP-43 choked up the machinery, the energy-making processes were disturbed to the point that cells died.

In the earlier work, the team showed that it was possible to prevent degeneration of neurons by preventing TDP-43 to get inside the mitochondria. The new study presents more proof that the approach works.

But part of the work, which may be more important, is the team’s search for a better drug. To get a treatment as fast as possible to patients, they are currently screening the Food and Drug Administration’s library of 700 approved orphan drugs (drugs that target rare diseases).

With the help of an assay the team developed, they can quickly learn if a drug affects TDP-43 accumulation in mitochondria. If the approach turns out to be successful, it could greatly reduce the time needed to bring a treatment to patients, as the compounds in the library are all approved for human use.

“This will be much faster and less expensive than creating a new drug, testing it, getting FDA approval, and bringing it to market,” Wang said. “We know that we could potentially help millions of people if we could find a drug that safely and effectively eradicates TDP-43. Our most cost-effective and efficient way to do that rapidly is to thoroughly investigate the FDA library.”

Wang and his team are also developing new compounds that could prevent TDP-43 from entering mitochondria.

In addition to ALS, the team believes their findings may have bearing on frontotemporal dementia, a condition that may be related to ALS, and on diseases such as Alzheimer’s, which is typically not linked to ALS.