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

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.

Magdalena is a writer with a passion for bridging the gap between the people performing research, and those who want or need to understand it. She writes about medical science and drug discovery. She holds an MS in Pharmaceutical Bioscience and a PhD — spanning the fields of psychiatry, immunology, and neuropharmacology — from Karolinska Institutet in Sweden.
Magdalena is a writer with a passion for bridging the gap between the people performing research, and those who want or need to understand it. She writes about medical science and drug discovery. She holds an MS in Pharmaceutical Bioscience and a PhD — spanning the fields of psychiatry, immunology, and neuropharmacology — from Karolinska Institutet in Sweden.
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  1. Mani says:


    why PM1 does not work in human? Because it has to many side effects or it does not inhibit the TDP-43 in human? Any infos abput that?


    • Magdalena Kegel says:

      Dear Mani,
      PM1 gave rise to gut problems in the animals and despite good effects on neurodegeneration, the mice in the study died early.

      • Mani says:

        Thanks four your reply! Why the mice died early? Because of side effects or because it doesn’t works on to right way with the TDP-43? Any cause why they don’t life much longer? Or does he die faster then normaly?


        BR Mani

        • Magdalena Kegel says:

          Dear Mani,
          The researchers did not elaborate on that point. They showed that PM1 prevented the hazardous effects of TDP-43 on mitochondria, prevented neurodegeneration and even restored movement and cognitive function in previously disabled mice. It is possible that the researchers do not know at this point why the mice died early, since the effects of a drug molecule can be very complex and take a long time to investigate.

          • Mani says:

            Thanks again for the reply, but the question is still open, died the mice faster order slower compared to the normally ALS mice? How long does the ALS mice life and how long does the ALS peptide Mice life? The point is not clear for me, it heals the motoric function, ok, but is this getting worse again and then he die as like the normally ALS mice (SOD1,or?) or does he died without motoric defizits?

            I ask because if he died without the regullary motoric deficits, maybe a side effect of the peptid killde he and maye if they find other ways the inhibit the TDP-43 without this side effects, the job is done.

            Hope we can clear the point, i think this is interesting for all reader of the article.


          • Magdalena Kegel says:

            Dear Mani,
            These are all indeed very relevant questions, which I am certain that the research team have or are currently addressing. However, I do not have the information since they did not provide further details in their report. It is possible that they have more data that they did not publish yet, and you are free to contact the researchers directly.

            Whenever we report on a study, the link to the original study is provided, and the contact information to the corresponding author can always be found there.

  2. John carlson says:

    Love these reports but never hear any results from them….nothing ever gets done within a timely matter. Some patients do not have 10 years to wait!

    • Magdalena Kegel says:

      Dear John,
      I can understand your frustration with the slow pace of treatment development, but scientifically robust studies take a long time.

      There are numerous unknown factors that treatment developers can encounter, and many approaches that look promising in early studies don’t make it all the way to approved drugs because it turns out that the treatment is either unsafe or is not beneficial to patients. It would be unethical and illegal to release treatments that have not been shown to be safe and to really help patients.

  3. Ray Haberly says:

    Will they still have to go through the clinical trial process if the are able to use one of the orphan drugs in FDA library.

    • Magdalena Kegel says:

      Dear Ray,
      For a treatment to get officially approved for the treatment of ALS, the drug would need to go through trials in ALS patients. Doctors are, however, allowed to prescribe drugs “off-label,” meaning that they are prescribed for another disease than they are approved for.

  4. John says:

    So the advantage is mainly off label use? This research sounds promising! If the drug can be prescribed off label,can they use the data from patients who use drug off label?

    • Magdalena Kegel says:

      Dear John,
      The advantage is not only off-label use. For a drug that is already approved for another disease, it only takes limited clinical trial testing in ALS patients, usually one or two Phase 3 trials.

      A drug that is not yet approved need to go through extensive studies examining its effects—both on the intended target and other effects that may contribute to side-effects, possible toxicity, studies of how the drug is metabolized, how it may interact with other drugs and so on. And all these things need to be done before testing in humans can begin.

      For data from off-label use to be meaningful, someone would need to design a study, in which other parameters are also taken into account. Such investigations of real-world use do exist, but they can’t form the basis for an FDA approval of a drug for a new indication, for which controlled clinical trials are needed.

  5. Sandy says:

    Hi Magdelena,


    What exactly is the chemistry of the compound that worked in mice? Has ALSTDI been recruited to help with the assay development? They have been doing this for years.


    • Magdalena Kegel says:

      Dear Sandy,
      The researchers have filed a patent application for the molecule and so, they have not disclosed any details.

  6. Keith Smith says:

    So, more progress, is that a tiny glimpse of daylight at the end of the tunnel? Maybe, but it’s definitely progress. 2 years ago I postulated a chemical synthesis of ubiquilin that could have the ability to recognise the misfolded protein TDP-43 and remove it from the MRNA, so it doesn’t get delivered to the neurons, clump up and starve them. over simplified a little but you see my point. dead end science I was told, no future treatment there was the general opinion. But my thanks in particular go to Prof. Wang, not just for his efforts but for having to courage to look beyond the naysayers and for following the chemical highway to a potential treatment that, if it can be adapted, will literally halt the disease progression and quite possibly reverse some of the symptoms. Good luck Prof Wang

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