Credit: yourgenome.org; Original image source found here.

Worming Our Way to a Possible ALS Treatment

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Whether you’re a worm, fish, mouse or human, the process of controlling or contracting a muscle differs very little. In fact, much of biology is conserved from the simplest organisms all the way to humans. This is what makes animal models a valuable tool towards understanding human disease. It’s how University of Montreal researchers went from a list of 3,850 chemical compounds and a paralyzed roundworm, to a phase II human clinical trial for Amyotrophic Lateral Sclerosis, or ALS.

ALS is a fatal disease caused by the death of the motor neurons that control muscle movement. Early symptoms include mild muscle weakness and slurred speech, but as more neurons die, ALS prevents voluntary muscle movement altogether, progressively taking away patients’ ability to walk, speak, and swallow. Ultimately, most people suffering from ALS die from respiratory failure, their muscles no longer capable of opening the lungs to be filled with air.

There’s only a single drug currently available to treat ALS, and it’s only modestly effective, prolonging survival by just a few months. That’s why, six years ago, two University of Montreal scientists, Dr. Alexander Parker and Dr. Pierre Drapeau, set out to find a more effective treatment for ALS. Their first step was to genetically modify two organisms to use as models of the disease. They chose the millimeter-long nematode worm Caenorhabditis elegans, and the small tropical freshwater zebrafish.

While a worm that’s barely visible to the naked eye and a fish that the uninitiated might easily mistake for a minnow might seem like odd choices, they were strategically chosen by Parker and Drapeau, and were instrumental in allowing the duo to initiate a small human clinical trial after only four years of work.

When it comes to contracting a muscle fiber, worms, fish, and humans aren’t all that different. If you find something that changes the process in worms and fish, there’s a good chance it will have a similar effect in humans. Additionally, the team had a library of 3,850 drugs to test. They were looking for a therapeutic needle in a chemical haystack. That’s where the worms and fish outcompete more common animal models like mice.

The worms are small and develop symptoms of ALS within hours of being born. In a plastic dish barely larger than your cell phone, 32 drugs could be tested in a span of six hours – an impossible pace if you’re using a mouse model. Parker and Drapeau quickly narrowed the list of 3,850 compounds to 13 drugs capable of improving paralysis in their worm models. They then narrowed this list further using their zebrafish model – whose small size and quick development allowed for a similarly quick turnaround in results – finally identifying a single potently effective compound: a neuroleptic or antipsychotic drug called Pimozide.

Once they were working with a single compound, the team incorporated a mouse model into their experiments. They found that Pimozide targets a structure called the neuromuscular junction. The neuromuscular junction, as the name suggests, is where a motor neuron contacts a muscle fiber – where the brain’s electrical command to move is translated into a physical contraction of muscle.

In ALS, scientists found that motor neuron death starts with destruction of the neuromuscular junction. Being the first step in disease progression makes the neuromuscular junction an attractive target for scientists looking to treat or prevent ALS. Excitingly, in their study, the University of Montreal researchers found that Pimozide stabilized and strengthened the neuromuscular junction in every model species tested.

In 2015, the University of Montreal researchers teamed up with Dr. Lawrence Korngut from the University of Calgary and took Pimozide into the clinic. They performed a six-week-long preclinical trial aimed at finding the maximum dose that is both safe and tolerable in ALS patients. In their short trial, they found evidence that the drug has similar effects on the neuromuscular junction as it did in the worms, fish, and mice, hinting at clinical efficacy. They published their findings on Nov. 16 in JCI Insight.

Korngut, with funding from ALS Canada and Brain Canada, is now following up with a longer phase II clinical trial. He’s recruiting 100 volunteers with ALS to test what impact Pimozide – which costs only nine cents per pill – has on disease progression and symptoms, as well as patients’ quality of life. Work that began six years ago with a paralyzed worm and a dizzyingly long list of chemicals, has led to a clinical trial involving 100 human patients and nine hospitals country-wide – all thanks to shared biology.

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Steven is a PhD candidate in the department of Molecular Genetics at the University of Toronto. He is passionate about CRISPR, computer programming, and science communication. Along with Research2Reality, Steven regularly contributes to the Ontario Institute for Regenerative Medicine as a writer for the Expression.