And immediately 2021
By Sophie Lorenzo, The Neuro
A diagnosis of ALS (amyotrophic lateral sclerosis) sends shock waves through an individual’s life. The disease can strike at any age, but most often between 55 and 75 years old. The average prognosis is only two to five years from the onset of the first symptoms. This motor neuron disease gradually paralyzes individuals as their nerve cells deteriorate, eventually affecting their ability to walk, speak, swallow, and breathe. In Canada, an average of 8 people die from ALS every day.
Over the past two decades, treatments to help slow the progression of the disease have finally been made available, but the gains in survival rate and slowing functional decline have been modest. For individuals faced with this difficult prognosis, time is running out. It is crucial to move forward in the development of new treatment avenues through clinical trials.
The Neuro’s Clinical Research Unit (URC), a leader in ALS trials, recently partnered with the Weizmann Institute of Science in Israel to lead research on a potential new approach to treating ALS. A clinical trial was recently launched at CRU which will build on preclinical research conducted in Professor Eran Hornstein’s lab at the Weizmann Institute.
Target a key enzyme
People with sporadic or familial ALS have decreased levels of microRNAs in their motor neurons. A key enzyme called DICER is essential for maintaining microRNA levels.
“DICER is inhibited in many forms of ALS so we thought it might be a therapeutic target. If we could find a way to improve its activity, it could be a way to restore microRNA levels and treat patients with ALS, ”says Professor Hornstein.
In previous biochemical studies, researchers had found that the drug enoxacin affected the activity of DICER. Professor Hornstein and his team hypothesized that it could help restore DICER activity in ALS.
The Hornstein lab tested the effects of enoxacin on DICER in motor neuron cells and in mice that were designed to develop ALS, and the results were promising enough to move on to the next phase of enoxacin testing in patients with ALS. “Enoxacin increases the enzyme activity of DICER and the production of microRNAs. We have seen a positive effect of improving ALS in preclinical studies in mice. It was a good sign that this would be a therapeutic candidate in a drug for patients, ”says Professor Hornstein.
Early clinical tests
In order to move the study of enoxacin to a clinical trial, Professor Hornstein contacted Dr. Angela Genge, director of the clinical research unit and the Center of Excellence for ALS research at The Neuro. The URC Phase 1 unit, the first of its kind for ALS, made this exciting study possible at The Neuro.
“This is an opportunity to see if we can relate something that has been shown to have an effect on the science of ALS, with a potential effect on the patient to see if it has a specific and direct impact on an terrible disease. And we would do that with a drug already developed that could open a new way for us to treat these patients, ”says Dr. Genge. Drs Genge and Hornstein have launched the REALS-1 trial, which is a Phase Ib / IIa trial that will examine the safety, tolerability and targeted drug use in people with ALS.
“We will look at the evidence that enoxacin enters the brain and spinal cord and may have an effect. And we will also be looking at biomarkers, ”says Professor Hornstein. The assessment of biomarkers and target engagement in this study responds to an important need for clinical research in ALS and demonstrates a high level of rigor even at this early stage.
Network advantages
Before the trial could begin, there was a roadblock: enoxacin was not readily available. Weizmann Canada, a local organization that supports the Weizmann Institute of Science in Israel, stepped in with a contact that has been essential moving forward: the Canadian pharmaceutical company Apotex, which produced the enoxacin and placebo for the trial. “The Weizmann Institute network has allowed us to build trust and communication. That says a lot about the ability to advance science and biomedical research through collaboration, ”says Professor Hornstein.
The co-investigators are cautiously optimistic at this very early stage of clinical research. The new trial could be the first step in an innovative pathway for the treatment of ALS. “I am eager to see if enoxacin progresses into the next trial phases and if its efficacy is demonstrated; this would open up a whole new avenue for using existing drugs in the development of treatments for ALS, which would dramatically speed up getting treatment to those who need it, ”concludes Dr. Genge.
The trial team thanks the CIHR, the FRQS and the Israel Ministry of Health (under the competitive ERARE-3 grant), as well as the Brain Canada Foundation, the ALS and Muscular Dystrophy Society of Canada. Canada for their generous financial support.
To learn more about the REALS-1 trial or to participate, visit The Neuro’s Clinical Research Unit: cru.mcgill.ca/en/sla
July 7, 2021
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