How does a new experimental treatment for ALS behave within the body?

Clinical trial evaluates the drug enoxacin as a therapeutic option for ALS, add-on studies supported by Discovery Grant

“Ideally, one day, the results of our work will mean that we will be able to provide a new remedy for patients suffering from ALS” – Dr. Eran Hornstein

An international Canada-Israel research partnership is taking important steps to determine whether a known drug has the potential to become a viable treatment for people with ALS.

Recently, using a mouse model, Dr. Eran Hornstein of the Weizmann Institute of Science in Israel showed that the antibiotic enoxacin holds promise at correcting a malfunctioning pathway known to contribute to the development of ALS. Now, his team is partnering with colleagues at The Neuro (Montreal Neurological Institute-Hospital) on the next step with a clinical trial at The Neuro’s Clinical Research Unit that is examining how the therapy behaves in human patients.

Critical funding recently provided through a 2020 ALS Canada-Brain Canada Discovery Grant will enable the team to conduct more in-depth analyses to further assess the value of enoxacin in ALS.

THE BACKGROUND: ISRAELI TEAM INFLUENCES A PROBLEMATIC PATHWAY

In healthy people, molecules called microRNA help control the kinds and amounts of protein that cells produce; when microRNA are not properly regulated, the result can be significant neuronal dysfunction and cell death, which in turn can provoke neurodegenerative disorders including ALS.

In his pre-clinical work with mouse models, Dr. Eran Hornstein used enoxacin to target the DICER pathway, which supports healthy regulation of microRNA. This pathway has been shown to underperform in ALS patients, leading to reduced levels of microRNA. Hornstein’s group was able to show that enoxacin has the potential to boost the faulty pathway and reverse the reduction of microRNA in motor neurons that has been observed in patients with ALS.

There is much work to be done, and Hornstein is eager to continue. He says the next step is ensuring the drug is safe and effective for humans.

AN AMBITIOUS INTERNATIONAL PARTNERSHIP

Following his initial discovery, European colleagues encouraged Hornstein to reach out to Dr. Angela Genge as an ideal collaborator to help move the enoxacin project forward. Genge is director of Clinical Research Unit and Centre of Excellence for ALS Research at The Neuro, home to a phase 1 unit for neurological clinical trials initially established specifically for work in ALS.

“This unit at The Neuro is known for our ability to run high-quality international clinical trials in ALS, at all phases,” emphasizes Genge. “It’s really been a collaborative effort,” she adds. “The funding from Brain Canada and ALS Canada is enabling the additional translational work that is occurring as part of this clinical trial, allowing us to determine target engagement; in plain English, this means we want to prove that the drug is doing what we think it’s doing for patients, which is to boost microRNA levels.”

In the clinical trial, 36 patients are each being treated with three doses of enoxacin and assessed for safety, while the movement and mechanisms of the drug in the body are measured in blood and cerebrospinal fluid samples. The researchers hope to see that the drug is distributed properly in their patients’ bodies, and that it is properly engaging with the targeted pathway, Hornstein explains. “Ideally, one day, the results of our work will mean that we will be able to provide a new remedy for patients suffering from ALS,” he adds.

ENHANCING THE CLINICAL TRIAL IN CANADA

The Discovery Grant has gifted the researchers with the capacity to enhance their trial, asking additional questions that will add to its value and impact. The funding allows Genge and Hornstein to expand the scope of their project: in addition to examining the safety and efficacy of enoxacin in human subjects, they will now have the ability to assess how the drug interacts with other therapies, such as riluzole, that patients may be taking. Critically, their teams will also have the ability to extend their attention to the question of biomarkers, evaluating both neurofilament light and microRNA as reliable benchmark measures to assess the efficacy of ALS treatments.

SUPPORTING COLLABORATION FOR A BETTER FUTURE

Hornstein and Genge’s clinical trial is now underway: “This partnership is promising,” says Hornstein, “because Dr. Genge is such an exceptional professional and runs an outstanding team of specialists; we have 100% trust in them.”

The organizations behind the Discovery Grants program are likewise enthusiastic to support the promising collaboration. “Our Discovery Grant funding adds a valuable dimension to this trial, and will increase its outputs in a meaningful way, ensuring that these talented researchers can achieve the richest possible results from this promising study,” says Dr. David Taylor, Vice President of Research for the ALS Society of Canada.

“The Discovery Grant Program helps bring together unique teams to accelerate scientific breakthroughs,” says Dr. Viviane Poupon, President and CEO of Brain Canada. “Brain Canada is proud to support research that joins together talented researchers internationally, to test new and promising ideas for the benefit of ALS patients – ultimately helping to achieve a future without ALS.”

The REALS team wants to thank its partners at Apotex Inc. and Weizmann Canada, as well as its funders at Brain Canada, ALS Canada, Muscular Dystrophy Canada, CIHR, FRSQ, and E-Rare for their assistance.

Funding that makes a difference

The Discovery Grant Program makes these connections possible with a funding model that favours interdisciplinary collaboration, bringing the best minds together to tackle complex problems. Discovery Grants give promising novel ideas the fuel they need to gain traction; in 2021, up to eight projects will benefit from $1M in total funding.

Since 2014, ALS Canada’s partnership with Brain Canada has resulted in more than $23 million being invested in leading-edge ALS research that has helped further understanding of the disease. The Discovery Grant Program is designed to fuel innovation that will accelerate our understanding of ALS, identify pathways for future therapies and optimize care to improve quality of life for people and families affected by this devastating disease.

The Discovery Grant Program has been made possible by Brain Canada, through the Canada Brain Research Fund (with financial support from Health Canada) and the generosity of provincial ALS Societies, ALS Canada donors and community-based efforts, including 40 per cent of net proceeds from the Walk to End ALS.