One of the hallmark characteristics of ALS is the clumping of proteins in motor neurons that are believed to cause toxicity and eventual death of the motor neurons, resulting in the loss of muscle control and mobility, and eventually, the abilities to eat and breathe. Many scientists are looking for ways to eliminate protein clumping or block protein production to slow ALS progression or, one day, to stop the disease in its tracks.

Right now, in Canada, riluzole is the only approved drug for treating ALS. A second drug, Radicava (edaravone), was approved by the U.S. Food and Drug Administration last May and is currently being reviewed by Health Canada. Both drugs have some effect on the disease in certain individuals, but more effective treatments are urgently needed.

What if there was a way to turn off the genes that make problematic proteins? Gene-silencing drugs called small interfering RNAs (siRNAs) are a new class of drug that can be easily engineered and have, in some studies, been shown to reduce levels of specific proteins by over 80 per cent for up to six months in humans. They are showing great promise in current, late-stage clinical trials for treating a variety of liver diseases.

While it’s exciting to think about how these drugs could be used in ALS, they have, to date, been problematic. “siRNAs have great potential to get rid of the toxic aggregating proteins that cause ALS,” said Dr. Derrick Gibbings, a researcher at the University of Ottawa. “Unfortunately, efforts to deliver them to motor neurons affected in ALS have not been successful and often resulted in harmful effects due to the chemicals used and inefficient methods used for drug delivery in animal experiments.”

It’s very difficult to get treatments into the brain because the body has a defence system called the blood-brain barrier, a tightly-controlled network of blood vessels that prevent foreign substances from entering. Dr. Gibbings and his colleagues have discovered a new technology that allows them to get siRNAs past the blood-brain barrier using exosomes, tiny, bubble-like bits of cells found naturally in large quantities in blood and other body fluids. The researchers have demonstrated that it’s possible to reduce ALS-associated SOD1 proteins in motor neurons of mice by 40 to 60 per cent by loading exosomes with siRNA specifically engineered to address SOD1. Their results suggest that exosomes might in the future be an effective way to deliver gene-silencing drugs through an injection into the bloodstream.

Dr. Gibbings and co-investigators Dr. Baptiste Lacoste and Dr. Maxim Berezovski at the University of Ottawa recently received a $125,000 grant from the ALS Canada Research Program to complete more testing of this innovative drug delivery vehicle. Dr. Gibbings is an expert in exosome biology and discovered a way to package exosomes with gene-silencing drugs. He has been consulting with a pharmaceutical company for several years on translating the technology to the clinic in other diseases. Dr. Lacoste is an expert in the blood-brain barrier and Dr. Berezovski is an expert in targeting drugs to specific tissues like the brain.

In this project, the researchers will determine the best doses and timing to reduce ALS-related protein levels in mice, generating important data to set the groundwork for a future clinical trial in ALS patients. After injecting mice intravenously with exosomes loaded with siRNAs, the researchers will measure how many exosomes cross into the brain, identify the route and timing of entry, and determine if the siRNAs can effectively reduce the level of target protein in the animals’ motor neurons. “Initially we will do our testing in the SOD1 mouse model. If it works, it will be easy for us to design siRNAs for additional ALS-associated proteins such as C9orf72 and ataxin-2 and test those as well,” Dr. Gibbings explained.

If successful, he anticipates that this new treatment method could be a viable way to reduce ALS-associated proteins in a large majority of people living with ALS. He also hopes that this research project will pave the way for administering lower doses of gene-silencing drugs using intravenous injection, a less invasive procedure than the current intrathecal method that infuses drugs directly into the cerebral spinal fluid through the intrathecal space located in the lower spine.

“We aim to generate strong evidence that will enable a clinical trial with human volunteers to begin in about five years and that future research will validate a new treatment for ALS patients,” said Dr. Gibbings.

This research project is one of 12 funded by the ALS Canada Research Program in 2017 following a rigorous scientific assessment by panels of global ALS experts. The panellists evaluated a larger pool of applications to identify the projects that are grounded in scientific excellence and have the potential to most quickly advance the field of ALS research in order to develop effective treatments.

ALS Canada is a registered charity that receives no government funding. Everything we do – from funding research to providing community-based support for people living with ALS – is possible only because of donor generosity and partnerships with provincial ALS Societies who contribute to the ALS Canada Research Program.

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