Current methods for diagnosing ALS can take up to two years and rely heavily on ruling out other conditions that share similar signs and symptoms. It is believed that by the time ALS is diagnosed, therapies may be less effective as the damage to neurons is too extensive. Therefore, a better way of diagnosing ALS earlier is desperately needed.

One of the hallmarks of 97 per cent of ALS cases is the accumulation of misfolded TDP-43 protein in motor neurons. One theory is that some dying motor neurons expel misfolded TDP-43. Some of this released, misfolded TDP-43 may end up in cerebrospinal fluid. If it does, then testing cerebrospinal fluid to measure misfolded TDP-43 levels could act as a biological marker, a “biomarker,” of ALS.

With a trainee award of $165,000 funded by the ALS Canada Research Program, in partnership with Brain Canada, Dr. Yulong Sun, a postdoctoral fellow working in the lab of Dr. Avi Chakrabartty at the University Health Network in Toronto hopes to develop a new lab test that can detect misfolded TDP-43 in the cerebrospinal fluid of people with ALS.

“If we can diagnose ALS earlier, we can identify and enroll volunteers into clinical trials when the disease is still at an early stage — when therapies would have a greater chance to be effective,” said Dr. Sun. “A new lab test for detecting misfolded TDP-43 in cerebrospinal fluid could also be used as a companion diagnostic in clinical trials to measure disease progression in response to new therapies.”

Designer antibodies

Antibodies are molecules made by the body to detect foreign objects by recognizing a particular protein on the invaders. For example, when you are sick with the common cold, your body makes antibodies that recognize the protein sequence on the cold germs and attach to them like flags so that your immune cells can identify the invaders and destroy them.

Dr. Sun and his research colleagues developed some promising antibodies that can successfully detect misfolded TDP-43 in lab experiments using post-mortem brain tissue. Unlike standard antibodies that bind to any TDP-43 protein, these new antibodies only bind to the misfolded form. To validate these new antibodies, Dr. Sun will use a tool that combines them with other commercially-available antibodies that contain gold particles. This method will allow him to identify and count the clusters of misfolded TDP-43 with an advanced imaging technology called immunogold electron microscopy.

Designing a new lab test to diagnose ALS

First, Dr. Sun will test the new antibodies to see if he can detect and count misfolded TDP-43 in 40 samples of cerebrospinal fluid already collected from people with ALS through the Sunnybrook Health Sciences Centre ALS Clinic in Toronto. He will compare the results to samples from people not expected to have TDP-43 misfolding. If the antibodies can successfully detect and measure levels of misfolded TDP-43 he plans to develop a simple lab test called an immunoassay that may someday help doctors diagnose ALS earlier in the clinic and monitor disease progression.

Advancing ALS Research

Dr. Sun has high hopes for his project given that Dr. Chakrabartty has used a similar approach to successfully develop a new antibody that only binds to a misfolded protein involved in another disease called transthyretin amyloidosis. The antibody attaches to misfolded transthyretin (TTR) protein that can form amyloid plaque deposits in blood vessels and lead to heart failure. Dr. Chakrabartty has advanced his innovation to the point where he is now working with a pharmaceutical company to use the antibody in a clinical trial for an experimental drug.

On its own, an ALS antibody may also have potential as a therapeutic strategy in the future. “If the antibody can bind to misfolded TDP-43, it may be possible to modify it so that it could help the body’s immune cells recognize and clear away the aggregates, similar to how the TTR antibody works,” Dr. Sun said. “Eventually, I would like to form a biotech start-up and advance a new immunoassay into clinical trials.”

This research project is one of 6 trainee awards funded in 2018 by the ALS Canada Research Program, which is the only dedicated source of funding for ALS research in Canada. ALS Canada trainee awards support Canada’s emerging ALS researchers, whether they are doctoral students, postdoctoral researchers, or clinical research fellows. Trainee awards encourage young researchers to choose ALS as their area of focus, helping to ensure that Canada has a strong base of talented ALS researchers today and into the future.

The funding of the project followed a rigorous scientific assessment by panels of ALS experts. The panellists evaluated a larger pool of applications to identify the projects that demonstrate scientific excellence and have the potential to most quickly advance the field of ALS research in order to develop effective treatments.

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Posted in: Research