Therapeutic Nanobodies for Amyotrophic Lateral Sclerosis


Research Profile: Dr. Jean-Pierre Julien

Vaccination is a preventative medical technique designed to assist the body in developing an immune response to specific infections. Exposure to weakened versions of these infections causes our body to produce substances called antibodies that neutralize the infection and stand ready to prevent illness should any additional exposure to the same infection occur.

The first ALS gene discovered to have an alteration that could be passed on through families (familial ALS) is called SOD1. These alterations (called a mutation) cause SOD1 to change its shape (we call this misfolding) in a way that makes it toxic to motor neurons and other cell types involved in the disease. Using this knowledge, researchers surmised that vaccination with misfolded SOD1 (in place of a weakened virus) could cause the body to have an immune response and develop antibodies that neutralize and specifically get rid of this toxic form. In animal models of ALS, the concept has shown some definite promise.

However, antibodies in our bloodstream are generally unable to pass the natural barrier between our blood and our brain/spinal cord (blood brain barrier), and if they could, they are far too large to enter motor neurons and other cell types where the majority of toxic SOD1 is found. As a result, the antibodies may only be accessing a small portion of the toxic substance.

2013 ALS Canada Research Fund recipient and world-renowned researcher at Université Laval, Dr. Jean-Pierre Julien is using a novel spin on the concept of antibodies as a  therapeutic agent that may bypass this access problem. Over the past decade, scientists have developed unique ways to deliver genes by using laboratory engineered viruses that can pass the blood brain barrier and harmlessly infect cells of the brain and spinal cord. Dr. Julien’s team is using a new technique where a gene can be artificially engineered to create the portion of antibodies required for neutralization of a target (called a nanobody). By using a virus to deliver this antibody gene to cells affected in ALS, he hopes to rid the body of much more toxic SOD1 than a traditional vaccination. In other work, Dr. Julien is using nanobodies as a means of targeting an internal mechanism that may be important to ALS pathogenesis. In previous work, his lab demonstrated that the ALS-causing gene TDP-43 has a toxic interaction with a substance called p65 that may be a crucial part of the disease process.

By developing a nanobody that prevents binding, it`s possible that the mechanisms leading to degeneration of motor neurons may be slowed down.

Canadian researchers continue to be on the cutting edge of ALS discovery and provide a significant contribution toward the global effort for understanding and treating the disease. It’s exactly this kind of forward thinking that demonstrates how the national Research Program funds the best peer-reviewed research in Canada and stewards ALS Canada donations toward the projects that have the most potential impact.

Article credit: 1-800-267-4257