Background
The need to close the gap between discovery research in the laboratory and clinical trials, in order to accelerate the delivery of safe and effective treatments to people with multiple sclerosis is an urgent priority. In 2014 the MS Society of Canada formed a collaboration with the Centre for Drug Research and Development (CDRD), a non-profit organization based in Vancouver that boasts an extensive drug development and commercialization platform. The purpose of the collaboration is to eliminate obstacles associated with developing promising treatments for people living with MS, especially progressive MS. As a step towards this goal, the MS Society and CDRD jointly announced a call for research proposals focused on progressive MS. Ten proposals were submitted from investigators in Canada and Europe, and a rigorous peer review by experts in MS and translational research narrowed down the pool to two outstanding applications:
- Dr. David Granville (The University of British Columbia)
- Dr. Veronique Miron (University of Edinburgh)
About the studies
Dr. David Granville – Targeting granzyme B to stimulate nerve repair
One of the weapons that certain immune cells use to destroy harmful invaders is an enzyme called granzyme B. In the MS brain, granzyme B mistakenly targets the body’s own nerve cells by programming them to self-destruct. Additionally, granzyme B stops young nerve cells from functioning properly, thereby preventing them from replenishing the pool of injured nerve cells and repairing the damage.
With the help of experts at CDRD, Dr. David Granville will study a selection of granzyme B inhibitors to determine the best candidate for a progressive MS therapy. Along with MS scientist Dr. Marc Horwitz from The University of British Columbia, Dr. Granville will use mice with an MS-like disease to block granzyme B to determine its effects on nerve cell damage and disease severity. Dr. Granville will also collaborate with Dr. Amit Bar-Or from the Montreal Neurological Institute, who will provide brain tissue from people with progressive MS to determine which brain cell types contain a marker for granzyme B. If successful, these experiments will be necessary stepping stones to eventually studying the safety and efficacy of granzyme B inhibitors in early clinical trials.
These experiments will enable Dr. Granville to grasp if and how granzyme B inhibitors function in the body, how they’re absorbed, metabolized and excreted, and whether they are toxic, and ultimately if they are promising therapeutic candidates for progressive MS.
Dr. Veronique Miron – Targeting activin-A receptor to promote remyelination
Another potential target for a progressive MS therapy is a protein called the activin-A receptor. Evidence suggests that activin-A stimulates myelin-producing cells called oligodendrocyte precursor cells (OPCs) to mature and produce new myelin, the sheath that protects nerve fibres that is damaged in MS.
With the aid of CDRD, Dr. Miron will test dozens of compounds available from CDRD’s libraries (a process referred to as a high throughput screen) to determine their effects on OPCs grown in the lab. Compounds that have the desirable effect of promoting activity of OPCs will then be pursued for further testing in rodent brain tissue, in order to test their ability to promote remyelination.
Since the development of remyelination therapies is a priority goal for progressive MS, narrowing down and validating the list of compounds that can stimulate the activin-A receptor and promote myelin repair will be a crucial step in filling the gap of progressive MS therapies. Future objectives will be to come up with ways to deliver the therapy with pinpoint accuracy to target the myelin-producing cells without activating the receptor on other cells that are not involved in the remyelination process.
Comment
While the pace of research aimed at investigating MS disease mechanisms and discovering new therapeutic targets has pushed forward, translating these findings into safe and effective therapies that will have a meaningful impact on the lives of people living with MS has proven to be a challenge. The steps necessary to translate scientific discoveries into therapies involve a great deal of risk, time, resources and expertise. The MS Society, together with CDRD, has risen to the occasion of overcoming those challenges. By tapping into the infrastructure and expertise in drug development and commercialization offered by CDRD, highly promising targets such as those being investigated by Dr. Granville and Dr. Miron can be taken to the next level and nudged into the treatment pipeline. This is especially important for drug discovery for progressive MS, which currently has no approved treatment option.