Translational research is a high-risk, iterative phase of the
drug development pipeline that involves a lot of trial and error
to assess if the drug will be safe and produce a beneficial
effect in animal models of the disease. Key questions are
answered about a potential drug in translational research: How
quickly is it absorbed? How is it distributed to different
tissues? How is it metabolized and excreted? At what dose is the
drug toxic? These are all crucial questions researchers must
answer to ensure that their compound will be both effective and
safe in humans.
Here, we feature two translational research projects that were
recently funded in collaboration with Centre for Drug Research
and Development (CDRD) that could lead to the development of
disease-modifying therapies for people living with progressive
MS.
Dr. David Granville (The University of British Columbia):
Granzyme B inhibitors to protect nerve damage in progressive
MS
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. Dr. David Granville and his research team have identified
an inhibitor of Granzyme B called VTI-1003. This inhibitor has
already shown to impact disease-like behaviour and promote repair
in an animal model of MS. However, more research is needed to
characterize this inhibitor. “Before advancing into humans, it is
essential that we determine if the drug is safe, how the body
clears the drug and if there are any potential side effects that
we should be aware of,” says Dr. Granville. The research team,
which was awarded $158,000 from the Society, will also identify
the optimal dose that the drug is effective while still
maintaining its efficacy. These studies will help guide drug
development as the team hopes to move the drug forward towards
testing in the clinic.
Dr. Rebecca Spain (Oregon Health and Science University):
Improving the tolerance and efficacy of supplement, lipoic acid,
for treatment of Progressive MS
A
natural substance produced by our own bodies and found in foods,
calledLipoic Acid (LA) is an over the counter antioxidant
supplement which has been shown to reduce inflammation and
disability in mice that have an MS-like disease. A pilot clinical
trial, led Dr. Rebecca Spain and her colleagues, showed LA
reduced brain volume loss suggesting the supplement had a
beneficial, protective effect on MS brains. However,many of the
participants experienced upset stomach and related side effects
to the LA. From blood samples, the team also discovered that not
everyone absorbed equal amounts of LA. Therefore, working with
CDRD with the support of the MS Society in the amount of
$126,800, Dr. Spain will develop a form of LA that does not cause
unpleasant side effects but will more uniformly be taken up into
the bloodstream between people. “Better oral tolerance will allow
more people to easily take lipoic acid, and it’s likely that more
uniform absorption of the supplement will allow for a more
uniform treatment effect,” says Dr. Spain.
The MS Society, together with CDRD, has risen to the occasion of
overcoming challenges in the drug discovery pipeline by funding
translational research. “While many targets show promise at the
cell or animal stage, it is important to identify the most
promising therapies for humans and to translate such findings
into the clinic,” says Dr. Granville. 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. Spain can be
taken to the next level and nudged into the treatment pipeline.
Dr. Spain expresses the importance of the drug discovery
pipeline, “This back and forth process between the laboratory
experiments, translation to clinical practice, and having that
practice inform the next set of experiments and treatments is
critical for the development of even more effective treatments,
and ultimately, a cure.”
