MRI of a mouse spinal
cord taken as part of a study investigation methods for detecting demyelination
using MRI. Image taken at 9.4T in the Experimental Imaging Centre c/o Nabeela
Nathoo.
Multiple sclerosis is a very complex
disease—scientists have found out a lot about it but there is no cure and the underlying cause
remains a mystery. The wealth of information is apparent by doing a search on
the term “multiple sclerosis” which shows that, at time of writing, 60401 scientific
papers have been written about this disease.
It would be wonderful if we could come
up with the trigger and create treatments that prevent MS from occurring. A
breakthrough in this area could literally come anytime. However in the mean
time we need treatments. Clinical colleagues of mine agree that there are a lot
more treatment options now then there were 10 years ago and more are in the
pipeline.
Research in these areas requires funding.
I’m excited to report that Dr. Wee Yong at the University of Calgary just
received funding from Alberta Innovates Health Solutions to study new treatment
options. This is in collaboration with our clinical lead, Dr. Luanne Metz and a
list of other scientists including myself.
So how does one come up with a new
drug? Just do a thought experiment for a moment. You need to understand the
processes that are ongoing through the disease. Much of what has been done to
date has been in this area. We know about inflammation and demyelination and we
know a lot about how to detect the disease through clinical exams and imaging—especially
MRI. Many of these findings were the result of studies in patients, but more were
from studies in animal models.
Much of what we take for granted in
terms of our understanding of brain structure and development has come from
studies of animal models. This is because we need tissue samples and people
aren’t too keen to volunteer to have their brain biopsied. Even MRI, which can
be done repeatedly on patients, requires a fundamental understanding of the
link between the MR signal and the structural changes in brain.
To validate imaging methods, we use
the animal model to triggering some aspect of multiple sclerosis, inflammation
related demyelination for instance. Then we undertake MR imaging and follow up with
a good histological study of the brain. You will often see reference to the EAE
model. This model is induced by stimulating the immune system at the same time
as injecting small proteins common to white matter. The immune system activates
against the white matter and you get demyelination. Another model, called the
lysolecithin model, is one where you inject this particular chemical into the
white matter and get rapid demyelination. The myelin then returns. By imaging
and then quantifying the pathological changes, we are able link the changes seen
in MR with a specific pathology.
When you get your next MRI you will hear
sounds banging away. Each pattern is related to a specific type of MR image.
Every few minutes the pattern will change, indicating that a new image type is
being collected. Every one of these imaging methods has been validated with animal
models by comparing the results of the image to the histological results.
Do get back to the drug studies, you
need the same type of paradigm. Some aspect of the biology of MS needs to be
understood and, if blocked or stimulated, expected to improve the condition of
the patient. Once the target is identified, one can look at the existing
pantheon of drugs to see if there is a candidate or you can begin to design a
drug. Animal models were needed to identify these landmarks, or processes,
which will be targeted. Once the process and drug are identified, animal models
are used to test the specific hypothesis that the treatment will do what you
expect.
Granted, many drugs which work in
animal models don’t work well in patients, but drugs do not make it to patient
care without some validation in animal models.
As a researcher in MR imaging, I’m
very much aware of the need for good animal model studies in the path to drug development. My PhD student Nabeela Nathoo and I became
aware that there was no such succinct argument in the literature pointing out
how best to use animal models in combination with imaging to study pathology
and treatment options in Multiple Sclerosis.
To fill this gap, we wrote a review on
how you would combine animal model studies with MRI in the drug development
path. My lab, and my collaborators have a lot of exciting new ideas about what
drugs might improve remyelination or reduce progression and we now are embarking
on testing some of these ideas. We worked with the Multiple Sclerosis Journal
to get this published. Thanks to editors Jack Antel and Duddy Martin as well as
everyone at the MS journal for working with us on this publication.
The citation and abstract are below.
If you would like a copy of the paper,
drop me a note at dunnj@ucalgary.ca.
Nathoo N, Yong VW, and Dunn JF.
2014. Using magnetic resonance imaging in animal models to guide drug
development in multiple sclerosis. Mult Scler 20: 3-11.
http://msj.sagepub.com/content/20/1/3
Major advances are taking place in the development of
therapeutics for multiple sclerosis (MS), with a move past traditional
immunomodulatory/immunosuppressive therapies toward medications aimed at
promoting remyelination or neuroprotection. With an increase in diversity of MS
therapies comes the need to assess the effectiveness of such therapies.
Magnetic resonance imaging (MRI) is one of the main tools used to evaluate the
effectiveness of MS therapeutics in clinical trials. As all new therapeutics
for MS are tested in animal models first, it is logical that MRI be incorporated
into preclinical studies assessing therapeutics. Here, we review key papers
showing how MR imaging has been combined with a range of animal models to
evaluate potential therapeutics for MS. We also advise on how to maximize the
potential for incorporating MRI into preclinical studies evaluating possible
therapeutics for MS, which should improve the likelihood of discovering new
medications for the condition.
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