Background: Effective treatments for progressive MS will need to target the pathophysiology of the disease
The drivers or mechanisms that lead to damage in progressive MS are unlike those in relapsing-remitting MS—hence different approaches are needed to identify novel therapeutics. Progressive MS causes damage to mitochondria (powerhouses of the cell), accumulation of iron-mediated neurotoxicity which leads to oxidative stress or damage in the brain along with immune cell overactivity while maintaining an intact blood brain barrier. This means it is essential for progressive MS drugs to be able to permeate the barrier to enter the brain. An effective treatment for progressive MS will need to address all these factors.
A recently published study in Nature Communications, led by Dr. Simon Faissner which included MS Society funded neurologist Luanne Metz and researcher V. Wee Yong, screened generic drugs to identify potential therapies that could target the damage caused in progressive MS.
The Study: Library of generic drugs were screened to identify which one(s) may be effective treatments
The research team screened generic drugs available at National Institute of Neurological Disorders and Stroke (NINDS) custom collection II (U.S. Drug Collection). All drugs were previously approved for other conditions, hence are safe for human use. The team reduced the vast list of drugs based on their ability to enter the nervous system, protect nerve cells from damage caused by iron, and reduce damage to mitochondria. The goal was to identify any generic drug that could be repurposed for the treatment of progressive MS.
Results: Clomipramine identified as a promising therapeutic for progressive MS
From the 1,040 medications in the NINDS collection, the research team selected 249 drugs that were taken orally and had the ability to cross the blood-brain barrier. The 249 drugs were narrowed down further to 35 candidates based on their ability to prevent iron-mediated toxicity, one of the components of progressive MS. The 35 drugs were further screened for those that could reduce excess T cell proliferation, and prevent neurotoxicity and mitochondrial damage.
In addition to these properties, the team also assessed the side effects and tolerability profiles of the candidate drugs.The list was ultimately narrowed down to one potential candidate: Clomipramine. Clomipramine, an antidepressant approved in Canada, was then shown to ameliorate clinical signs of MS in two different animal models suggesting that it may be a promising therapeutic for progressive MS.
Comment:
Overall, using their screening approach, the team discovered several additional generic compounds that have the potential to be neuroprotective in MS. Clomipramine showed particular promise because of its ability to address many of the factors that cause damage in progressive MS. However, the researchers do highlight some limitations of the study.The sequence of tests used to screen the library of drugs, starting from the iron mediated neurotoxicity to effects seen on T cells, does not reflect the pathophysiology that is most important in progressive MS. Had the sequence of tests occurred in a different order, other leading compounds may have been identified. Furthermore, there are no animal models of MS that fully reflect all aspects of progressive MS, therefore the effects seen in animal models may not reflect those that will occur in humans.
We need better treatment options for progressive MS.Funding of research that will yield answers about the nature of progressive MS and identify treatments that will slow accumulation of disability and reverse damage in the nervous system continues to be a top priority for the MS Society.
Source:
Faissner S et al. (2017) Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic. Nat Commun. 8(1): 1990.