Multiple Sclerosis drug discovery – How do we increase our chances of success?
Multiple sclerosis (MS) is a chronic progressive disease that affects the nerves in the brain and spinal cord. It is estimated that there are around 2.8 million people worldwide living with MS*and there is currently no cure.
Existing medicines are used to alleviate the symptoms and delay the progression of the disease.
The medicines we use today can be different depending on whether treatment is needed in the early stages of relapsing-remitting multiple sclerosis or the later stages where patients have developed progressing disease
There is a clear need for new medicines that can improve on the existing limited treatment options. However, to develop these, we need suitable laboratory-based models that can effectively test the novel hypotheses for how they will work.
To begin to think about what models are needed for a drug discovery project in MS, it is first necessary to consider how the drug might produce an effect on the body, or in other words, what its proposed Mode of Action (MoA) is. If you want to develop novel and transformative medicines, then just using assays that worked for previous drugs is not going to cut it. You may not see an effect. Not because the drug is ineffective, but because your new drug’s MoA is not well reflected in the existing laboratory assay.
MS is a degenerative autoimmune disease where the bodies’ own immune system wrongly begins to attack the protective covering (called myelin) on nerve fibres in the brain and spinal cord. The loss of integrity of this myelin, whose job is to protect and insulate the nerves, leads to faulty transmission of electrical impulses along nerves. This is responsible for the symptoms that develop. There are natural repair systems that the body can use to regenerate the myelin that has been damaged. However, eventually in MS these processes are overwhelmed or cease to function and are unable to provide the regenerative protection required.
Correcting the fault of the immune system is clearly therefore, a very important area of therapeutic intervention in MS. There are demonstrated successes targeting myelin-attacking immune cells with treatments such as Fingolimod and Ocrelizumab, as well as a range of other approved drugs that aim at restoring the normal function of the immune system and stopping it from damaging myelin. However, even within this group of drugs, a clear understanding of the MoA is critical to selecting the right pre-clinical model system.
Another area of research targets the regenerative potential of cells in the brain called oligodendrocyte precursor cells (OPCs). Once they sense the presence of damaged myelin, these immature cells can proliferate and then give rise to new professional myelin-producing cells called oligodendrocytes. Oligodendrocytes can restore the myelin covering around damaged nerves, and thus rescue nerve function. This is another promising area of MS research which requires very different model systems to the immune cell-modulating approaches.
It’s clear that, for each novel MS drug discovery program, a novel cascade of assays is needed to interrogate and predict the activity of test drugs. These custom-designed assays need to consider the proposed MoA and hypotheses to deliver success.
Elise Malavasi, is discussing some of these challenges in her webinar this week Innovative Assays for Neurodegeneration Drug Discovery Programs. She outlines available in vitro and ex vivo models for neurodegeneration and discusses an approach to the bespoke design of assay cascades for MS.
Translating pre-clinical research to clinical efficacy is nowhere more challenging than for brain diseases, including neurodegeneration. These complex new multicellular and ex vivo models, combined with human models (e.g. induced pluripotent cells), provide a way to increase our success rates in the future.
* Mult Scler. 2020 Dec; 26(14): 1816–1821. doi: 10.1177/1352458520970841
Further reading