Multiple Sclerosis Research at NYSCF

Our knowledge on pathogenic mechanisms in MS has greatly advanced over the years, but the more we study this disease, the more its complexity becomes evident, and new critical factors are entering the picture. Many studies over the past century focused on the immune cells and how the immune cells infiltrate the brain and damage oligodendrocytes (the cells that form myelin) as well as the neurons. We have remarkably improved our knowledge on the immune side of MS and also identified genetic variants that increase the risk of MS and are linked to immune genes. However, we still know very little about the progressive forms and the general neurodegeneration that is ongoing from the onset of the disease and is at least partially independent for the focal demyelinated lesions typical of the relapsing-remitting phase.

The current approved drugs for MS are all targeting the immune component of the disease. They have different mechanisms of action (and some of the mechanisms are not yet fully elucidated), but in general, they prevent immune cells from infiltrating the brain and the spinal cord. They can do this by trapping the cells in the lymph nodes or preventing the crossing of the blood brain barrier, or they act on lymphocytes to make them less aggressive, or they deplete some of the lymphocytes that are believed to have a major impact in the formation of the lesions.

Technological developments have primarily impacted the techniques of MRI imaging. MRI imaging can be used as diagnostic tool and for following and studying the progression of the disease. These techniques have better sensitivity, and new analyses have been developed to increase the number of parameters we can investigate. This helps us better quantify and understand brain atrophy, myelin content, and regional differences in the process of neurodegeneration.

New therapies are focusing on the process of re-myelination rather than on immune cells and could be complementary to the immune-modulation therapies. These are, for example, Clemastine and Ketoconale. The most recent approved MS drugs, such as Ocreluzimab, are antibodies that selectively deplete some subtypes of immune cells (Ocreluzimab binds specifically to B-cells, for example).

One of the major challenges of bringing a drug to market is the design of the clinical trial. Drugs that are targeting the immune cells have been evaluated over the past two decades by looking at active lesions in the brains. These lesions can be measured by MRI, which provides an objective parameter. We still don’t have easy, quantifiable markers to assess, for example, neuronal protection or re-myelination in the short time frame of a clinical trial. Therefore, being able to prove the efficacy in humans is not always a straightforward process.

There is certainly a bigger focus on progressive forms of MS today. Relapsing-remitting MS patients can now choose between a fairly good range of treatments, and many patients are responding very well with a significant decrease in the number of relapses. Unfortunately, we still need to find drugs that are able to stop primary or secondary progressive MS.

Several clinical trials have been testing the safety and efficacy of blood stem cell transplantation in MS. These studies are still somewhat limited in the number of patients enrolled, which is why we don’t yet have definitive conclusions. However, the data are very promising, and for some patients, the treatment seemed to be highly effective in stopping the relapses. In particular, patients affected by an aggressive form of the disease, with frequent relapses and within 10 years from the diagnosis, received the most benefits from the transplantation.

Unfortunately, the procedure of blood stem cell transplantation is highly invasive: blood stem cells are isolated from the patient, who is then subjected to chemotherapy treatment (called conditioning regimen) to eliminate any residual immune cells from the blood. This leaves the patient highly vulnerable to infections and there is a concrete risk of fatalities. For example, in the study conducted in Canada by the team of Dr. Mark Freedman (published in 2016) one patient out of 24 died. Because of the much safer profile of the first line therapies currently approved, for the majority of patients it is not recommended to enroll in a therapy trial that carries fatal risks. The option of being enrolled in a blood stem cell transplantation trial is currently recommended for patients with highly active relapsing-remitting multiple sclerosis (as shown by clinical relapses and MRI lesion activity), within 5 years from the diagnosis, and not responsive to first line approved medications.

There are two types of adult stem cells currently used for transplantation: blood stem cells and mesenchymal stem cells. There is also a clinical trial in Italy to test the safety and efficacy of fetal neural stem cells, which are isolated from aborted fetuses. There are currently no trials with embryonic stem cell-derived cells (ESC) or induced pluripotent stem cell-derived cells (iPSC) in MS. Some studies are considering the possibility of generating oligodendrocyte progenitor cells (the myelinating cells in the brain) from ESC or iPSC for cell transplantation to promote re-myelination. Safety studies will be needed at the preclinical phase before being able to test this treatment in humans. ESCs have been used in the dish to test for new pro-myelinating compounds. For example, Ketoconazole was identified by screening drugs in ESC-derived oligodendrocyte progenitor cells.

Blood stem cell transplantation (aka AHSCT, meaning transplant of the patient’s own blood stem cells) showed impressive results in some patients, but it is not as safe as first line treatments. This means that there are several side effects, including fatalities, due primarily to the conditioning regimen (chemotherapy given to the patient after isolating the cells from the bone marrow). Other risks include opportunistic infections, infertility, febrile neutropenia, allergic and autoimmune complications. At the moment, the clinicians need to evaluate the ratio of risks to benefits and decide on a case-by-case basis the best options for patients.

There are several ongoing studies that aim to reduce the side effects, and recent data presented at neurology meetings are encouraging.  For example, two studies were presented at the 2018 Annual Meeting of the American Academy of Neurology. In one study, none of the 19 patients from MS centers across the world, treated with autologous hematopoietic stem cell transplantation (AHSCT), had clinical relapses following the procedure, and there were no fatalities reported. A second study compared about 50 patients treated with AHSCT with a similar number of patients on approved medications. Again, no fatalities were reported and AHSCT outperformed in relapsing-remitting patients with more than 2 relapses per year. In relapsing-remitting MS, AHSCT is today a viable option in some appropriate MS centers.

We are understanding more and more that MS is a complex disease: it has an immune component, a neurodegenerative component, genetic risk, environmental factors, etc.  I think that interdisciplinary studies should be highly encouraged to tackle the problem from all different perspectives.

Any technical advancement will be beneficial. There are many areas currently in huge expansion, not just for MS but for all other incurable disorders affecting our society: developing better machines for imaging, better software to analyze the data, software for collecting all the clinical data from the patients in a way that they can be shared with other institutions, creating a huge database accessible to all researchers, remotely-controlled devices that a patient can carry without needing to go to the hospital, and – last but not least- artificial intelligence, such as applying deep learning to the interpretation of biological data.

Because of all the developments mentioned above, this is really an exciting time for MS research. Maybe 10 years is a short time frame and there will not be dramatic changes for the patients, but within these ten years there will be significant progress for a more long-term future. I also think that there will be more attention to things like lifestyle, diet, exercise, and stress levels. These are relatively easy things that the patients can modify and can help them feel more in control of the disease, sometimes with a significant psychological impact that ultimately improves the patient’s general wellness.