Publication / Source: Neuro Central
Authors: Sharon Salt, Editor
In line with our focus this month on ‘emerging techniques and approaches’, we’ve brought together a panel of experts to discuss emerging therapies in multiple sclerosis (MS) in a two-part discussion. How extensive is our current knowledge of the mechanisms behind MS? What are the primary targets for existing therapies and future treatments? How could MS therapies change in the next 10 years? We’ve also incorporated the questions that you wanted to ask our experts, including the use of hematopoietic stem cell transplantation (HSCT) as a treatment option and how adult stem cells fare in relation to other stem cell sources.
Bringing together insights from across research and the pharmaceutical industry, our experts are Rick Munschauer (MedDay Pharmaceuticals, MA, USA), Luke Lairson (The Scripps Research Institute, CA, USA) and Valentina Fossati (New York Stem Cell Foundation, NY, USA). Take a look at the first installment of this discussion below, which looks at the mechanisms, therapies and challenges involved in MS research.
You can also read Part II of the discussion, which delves deeper into the use of stem cells and future research priorities for MS.
How extensive is our knowledge of MS and its mechanisms at present?
Rick Munschauer: In the last 30 years, we’ve seen significant evolution in our understanding of the immunopathology of MS. We have a much firmer idea about the activation of the immune system, the nature of inflammation itself within the CNS, mechanisms of neuronal loss and the biology of repair. This understanding has been tremendously augmented by the evolution of imaging techniques – particularly MRI. MRI has allowed us to measure MS disease activity, progression and response to therapy. Because of the power to assess the impact of the disease, MRI is routinely used in therapeutic decision making. That’s the good side of the story.
The disappointing side of the story is that we have gained very little insight into the true etiology of the disease. Despite extensive research into both genetic susceptibility and into environmental triggers, we have yet to identify people at high risk of developing MS. We also have no good measures of why MS is much more severe in some patients than others. We’ve known for quite some time that after 5–15 years, patients with relapsing MS frequently develop a progressive form without clinical or MRI evidence of overt inflammation. These patients have more trouble with function, which can involve any combination of ambulation, upper extremity function, vision, or cognition. The pathologic basis of this degenerative process is also not well understood and may be multifactorial.
Valentina Fossati: 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 have focused on immune cells and how they infiltrate the brain and damage the cells that form myelin – the oligodendrocytes – as well as the neurons. We have remarkably improved our knowledge on the immune aspect 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 very onset of the disease, and is at least partially independent for the focal demyelinated lesions typical of the relapsing–remitting (RR) phase.
What are the primary targets for existing MS therapies?
Luke Lairson: The primary targets for existing (approved) MS therapies exclusively target the immune aspect of the disease. Historically, these have primarily focused on targeting T-cell function. For example, Gilenya® is thought to function in MS by modulating lymphocyte migration. More recently, B cell-targeting antibodies have been demonstrated to be efficacious. In most cases, the mechanisms responsible for disease-modifying activity in patients is not completely clear. Modulation of S1P receptor function, by Gilenya and other S1P receptor-targeting agents, has the potential to impact multiple aspects of MS diseases beyond T-cell function. It is also unclear exactly how B cell-targeting therapies function in MS. A reasonable hypothesis is that they function by inhibiting antigen presentation.
RM: In the late 80s/early 90s, it was thought that perhaps MS was caused by a virus. β-interferon had known antiviral activity and it was hypothesized that it could therefore have a therapeutic effect. Multiple clinical trials have established that β-interferon can modify disease activity, but after decades of search, no unique virus has been identified. We now know that interferons have a very complex immunomodulatory effect and that this may underlie the way in which they are effective in the relapsing forms of MS. Fast forwarding from the 1990s to modern day, we now have approximately 15 approved treatments for the relapsing form of MS. All these therapies involve suppressing or modulating the immune system in some way. There is an emerging theory that if you acutely suppress the immune system, then as the immune system reconstitutes itself, you may have an immunophenotype that is less likely to result in increased inflammation within the CNS. A recently approved immunosuppressant therapy, ocrelizumab, is an anti-CD20 monoclonal antibody that depletes B cells rather profoundly.
Looking ahead, the focus is going to be on finding treatments for the degenerative phase of MS. Many investigators, both in the academic and pharmaceutical world, are trying to understand the mechanism by which this secondary progression occurs, independent of any immunologic activity. There are many hypotheses; one under active investigation relates to neurodegeneration resulting in energy failure associated with demyelination. We know that the demyelinated axon is associated with increased energy requirements. Mitochondria accumulate in the demyelinated section of an axon and appear morphologically stressed. This may subsequently lead to neuronal death. That is one putative mechanism by which neurodegeneration occurs independent of inflammatory activity. We need to identify pathophysiological mechanisms associated with neurodegeneration in order to develop specific therapies that would preserve neurons and perhaps preserve or improve function.
More recently, we have begun to think of therapies that not only prevent degeneration but perhaps facilitate repair. There are many clinical trials where the objective is to promote remyelination, but other interventions are emerging. For example, researchers have been investigating the role of gliosis in preventing both remyelination and axonal growth. The next generation of therapeutic interventions in MS will address these two fundamental areas: (i) how we can prevent neurodegeneration and (ii) how we can facilitate repair. I think that that is the most exciting aspect of our current approach to MS therapeutics.
To what extent have recent technological developments advanced our understanding of MS?
VF: Technological developments have primarily impacted the techniques of MRI imaging, which 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 numbers of parameters investigated to better quantify and understand brain atrophy, myelin content and regional differences in the process of neurodegeneration.
What therapies are currently emerging in the field of MS and how do they compare to traditional treatments?
VF: New therapies are focusing on the process of remyelination rather than on immune cells, and could be potentially complementary to the immune-modulation therapies. These are, for example, clemastine and ketoconazole. The most recently approved MS drugs, such as ocrelizumab, are antibodies that selectively deplete some subtypes of immune cells – in this instance, B cells.
LL: Complimentary therapies that target disease mechanisms beyond peripheral immune cell trafficking and function are beginning to emerge for the treatment of MS. For example, therapies aimed at stimulating the regenerative process of remyelination are being developed by multiple large pharma and biotech companies. Results from the recently completed ReBUILD trial, evaluating clemastine as a remyelinating therapy for MS, were encouraging. Clearly, however, there is a need for the identification of alternative potential efficacious agents and/or the establishment of well-defined dosing regimens. Therapeutic strategies aimed at axonal protection or the directed targeting of reactive glial cells within the CNS are also being explored. These therapies will all be complementary to traditional treatments that target peripheral immune cells. Evidently, robust long-term disease-modifying activity will require the effective targeting of multiple aspects of this multi-faceted disease.
In your opinion, what are the biggest challenges associated with developing and applying these therapies?
LL: Major challenges associated with the development of these therapies include the need for drug candidates to be evaluated in clinical studies that have well-defined inclusion criteria, where drug candidates are evaluated at a defined stage of disease as part of a fixed-dose combination with a standard-of-care drug. Historically, based on retrospective analysis, the observed efficacy of MS drug candidates varies significantly based on the stage of disease at the onset of treatment. It is easier to establish efficacy when drug candidates are evaluated at the early stages of disease. Further, with respect to developing potential remyelination-enhancing drug candidates, there are technical limitations associated with the ability to directly monitor impact on remyelination in patients.
VF: One of the major challenges for bringing a drug to market is the design of the clinical trial. Drugs targeting immune cells have been evaluated over the past two decades 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 remyelination in the short time frame of a clinical trial – and therefore being able to prove the efficacy in humans is not always a straightforward process when moving from the preclinical data.
Is there a significant difference in the current status of emerging therapies for different variants of the disease, for example, relapsing, primary progressive or secondary progressive MS?
LL: Unfortunately, yes. It is unclear whether drug therapies aimed at enhancing remyelination will be impactful for patients suffering from primary progressive MS. The underlying mechanisms that separate RRMS from primary progressive MS are unclear. Functional remyelination is responsible for disease remission in RRMS. In primary progressive MS, it is unclear if functional remyelination is possible. Clearly, there is a desperate need to understand the underlying differences between these two forms of the disease. With respect to secondary progressive forms of MS, an optimistic few would be that by enhancing remyelination it will be possible to prevent the disease from progressing beyond the RR form of disease.
About the experts
Frederick Munschauer (Rick) – MedDay Pharmaceuticals
Frederick Munschauer, who also goes by the name Rick, is the Global Head of Medical at MedDay Pharmaceuticals (MA, USA), a company that is in clinical development for drugs for the progressive form of MS and other indications in neuroscience. Before joining industry 9 years ago, Dr Munschauer was the Smith Professor and Chair of Neurology at the University of New York at Buffalo (NY, USA) and has been involved in MS research for 30 years.
Luke Lairson – The Scripps Research Institute
Luke Lairson obtained his BSc in Biochemistry from the University of Guelph (Canada) and his PhD in Chemistry from the University of British Columbia (Vancouver, Canada). He performed postdoctoral research, in the fields of chemical biology and regenerative medicine, as a Canadian Institute of Health Research (CIHR) fellowship at The Scripps Research Institute (CA, USA). Dr Lairson worked as a Research Investigator at the Genomics Institute of the Novartis Research Foundation (GNF; CA, USA), in the fields of regenerative medicine and preclinical drug development. He went on to become a founding member of the California Institute for Biomedical Research (Calibr; CA, USA), where he served as Director of High Throughput Discovery and Principal Investigator. He is currently an Assitant Professor in the Department of Chemistry at the Scripps Research Institute, where his lab is focused on the identification of mechanisms and potential drug candidates for the treatment of demyelinating diseases.
Valentina Fossati – New York Stem Cell Foundation
Valentina Fossati is a New York Stem Cell Foundation (NYSCF; NY, USA) Senior Investigator at the NYSCF Research Institute, where she focuses on advancing preclinical studies of neurodegenerative and neuroinflammatory disorders, including multiple sclerosis; utilizing human induced pluripotent stem cell-derived brain cell studies. Dr Fossati established highly reproducible protocols to generate oligodendrocytes, astrocytes, microglia and neuronal cell types and is developing culture systems with multiple cell types to identify and target the key pathogenic mechanisms leading to neurodegeneration and/or demyelination in progressive MS, Alzheimer’s disease and other disorders of the CNS.