Multiple Sclerosis Research at NYSCF
At NYSCF, we are using the power of stem cells to create the actual human cells affected by multiple sclerosis (MS). Many current MS treatments target immune cells in the body to prevent them from attacking myelin, but other cell types within the brain are also likely involved in the disease. Our goal is to study how these cells contribute to MS causes and develop therapies to target them. We strive to accomplish this is several steps:
- At the NYSCF Research Institute, we are using our own, powerful robotic system for creating stem cells. Our NYSCF Global Stem Cell Array® can rapidly, cleanly, and reproducibly create stem cells from skin or blood, and then reprogram them to become the different brain cells implicated in MS.
- We then study how these cells function, interact, and degenerate by exposing them to the type of inflammation found in MS and studying their response. This information can be used to develop effective therapies.
- Lastly, we analyze the genetic information in each of these cells to see if they carry any mutations that may drive the disease.
About Multiple Sclerosis
MS is a complex disease involving multiple cell types in the brain and affecting over 2.5 million people worldwide. In MS, the immune system attacks myelin, the protective coating surrounding nerve fibers that helps them send signals. MS symptoms can include numbness, weakness, vision loss, tremor, fatigue, and cognitive impairment.
A patient’s MS diagnosis has been traditionally classified into one of three major groups, but the MS definition undergoes continuous revisions to better reflect the advancements in our knowledge of the disease:
- In relapsing-remitting MS, a patient’s symptoms come and go.
- Secondary progressive MS occurs when symptoms from relapsing-remitting MS begin to persist.
- Primary progressive MS is a rarer, yet severe, case in which patients immediately show persistent symptoms without ever undergoing the relapsing-remitting phase.
Our research focuses on the progressive forms, as they are the most aggressive and do not respond as well to current MS treatments, resulting in a poorer prognosis.
Multiple Sclerosis Stem Cell News
The Context: In multiple sclerosis (MS), brain cells degenerate and malfunction, leaving patients with symptoms such as numbness, weakness,...
The Context: In multiple sclerosis, the immune system attacks myelin (the fatty substance that surrounds neurons and helps...
Below are select publications outlining recent advancements in MS research from NYSCF scientists.
CD49f is a novel marker of functional and reactive human iPSC-derived astrocytes
Lilianne Barbar, Tanya Jain, Matthew Zimmer, Ilya Kruglikov, Jessica Sadick, Minghui Wang, Kriti Kalpana, Indigo V.L. Rose, Suzanne R. Burstein, Tomasz Rusielewicz, Madhura Nijsure, Kevin A Guttenplan, Angelique di Domenico, Gist Croft, Bin Zhang, Hiroko Nobuta, Jean M. Hébert, Shane A. Liddelow, Valentina Fossati. Neuron. 2020. DOI: https://doi.org/10.1016/j.neuron.2020.05.014
This study creates astrocytes – an integral support cell in the brain – from stem cells and shows that in disease-like environments, these normally helpful cells can turn into neuron-killers. Learn more about this study from a recent panel discussion on inflammation and neurodegeneration.
Researchers from the City University of New York (CUNY) and the Icahn School of Medicine at Mount Sinai in collaboration with The NYSCF Research Institute’s Dr. Valentina Fossati examined how CSF (a fluid found in the brain and spinal cord that bathes the cells in our central nervous system) taken from MS patients affected the function of rat brain cells. The team found that brain cells exposed to the CSF of progressive MS patients had impaired mitochondrial activity, an indicator that the cells might not be able to produce enough energy to sustain themselves, leading to their eventual degeneration.
Cerebrospinal fluid biomarkers link toxic astrogliosis and microglial activation to multiple sclerosis severity.
Ruturaj Masvekar, Tianxia Wu, Peter Kosa, Christopher Barbour, Valentina Fossati. Multiple Sclerosis and Related Disorders. 2018. DOI: https://doi.org/10.1016/j.msard.2018.11.032
Using machine learning techniques, the team identified potential biomarkers indicating activity of different cell types in MS. Specifically, these biomarkers suggested that activity of toxic astrocytes (a type of support cell in the brain) could help drive the disease, and that this toxicity could be triggered by cells called microglia, the immune cells of the brain.
Induction of myelinating oligodendrocytes in human cortical spheroids.
Madhavan M, Nevin ZS, Shick HE, Garrison E, Clarkson-Paredes C, Karl M, Clayton BLL, Factor DC, Allan KC, Barbar L, Jain T, Douvaras P, Fossati V, Miller RH, Tesar PJ.
Nature Methods. doi: 10.1038/s41592-018-0081-4.
In a collaborative study between Case Western Reserve University, the New York Stem Cell Foundation (NYSCF) Research Institute, and George Washington University, researchers have developed a new procedure for generating miniature 3D tissue called “brain organoids” from human stem cells. These organoids contain all major cell types in the cerebral cortex, modeling the brain’s structure and function more closely than ever.
Directed differentiation of human pluripotent stem cells to microglia. Douvaras P, Sun B, Wang M, Kruglikov I, Lallos G, Zimmer M, Terrenoire C, Zhang B, Gandy S, Schadt E, Freytes DO, Noggle S, Fossati V.
Stem Cell Reports. 2017. doi: 10.1016/j.stemcr.2017.04.023.
In this study, NYSCF researchers developed a protocol for turning stem cells into microglia (the immune cells of the brain) to study their role in neurological disease.
Generation and isolation of oligodendrocyte progenitor cells from human pluripotent stem cells.
Douvaras P, Fossati V.
Nature Protocols. doi: 10.1038/nprot.2015.075.
This paper outlines how NYSCF researchers improved a method for deriving oligodendrocyte progenitor cells – the types of brain cells implicated in MS and other disorders – from induced pluripotent stem (iPS) cells in only 55 days.
Efficient generation of myelinating oligodendrocytes from primary progressive multiple sclerosis patients by induced pluripotent stem cells.
Douvaras P, Wang J, Zimmer M, Hanchuk S, O’Bara MA, Sadiq S, Sim FJ, Goldman J, Fossati V.
Stem Cell Reports. 2014. doi: 10.1016/j.stemcr.2014.06.012.
For the first time, NYSCF scientists generated induced pluripotent stem cell lines from patients with primary progressive MS and developed an accelerated protocol to turn these stem cells into oligodendrocytes, the myelin-forming cells of the central nervous system.
Invited podcasts and webinars:
Google hangout organized by TrialReach
The Stem Cell Podcast
Advances In Multiple Sclerosis (AIMS) Podcast
NYSCF Webinar Series: Multiple Sclerosis and the Promise of Stem Cell Research
NIH Summit Panel
NYSCF’s Valentina Fossati recently conducted an interview with NeuroCentral. Read the interview below.
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.