Transcript No Slide Title

Multiple Sclerosis Research Update
Mark B. Skeen, M.D.
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MS Research Update
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Bone Marrow Transplantation – “The Cure”
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Stem Cells for Multiple Sclerosis
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Myelin Repair in Multiple Sclerosis - Lingo
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“Antisense” for Multiple Sclerosis
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“Allergy Therapy” for Multiple Sclerosis
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MS Research Update

Bone Marrow Transplantation – “The Cure”

Stem Cells for Multiple Sclerosis

Myelin Repair in Multiple Sclerosis - Lingo

“Antisense” for Multiple Sclerosis

“Allergy Therapy” for Multiple Sclerosis
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Bone Marrow Transplantation
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CNS autoimmune disease in which inflammation leads to transient neurologic
dysfunction – relapses and remissions – with intervening repair. As damage
accumulates, repair becomes inadequate and leads to accumulated disability
in the setting of smoldering inflammation.
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Current therapies are largely aimed at reducing inflammation through control
of abnormal immune responses
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The idea behind bone marrow transplantation is that the entire immune
system is ablated (wiped out) with chemotherapy, radiation, or biologics.
Later a new immune system is started by transplanting bone marrow-derived
cells.
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Bone Marrow Transplantation
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Patients with malignancy and MS who underwent BMT for malignancy were
demonstrated to have marked resolution of MS disease activity
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Many different techniques of stem cell mobilization and collection
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Many different techniques of ablation.
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After the ablation of the immune system the patient is at risk for various
severe infections prior to the re-establishment of the new immune system
through transplantation of bone marrow cells.
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Perhaps as many as 600 patients have undergone BMT for MS.
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Bone Marrow Transplantation
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The goal of BMT in MS is replace a diseased immune system with a new
immune system that is not prone to developing MS
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Perhaps this is “the cure”
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Mortality from BMT was previously 3-5%. Some recent publications suggest
it may now be less than 2%.
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In one study, EDSS was reduced in 27% of patients. Some reports
suggested that improvement in EDSS is not sustained
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Although a few patients have had dramatic improvements after BMT, most
reports of improvement are modest
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Bone Marrow Transplantation
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Although the MS may be suppressed after BMT, nearly 10% of patients
develop a second autoimmune disease within the first 2 years after HSCT. mostly autoimmune thyroid disease. - perhaps relates to alemtuzumab
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BMT/HSCT appears most beneficial for patients with highly active MS, early
in the disease course, who are otherwise healthy, and are progressing and
refractory to conventional MS therapies
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Risk vs. Benefit – most beneficial early in very inflammatory disease
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How does this therapy compare with other MS therapies in terms of risk and benefits
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The difference is THIS IS PERMANENT – sort of
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MS Research Update

Bone Marrow Transplantation – “The Cure”

Stem Cells for Multiple Sclerosis

Myelin Repair in Multiple Sclerosis - Lingo

“Antisense” for Multiple Sclerosis

“Allergy Therapy” for Multiple Sclerosis
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Stem Cell Therapy
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What is a stem cell, and why are we interested?
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A stem cell is a precursor cell that is pluripotent – it can differentiate or mature
into any kind of cell – all of the cells in the body have all of the genes necessary
for them to become any type of cell. In theory at least, any cell could have
become a bone cell or a brain cell. What determines what cell they become is
what genes are turned on and off as the cell is developing into a mature cell.
Once a cell differentiates or begins maturing however, it cannot go back. Stem
cells therefore are cells which can be controlled by genetic manipulations to turn
into a specific form of cell
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Stem Cell Therapy
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What is a stem cell, and why are we interested?
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The interest in stem cells as therapy for MS was initially based on the idea that we
might be able to replace damaged or injured nerve cells by using stem cells,
placing them in the nervous system and then causing them to mature into nerve
cells to replace the damaged or injured nerve cells.
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Many experiments have been performed in animal models of MS to see if this is
possible
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It turns out that these experiments have shown some benefit in animal models of
MS, but not because the stem cells turned into nerve cells – for the most part they
do not
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Stem Cell Therapy
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It turns out that it’s not easy to turn a stem cell into a nerve cell with our current level of
understanding.
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Most of the stem cells in current use, tend to turn into the kind of cells from which they
came – cells from the bone marrow, mostly want to become bone marrow type cells,
etc. So a stem cell isn’t always completely a stem cell
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Most of the stem cells we have tried to transplant are not rejected by the immune
system and therefore can function where they are transplanted, but many do not
survive
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Stem cells appear to have many positive effects on the immune system and may have
an impact in limiting autoimmune disease even if they don’t turn into nerve cells
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Stem Cell Therapy
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Several lines of evidence suggest that stem cells can inhibit autoimmune disease and
support some degree of tissue repair in the CNS
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In the current animal models stem cells can limit autoimmune activity and promote
healing, but they do so best early in the inflammatory stage of disease and less so in
the chronic stage when damage and disability have occurred.
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There are some problems and concerns. In at least one study in which stem cells
were placed into the ventricles, they spread inside the brain as desired, but then
created masses of scar-like tissue.
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There is also concern that the effect of stem cells might induce tumor cell growth and
allow for greater growth or invasion of brain tumors or metastatic tumors
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Stem Cell Therapy
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It turns out that there are a form of “stem cell” already in the CNS, oligodendrocyte
precursor cells (OPCS) whose function it is to turn into oligodendrocytes and form
myelin
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To do so, the oligodendrocyte precursor cells (OPCs) must become activated, travel to
where they are needed, and mature into functioning oligodendrocytes.
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The evidence at present is that in MS, the OPCs often travel to the site of
inflammation, but they don’t adequately mature and form myelin. It does NOT appear
that the problem is an inadequate number of OPCs, but rather inadequate function.
Therefore the answer is not more cells, but rather finding a way to change the
microenvironment within the brain that would help these cells function better. It
appears that the chronic inflammation in MS may be responsible for why these cells
don’t remyelinate very well.
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Stem Cell Therapy
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For some reason, when nerve cells are injured, the surrounding oligodendrocytes
which could form myelin are also injured and tend to die. Even when the damage is
due to spinal cord injury (not MS), the oligodendrocytes in the region of the injury
usually do not result in remyelination, but rather they function poorly and tend to die.
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Precisely when and where we need the oligodendrocytes to function and cause
remyelination, they don’t work and instead tend to die along with the neurons. Why
this occurs is still not understood
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Stem Cell Therapy
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Therefore the emphasis has shifted somewhat from providing more cells, to perhaps
better defining the stimulatory and inhibitory mechanisms that control the function of
the OPCs/oligodendrocytes. Although several stimulatory molecules have been
identified, our ability to use them to stimulate remyelination is still in its infancy.
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Therefore although we have significant data to suggest that stem cells can limit
autoimmune responses and promote repair, they do not do so by replacing damaged
cells. The current evidence suggests that we still need to learn more to maximize their
effects
pg21
MS Research Update

Bone Marrow Transplantation – “The Cure”

Stem Cells for Multiple Sclerosis

Myelin Repair in Multiple Sclerosis - Lingo

“Antisense” for Multiple Sclerosis

“Allergy Therapy” for Multiple Sclerosis
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Myelin Repair
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In the developing brain, various cells at various levels of maturation, migrate to form
different areas of the brain and spinal cord, make connections with other nerve cells,
and some are myelinated by other cells in order to speed the conduction of impulses.
This process is controlled by many genes and those genes are turned on and off over
time to accomplish the goal of creating a working nervous system.
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Neurons and oligodendrocytes contain a cell surface receptor called Nogo. The
workings of the Nogo recpetor are complex, but part of the story is when a molecule
called Lingo binds to the Nogo recptor myelination, neurite outgrowth and axon
guidance are inhibited.
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Myelin Repair
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Several experiments suggest that Nogo and Lingo are involved in controlling nerve
growth and myelination during development and in response to injury.
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Lingo
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Anti-Lingo
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Anti-Lingo
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Anti-Lingo
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Anti-Lingo
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MS Research Update

Bone Marrow Transplantation – “The Cure”

Stem Cells for Multiple Sclerosis

Myelin Repair in Multiple Sclerosis - Lingo

“Antisense” for Multiple Sclerosis

“Allergy Therapy” for Multiple Sclerosis
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Antisense Therapy
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Antisense
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ATL1102 is a second-generation antisense oligonucleotide to CD49d RNA, the alpha
chain of VLA-4.
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It binds by Watson-Crick base pairing and recruits intracellular Rnase H leading to
degradation of the RNA strand of the RNA:DNA duplex. Therefore it reduces VLA-4
expression in numerous cell lines, and inhibits cell adhesion
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ATL1102 is rapidly cleared from the blood after administration.
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The aim of this trial was to evaluate whether ATL1102 treatment was able to reduce
brain lesion activity and to determine its safety profile in patients with RRMS
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Antisense
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MS Research Update

Bone Marrow Transplantation – “The Cure”

Stem Cells for Multiple Sclerosis

Myelin Repair in Multiple Sclerosis - Lingo

“Antisense” for Multiple Sclerosis

“Allergy Therapy” for Multiple Sclerosis
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“Allergy Therapy” for MS
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“Allergy Therapy” for MS
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Antigens are the molecules or parts of molecules that the immune system recognizes
as either “self” or “foreign” and therefore responds to
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If the immune system recognizes an antigen as “self” we say that it is “tolerant”
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Auto-immune conditions occur when “self” antigens are not tolerated and are treated
as “foreign” antigens with the initiation of an immune response to destroy the antigen
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In allergy therapy, the antigen(s) to which the individual is allergic are injected in
gradually increasing doses so that they don’t get a bad allergic reaction, but also so
that the part of the immune system responsible for the allergic response gradually
recognizes that antigen as self or becomes “tolerant” of the antigen again
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“Allergy Therapy” for MS
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In this research the authors used one of the antigens involved in an animal model of
MS (EAE) and injected it into affected mice in gradually increasing doses and studied
the immunologic effects over time.
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The goal of the study was to define an optimal strategy for safe and effective antigenspecific immunotherapy. While performing this escalating dose immunotherapy in
mice they studied what inflammatory and anti-inflammatory gene products were being
produced over time to better understand the process.
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The authors believe that they better understand how escalating dose immunotherapy
affects IL-10 and CD4+ T-cell function and suggest that we are nearly ready to begin
clinical trials of escalating dose immunotherapy
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“Allergy Therapy” for MS
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Potential Problems with this approach
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In multiple sclerosis we’re not so sure what the specific antigens are, whether they
are the same in all patients, and whether or not the targeted antigens are actually
the same over time in a given patient
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We don’t really understand how the dose escalation process results in improved
antigenic “tolerance”
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It is clear that the form of antigen used, the antigen dose, and the frequency of
injection all impact the development of antigenic tolerance, and we do not currently
understand what would be optimal.
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