Pg1 Multiple Sclerosis Research Update Mark B. Skeen, M.D

pg1pg1

Multiple Sclerosis Research Update

Mark B. Skeen, M.D.

pg2

pg3

pg4

pg5

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

pg6

MS Research Update






pg7

Bone Marrow Transplantation

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.

Current therapies are largely aimed at reducing inflammation through control

of abnormal immune responses

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.

pg8


Patients with malignancy and MS who underwent BMT for malignancy were

demonstrated to have marked resolution of MS disease activity

Many different techniques of stem cell mobilization and collection

Many different techniques of ablation.

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.

Perhaps as many as 600 patients have undergone BMT for MS.

pg9

pg10

pg11


The goal of BMT in MS is replace a diseased immune system with a new

immune system that is not prone to developing MS

Perhaps this is “the cure”

Mortality from BMT was previously 3-5%. Some recent publications suggest

it may now be less than 2%.

In one study, EDSS was reduced in 27% of patients. Some reports

suggested that improvement in EDSS is not sustained

Although a few patients have had dramatic improvements after BMT, most

reports of improvement are modest

pg12


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

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

Risk vs. Benefit – most beneficial early in very inflammatory disease

How does this therapy compare with other MS therapies in terms of risk and benefits

The difference is THIS IS PERMANENT – sort of

pg13

MS Research Update






pg14

Stem Cell Therapy

What is a stem cell, and why are we interested?

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

pg15

Stem Cell Therapy

What is a stem cell, and why are we interested?

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.

Many experiments have been performed in animal models of MS to see if this is

possible

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

pg16

Stem Cell Therapy

It turns out that it’s not easy to turn a stem cell into a nerve cell with our current level of

understanding.

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

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

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

pg17

Stem Cell Therapy

Several lines of evidence suggest that stem cells can inhibit autoimmune disease and

support some degree of tissue repair in the CNS

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.

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.

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

pg18

Stem Cell Therapy 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

To do so, the oligodendrocyte precursor cells (OPCs) must become activated, travel to

where they are needed, and mature into functioning oligodendrocytes.

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.

pg19

Stem Cell Therapy

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.

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

pg20

Stem Cell Therapy

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.

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






pg22

Myelin Repair

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.

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.

pg23

Myelin Repair Several experiments suggest that Nogo and Lingo are involved in controlling nerve

growth and myelination during development and in response to injury.

pg24

Lingo

pg25

Anti-Lingo

pg26

Anti-Lingo

pg27

Anti-Lingo

pg28

Anti-Lingo

pg29

MS Research Update






pg30

Antisense Therapy

pg31

pg32

Antisense

ATL1102 is a second-generation antisense oligonucleotide to CD49d RNA, the alpha

chain of VLA-4.

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

ATL1102 is rapidly cleared from the blood after administration.

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

pg33

Antisense

pg34

MS Research Update






pg35

“Allergy Therapy” for MS

pg36


Antigens are the molecules or parts of molecules that the immune system recognizes

as either “self” or “foreign” and therefore responds to

If the immune system recognizes an antigen as “self” we say that it is “tolerant”

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

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

pg37


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.

The goal of the study was to define an optimal strategy for safe and effective antigen-

specific 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.

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

pg38


Potential Problems with this approach

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

We don’t really understand how the dose escalation process results in improved

antigenic “tolerance”

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.

pg39

Documents

Pg1 Multiple Sclerosis Research Update Mark B. Skeen, M.D