Download Why we need many “therapeutic targets”

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Why we need many
“therapeutic targets”
W
e are in an all-out search
for the Cure. This is what
we all want for people with
MS. A significant part of this effort
must be aimed at stopping the clinical attacks that result in worsening MS
symptoms as well as preventing all of
the silent damage that is detected only
on MRI scans.
Our current disease-modifying
therapies are only partially effective at
doing this. How will we get the rest of
this job done?
We researchers often speak about
needing “new therapeutic targets” and
say that having more targets is central
to stopping MS completely. We use
the terms “immune system targets” or
“therapeutic targets,” usually assuming that everyone understands exactly
what we mean. I’ve learned that we
often baffle people when we talk about
“targets.” So, this column is aimed at
removing some of that mystery.
How immune “activation” works
It appears that “activated” T cells
orchestrate MS attacks in the central
nervous system (brain and spinal
cord). Most of the body’s supply of
these immune system cells is in a
quiet, relatively inactive stage most of
the time. The process of activating T
cells involves a number of proteins,
activated
T-cell
New treatments
being developed
focus on blocking
the CD28 molecule,
which plays a role
in activating T cells.
B7
other immune cell
October–November 2006
CD28
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including the “T-cell receptor,” a molecule
on the surface of a T cell that recognizes
and binds to proteins from the cells or
tissues that will subsequently be attacked
by the immune system. The same T-cell
receptor also binds to molecules on other
cells of the immune system as part of the
systemwide activation process.
The entire activation sequence
involves a still larger number of molecules. For example, “accessory” molecules
on T cells also bind to proteins on other
immune cells as part of the activation
process. All of these actions are extremely
specific. For example, researchers have
learned that the “CD28” molecule on T
cells must bind to the “B7” molecule on
other immune cells in order for the T
cells to be fully primed to attack the nervous system.
New treatments, now under development, aim at blocking the functions of
the T-cell receptor and the CD28 molecule in order to dampen attacks on the
nervous system. This is why we call the
T-cell receptor and the CD28 molecule
“therapeutic targets.”
activated
T-cell
‘sticky’
proteins
New targets are in our sights
Once T cells and other immune cells have
become fully activated (which usually
takes place while the cells are in one of
the body’s lymph nodes), they use certain
molecules on their surface to control their
movement out of lymph nodes and into
the blood stream. One of these molecules
is called the “sphingosine-1-phosphate
receptor.”
Once the immune cells are in the
bloodstream they use other molecules
called “intercellular adhesion molecules,”
or ICAMs, to help them exit and enter the
brain or spinal cord. The ICAMs do this
by binding to other adhesion molecules
on the surface of the cells that make up
blood vessel walls. Thus, these two molecules—on immune cells and on blood
vessel walls—are also important targets
for MS therapies. By blocking these two
sets of adhesion molecules, which normally function like the two sides of velcro, the activated immune cells can be
forced to continue to speed through the
bloodstream, propelled by blood flow,
and prevented from wedging their way
Tysabri binds
to the sticky
proteins called
ICAMs, preventing the activated
T cell from sticking to the blood
vessel wall.
Tysabri
blood vessell wall
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through the blood vessel wall and into
the central nervous system.
Tysabri (or natalizumab) binds to an
ICAM and blocks its function, thereby
stopping activated immune cells from
leaving the bloodstream. A new therapy
called fingolimod, or FTY720, works earlier in the process. It binds to the sphingosine-1-phosphate receptor described
above, and stops activated immune cells
from exiting the lymph nodes in the first
place. It is currently being studied in a
phase 3 clinical trial involving more than
1,000 people with MS.
Combination therapy may be essential
Why can’t we find just one therapy, powerful enough to get the job done and
stop MS cold? It is possible that completely blocking the function of any given
immune system molecule could stop
the system so profoundly that unwanted
infections would develop.
A promising alternative strategy is to
partially block several different target
molecules simultaneously. This might be
accomplished by using a combination, or
“cocktail,” of drugs. Combined therapies
are already in use by some MS specialists who give an interferon with monthly
pulses of steroid and/or a mild oral
chemotherapeutic agent, such as methotrexate, to some of their MS patients.
Similarly, the combination of Avonex and
Copaxone is currently under study. (See
the Spotlight on CombiRx on page 58.)
It should be mentioned here that Tysabri
is not recommended for use in combination with other chronic immune modulating agents.
October–November 2006
Thus, our search for new therapeutic
targets involves more than identifying
agents that will prove to be more powerful or effective than those currently available. We hope to identify agents that can
be safely combined with others, magnifying their effects against MS while minimizing the risk of infection.
Gene studies will help us
find more targets
Researchers will be greatly aided in this
work by the many studies that we currently
fund to identify the genes that predispose
people to developing MS. This is because
genes direct the production of proteins—
and we are certain that some of the MS
susceptibility genes will prove to control
the production of proteins that are essential for the destructive MS process. Blocking the function of these proteins is likely
to be useful therapeutically. Thus, the identification of genes that predispose people
to develop MS will almost certainly pinpoint important new therapeutic targets.
Multiple paths to tomorrow’s
multiple therapies
To develop the cure that we all want, the
National MS Society is not only funding
trials of new therapeutic agents that are
ready to be studied in people with MS—
we are also continuing to fund the basic
science studies needed to identify new targets. Both kinds of research are leading us
to the MS therapies of tomorrow. n
Dr. John Richert is vice president for
Research and Clinical Programs at the
National MS Society.
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