Why we need many "therapeutic targets".

We 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, 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."

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 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.

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 maW 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.

Dr. John Richert is vice president for Research and Clinical Programs at the National MS Society.