Emerging approaches to MS therapy

The main challenges in MS research are to reduce the damaging effects of inflammation in the CNS, and to restore nerve function caused by neurodegeneration so as to prevent or delay disability. If you were an MS researcher, how would you meet those challenges? What ideas would you pursue to counter the problems of inflammation and neurodegeneration?

What are the possible targets of MS therapy?

Let’s look at the different stages of the MS course and how therapies can target different aspects to reduce the disease severity.

The initial On-switch: It isn’t known what initially turns on the immune system hyperresponse in MS. One possibility is a viral infection in childhood or adolescence. A viral protein may resemble one of the body’s own myelin proteins (called molecular mimicry). After the immune system learns to recognize the viral protein, it may then attack the myelin proteins that resemble the virus.

But this is speculation. Several viral or bacterial candidates (e.g. herpes virus, Chlamydia) have been proposed, but none has been shown to initiate the MS disease process. If this initial “switch” is ever found, researchers may be able to find ways to turn it off before any damage occurs.

Immune system activation: Turning on the immune system is a complex process. In MS, after the APC/MHC complex has taken up an antigen, it activates the T cell by attaching to it via a T cell receptor (TCR). In addition, a number of other molecules are required (such as CD28) before activation can occur. Once activated, the T cell will start to proliferate as one of several subtypes of T cell. For example, Th1 cells promote inflammation, whereas Th2 cells have anti-inflammatory effects.

This early step in the inflammatory process offers a number of opportunities to stop inflammation before it gets started:

1. One or more components required for activation could be targeted. For example, if the T cell receptor were blocked, the T cell could not become activated.
2. The type of T cell proliferation can be influenced. As we’ve discussed in previous chapters, the immunomodulatory drug glatiramer acetate (Copaxone^®) is thought to shift the Th1/Th2 balance toward a Th2 response. This means that after being activated, the T cells will tend to be anti-inflammatory and cause less damage in the CNS.
3. Many bodily processes are in a delicate balance, and the body has its own built-in Off switches when this balance is disturbed. When you put food in your mouth, digestion gets turned on; once the food is gone, the digestion signal gets turned off. MS appears to be a problem not only of abnormal activation of the immune system, but also persistent activation: at some point the inflammatory response should turn off, but it doesn’t. As more is learned about this self-suppressor function, we may be able to design therapies that stimulate the body to activate its Off switch.
4. T cell proliferation could be turned off entirely. This is what happens with many immunosuppressant drugs. T cells become activated, but they self-destruct when they try to divide. However, this approach cannot be used long-term because prolonged suppression of the entire immune system leaves your body susceptible to infections. The opportunity does exist, however, to suppress T cell proliferation more selectively.

Invasion of the central nervous system (CNS): Once T cells become activated, they migrate to the blood-brain barrier (BBB), a layer of tightly-packed cells that normally blocks the passage of most molecules into the CNS. The BBB can be thought of as the wall of a castle. Invading T cells have several strategies to breach that wall. A number of molecules have been identified that allow T cells to attach to the BBB. Adhesion molecules (such as alpha-4 integrin, also known as very-late antigen [VLA]-4) act like a ladder – a first step in getting over the wall. On the BBB wall itself, these adhesion molecules bind with other adhesion molecules (such as vascular cell adhesion molecule [VCAM]-1), creating a connection so the T cell can cross over into the CNS.

A more direct way is simply to batter down the wall, which is the function of enzymes called MMPs (matrix metalloproteinases). These enzymes erode the BBB, creating “holes” in the wall that allow more activated T cells to get inside.

Both of these approaches offer opportunities for a therapy to interrupt the process. The molecules needed for T cell adhesion to the BBB could be blocked, and/or the MMP enzymes could be inhibited so they didn’t degrade the BBB. In fact, this is one of the ways that beta-interferons (Avonex^®, Betaseron^®, Rebif^®) appear to work. It is presumed that this class of medication partially blocks T cells from attaching to the BBB, and also inhibits the MMP enzymes.

Reactivation of T cells in the CNS: Once T cells enter the CNS, they come into contact with new antigen and become reactivated. As with the initial T-cell activation, there are a number of ways that this process could be interrupted. For example, T cells that have previously reacted to glatiramer acetate outside the CNS release a variety of chemicals that suppress the local autoimmune and inflammatory reactions inside the CNS. This means that CNS inflammation is less damaging to myelin and neurons.

Neurodegeneration. As we’ve seen in previous chapters, neurodegeneration may occur as a result of the damaging effects of inflammation, and may also proceed somewhat independently of inflammation. There are a number of possible targets for therapy, and new ones will likely emerge as more is learned about this process. Simply stated, a treatment could try to:

• Prevent or reduce myelin damage
• Enhance myelin repair by cells (such as oligodendrocytes) that re-cover axons with myelin
• Stimulate axonal repair or regrowth following damage to the axon, e.g. by increasing production of nerve growth factors (neurotrophins, e.g. BDNF) or other CNS constituents.

New approaches

When considering the future of MS therapy, we can think of new ways of using medications that are already established to treat MS, new uses for non-MS medications, and entirely new drugs that will target some aspect of inflammation and/or neurodegeneration.

Combination therapy

There are several single agents to treat MS. These include glatiramer acetate (Copaxone^®), and the beta-interferons (Avonex^®, Betaseron^®, Rebif^®). Ideally, one drug would give an individual all the treatment they’d need.

But that is fairly uncommon in medicine. For example, someone with heart disease may take one medication to lower blood pressure, a second to lower cholesterol levels, and a third to prevent blood clotting.

Combination therapy – using two or more drugs in treatment – offers doctor and their patients a number of advantages over single-agent therapy. By using a combination of drugs, the doctor can direct therapy at more than one aspect of the disease process, using a “scattershot” approach rather than focusing on one specific target. A drug that relieves inflammation may not treat neurodegeneration, and vice-versa. Using two drugs, for example, may enable treatment to achieve two goals.

This is now being explored with various combinations. A number of trials are now investigating the potential benefits of combining immunomodulatory drugs with corticosteroids; immunosuppressants; immune-specific agents that narrowly target an aspect of the immune response; and anti-oxidants, which may be able to prevent some of the neurodegeneration seen in MS.

Combining drugs may produce important synergies, i.e. two drugs may interact to achieve a greater effect than either one alone. Drugs can also be used in sequence, creating a “one-two” punch that is more powerful than a single blow.

New uses for non-MS medications

When a new medication is approved for use it means that it has been shown to be effective and generally safe for patients with a given medical condition. But that isn’t always the end of the story. As medical research advances and more is learned about how an illness works, there may appear to be a role for an older medication with a known mechanism of action. Further testing of a drug may also uncover effects that weren’t apparent before. Think of Aspirin^®: originally developed to treat fever, it was later found to have important anti-clotting effects on the blood that may be life-saving in people at risk of a heart attack.

Similarly, a great deal has been learned about the MS disease process in the past decade. As doctors understand more about the disease, they realize that they may already have medicines in their black bag that could do some good.

New MS drugs

Now that we know something about how the current crop of MS drugs works, new medications can be developed that target those same processes. This can lead to drugs that are more effective, or which have fewer side effects. More importantly, not everyone will respond to a given drug, but they may respond to a slightly different agent even if it works in a similar way as the first drug. This provides doctors with an opportunity to treat a wider range of people more effectively.

In addition, the wealth of MS research has uncovered possible new targets for which no treatment is now available. This challenges researchers to think of ways of developing an entirely new therapy for the new target.

Finally, ideas generate ever more ideas, and there have been some novel concepts over the past few years that may have some application in MS. For example, the brain produces large amounts of oxygen “free radicals”, which react with other molecules to cause damage to myelin and axons in the brain. This phenomenon may be countered by anti-oxidants, and several new drugs are now being investigated.

What the Future Holds

The development of two classes of drug – glatiramer acetate and the beta-interferons – a decade ago had led to an explosion in MS research. New drug combinations are being tested to see if they can provide added benefits to people with MS. In addition, over 150 drugs are now in development and are undergoing clinical trials.

This is a time of great hope for people with MS. The current medications can reduce the frequency and severity of MS relapses, and may delay the onset of disability. The next generation of therapies may be able to surpass these achievements.

However, many fundamental questions still remain:

• Is MS an autoimmune disorder?
• Is there a trigger, such as a viral or bacterial infection, that dysregulates the immune response?
• Why does inflammation persist in the CNS without shutting off?
• How do demyelination and neurodegeneration occur?
• Can treatments prevent or reverse neurodegeneration?
• Can the disability caused by neurodegeneration be prevented?

These questions are critical to our understanding of MS. If some of them can be answered, we will be that much closer to transforming MS into a more benign condition. A cure for MS may be beyond our reach – at least in the foreseeable future – but it may be more controllable with the right therapies. Think of acquired immune deficiency syndrome (AIDS) or certain types of cancer. They can’t be cured at the moment, but they can be controlled to such a degree that sufferers can live longer, more productive lives.

Ongoing research may be able to accomplish the same for MS. If inflammation and neurodegeneration – the twin processes underlying MS – could be controlled with therapy, people with MS might be able to live their lives without the fear of becoming disabled. That would eliminate a lot of the uncertainty experienced by people living day-to-day with the illness.

Importance of early treatment

MS is a process that typically begins in childhood or adolescence and continues throughout a person’s life. In the relapsing-remitting form of MS, relapses are experienced as periodic flare-ups. But in between relapses, there is still a “slow burn” going on in the background which is less apparent because this inflammatory disease process isn’t associated with symptoms. Over time, the body’s self-repair mechanisms can’t keep up with the damage caused by CNS inflammation. The result is a steady accumulation of irreversible neuronal damage that ultimately reveals itself as neurological deficits and disability. That is why starting a therapy is so important: to slow down the disease and to try to prevent disability.

It may be possible to alter the natural course of the disease with immunomodulatory treatments, such as glatiramer acetate (Copaxone^®) or a beta-interferon (Avonex^®, Betaseron^®, Rebif^®) first line treatments. It is now well-established that irreversible damage can occur early in the course of MS, and so early treatment has been recommended by a number of groups, including the MS Society of Canada, the National MS Society in the U.S., an international working group of researchers, and the Canadian MS Clinics Network. According to these experts, treatment with glatiramer acetate or one of the beta-interferons should be considered as soon as possible. The hope is that early therapy will arrest the disease process and prevent the accumulation of damage in the CNS that is responsible for disability later in life.

Imagining MS without disability

As recently as the 1980s, there were no effective treatments to control the MS disease process. Since the 1990s, we have made a great deal of progress in reducing the frequency and severity of MS relapses.

Now imagine if MS relapses were rare events. Imagine if there were few uncomfortable symptoms: no tingling or numbness, little fatigue, no difficulty walking, no incontinence. Imagine if MS didn’t lead to disability.

These are not impossible goals. It may be possible to re-regulate the inflammation and neurodegeneration that cause MS symptoms and disability. The current immunomodulatory therapies used alone or in combination with other medications, and new therapies currently in development, may enable doctors to individualize treatment for each person’s specific needs. These medications may allow people with MS to live virtually free of symptoms, prevent neurodegeneration with a neuroprotective agent, and restore function to damaged axons.

These important goals of MS research – controlling inflammation, eliminating neurodegeneration and preventing disability – are still being researched. We don’t have all the answers and all of our goals of treatment have not been attained yet. Such achievements lie in the future.

But the future is always sooner than you think.