Long-term
treatment of MS began with the idea of slowing down the immune response.
This type of treatment is known as immunosuppression, and several chemotherapy
agents have been investigated to combat disease progression.
Long-term
treatment of MS began with the idea of slowing down the immune response.
This type of treatment is known as immunosuppression, and several chemotherapy
agents have been investigated to combat disease progression.
Also known
as cytotoxins, these drugs are frequently used to treat cancers, as they
damage or destroy rapidly dividing cells. With MS, the strategy behind
immunosuppression is to dampen the immune system's attack on myelin.
These types of drugs are only partially effective and can have considerable
side effects and toxicity.
To date, the only FDA-approved immunosuppressive therapy for MS is mitoxantrone
(Novantrone®). Other approved immunosuppressive drugs that are not
specifically FDA approved for MS but are often used to treat rapidly
progressing MS include cyclophosphamide, methotrexate, and azathioprine.
Intravenous immunoglobulin (IVIg) is another type of immunosuppressant.
Cladribine (2-Chlorodeoxyadenosine) is an immunosuppressive drug that initially showed positive results in a two-year study with individuals with progressive MS. After the first year, participants exhibited stable neurologic scores and lesion volumes on MRI. In a phase III study, however, no significant effect on disease progression or attack rate was found.
Although cladribine appears to reduce the volume of gadolinium enhancement in patients with both relapsing and progressive forms of MS, it carries an increased risk of bone marrow suppression and viral infections, along with a lack of clinical benefit. For these reasons, cladribine is not generally recommended for the treatment of MS.
Cyclosporine A is an immunosuppressant whose primary use has been with organ transplants. While it provided some benefit for individuals with progressive MS – in terms of slowing the rate of progression – severe side effects greatly outweigh any positive effects of the drug and cyclosporine A is considered unacceptable in the treatment of MS.
Drugs and therapies under investigation in this category include mofetil (Mycofenloate®) – a drug similar to azathioprine, and tacrolimus, an immunosuppressant used for graft rejection. Bone marrow transplants (BMT) or stem cell transplants also involve suppressing the immune system and carry a high risk.
Bone marrow transplants were conducted for the first time with individuals
with MS in 1996. While only a few people with MS have undergone this
procedure, some positive effects are being reported. The bone marrow
transplants are performed by removing some of the patient's marrow and
extracting the stem cells (which mature into different types of blood
cells in the body).
The
patient then undergoes chemotherapy and total body irradiation to destroy
the remaining marrow.
Afterward,
the stem cells are infused back into the patient so they may grow a new
immune system. These experiments with BMT are actually a type of stem
cell transplant. Another area of stem cell research that may benefit
individuals with MS is the placement of stem cells directly into an MS
lesion in the brain, which is discussed later in the section under "remyelination."
BMTs are a high-risk procedure (mortality rate is between two and 10
percent) and are only being used experimentally with severe and quickly
progressing cases of MS. The degree of success for treating MS with this
procedure has yet to be determined. In light of the fairly normal life
expectancy of those with MS, the increased mortality associated with
BMTs limits its applicability to a small population of people with MS.
Anti-T-cell antibodies are used to reduce the number of T-cells that
could enter the CNS and cause damage to the myelin. CAMPATH-IH is a monoclonal
antibody (MAb) that is aimed at certain immune cells.
Humanized anti-CD4
antibody and anti-CD4 monoclonal antibody specifically target CD4+ helper
T-cells, which appear to play a vital role in autoimmunity. By reducing
their numbers, the autoimmune response may be lessened in those with
MS.
As researchers learn more about the cellular changes that occur with
MS, new agents may be developed that selectively target certain mechanisms
within the immune system. This offers several advantages over "global immunosuppression," which
targets the entire immune response. Selective immunosuppression limits
only certain functions and may result in greater efficacy and fewer side
effects.
The next step in developing treatments for MS has been to modify certain actions of the immune system. Through immunomodulatory treatments, the functions of individual cells may be disrupted, redirected, or altered in some way so their damage to the CNS cannot be completed. Interferon beta (Betaseron®, Avonex®, and Rebif®) and glatiramer acetate (Copaxone®) fall under this category of treatment.
Cytokines are believed to have much control over the immune system. Th-1 cellular-induced cytokines (such as IFN-gamma, IL-12, IL-6, IL-2, and IL-1) appear to cause inflammation, while Th-2 cellular-induced cytokines (which include alpha IFN, IL-10, and IL-4) appear to reduce inflammation. Treatments aimed at reducing or disrupting Th-1 cells, or increasing Th-2 cells, may have the potential to slow or stop MS exacerbations and possibly stop damage to the CNS.
Statins are a class of drugs that reduces brain-damaging inflammation. Simvistatin (Zocor®) is a type of statin that is widely used for reducing cholesterol, and investigators are now looking to see if this drug may be effective in stopping the progression of MS. In previous laboratory work, statin drugs have been found to be effective in blocking the activation of inflammatory cells by affecting cyctokine signaling. Studies using simvistatin with animal models of MS have shown encouraging results.
Salbutamol (albuterol) has been used for many years to treat asthma. Increasing evidence of immunomodulatory properties – specifically its ability to decrease the production of IL-12 (a key cytokine for Th-1 cell development) – has made this agent a candidate for MS treatment. In a brief study, 21 individuals with SPMS were given oral salbutamol for two weeks. The results yielded a significant decrease in the percentage of IL-12 producing cells, which lasted for up to a week following treatment.
Alpha IFN is very similar to IFN-beta and is a Th-2 (anti-inflammatory) cellular-induced cytokine. Studies with this agent (recombinant IFN alpha-2a, or rIF-alpha-2a) are showing limited positive results. Participants in a small study were given intramuscular injections of this drug, while animal studies are showing efficacy with oral IFN-alpha. Initial studies with patients taking oral doses have not been very successful but are still under investigation.
Another interferon receiving attention is IFN-T. This is a pregnancy recognition hormone that is believed to suppress immune responses to the baby when a woman is pregnant. This hormone is being studied because women often go into remission during their pregnancy. Oral and injected versions of IFN-T have been effective in animal studies. Studies with individuals with MS have not been reported.
Male
mice have a reduced susceptibility in developing EAE (animal model of
MS). This reduced risk is thought to be a result of the protective properties
of the male hormone (testosterone). During late pregnancy, female mice
experience a decrease in disease activity, and this is at least partly
attributed to raised levels of estriol, the female sex hormone.
Additionally, high levels of both estriol and progesterone are observed late in pregnancy, and these are believed to inhibit nitric oxide and TNF-alpha production. These actions may contribute to the reduced disease activity often experienced late in a pregnancy. Estriol produced very positive results in animal studies, and may present potential in the treatment of MS.
Tumor necrosis factor (TNF-alpha) is a cytokine that appears to be involved with the worsening of MS. Rolipram, cilomilast, propentofylline, and oral pentoxifylline are phosphodiesterase 4 (PDE4) inhibitors that interfere with cytokine production and particularly target TNF-alpha. These agents, which have well documented anti-inflammatory effects, are being assessed in animal studies and early patient trials.
A recent phase II study was conducted to evaluate the safety, tolerability, and efficacy of Rolipram in RRMS and SPMS. The drug was originally developed as an antidepressant, but was also found to have immunomodulatory properties.
Cells communicate and interact with each other to perform their various functions. Pairs of cell adhesion molecules (CAMs) allow cells to interact with one another, and cytokines can control immune system activities by changing the expression of these CAMs. Researchers are looking for ways to disrupt the interactions between CAMs. To reduce the movement of inflammatory Th-1 cells into the brain, humanized mouse monoclonal antibodies (MAbs) against human alpha-4 integrin, and anti-CD11 and CD18 MAbs, have been used. Studies have been conducted with these agents to measure their effects on treating and preventing acute relapses.
Humanized mouse monoclonal antibodies (MAbs) against human alpha-4 integrin – known as natalizumab (Antegren®) – shows promise in the treatment of MS. To determine its effect on MS lesion activity (measured by MRI), a randomized, double-blind, placebo-controlled study was conducted in the UK with 72 individuals with RRMS and SPMS.
Short-term treatment was well tolerated and resulted in a significant decrease in the number of new, active lesions. Clinical effects and long-term results were not included in this study, and additional trials are necessary to determine these outcomes.
A clinical study is in progress (at the time of this writing) to look at the safety and efficacy of Antegren® for individuals with RRMS. Investigators hope that this drug will prevent certain white blood cells from passing through the BBB and causing inflammation as well as damage to the myelin and axons.
Other interactions are necessary for the immune system to be activated, including a costimulatory signal. This antigen-independent signal, paired with an antigen-specific signal, must be received before a T-cell may be activated. Anti-CTLA antibody is an MAb that may attach to certain molecules involved with these signals – and thus potentially interrupt the signal. If the T-cells are not activated, then theoretically, the disease process could be stopped.
Another area of research includes metalloproteinases. These are enzymes that break down certain cell substances needed to help keep tissues intact. In addition to other immune system functions, these enzymes also help white blood cells enter the CNS. Agents that inhibit their activity and have had encouraging results in animal studies include D-penicillamine, Ro31-9790, and BB-1101.
Researchers are looking at how cell death comes into play in MS, and how immunomodulation may interfere with this process. The free radical nitric oxide (NO) may be involved with oligodendrocyte and neuronal injury. Nitric oxide also produces other reactive oxygen species (ROS), which can injure cells.
To
possibly avoid CNS tissue damage, several agents that interfere with
the production of nitric oxide are being considered. The following agents
affect either nitric oxide or ROS, and have shown positive results in
animal studies: antisense oligodeoxynucleotides, butylated hydroxyanisole,
aminoguanidine, catalase, EUK 8, uric acid, and 2-phenyl-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide.
Avoiding axonal injury is a very important area of research and drug development. Researchers have yet to discover how the neurons are specifically injured – whether the immune system attacks them directly, or if the injury results from the nearby attack on the myelin.
Other mechanisms could cause neuronal injury as well. Receptors may be involved, one of which is the NMDA receptor. A new agent, MK-801, is an antagonist to the NMDA receptor, and animal studies have been performed to determine the effects of this drug.
Dexanabinol (HU-211) is an NMDA receptor that appears to exhibit more effective antioxidant and anti-inflammatory properties than MK-801. It suppresses TNF-alpha production and is generally well tolerated. The results of animal studies suggest that this drug may be useful in the treatment of acute MS exacerbations.
Apoptosis or programmed cell death may also play a role in the progression of MS. When a cell has completed its function, it is programmed to die on its own. Apoptosis appears to be directly involved with the myelin and axons in the progressive phases of the disease. With RRMS and the early stages of SPMS, when relapses may still be present, damage is thought to occur as a result of inflammation and the cells that attack the myelin and possibly the axons.
With PPMS, and with SPMS without relapses, inflammation is lessened; myelin, oligos, and nerve cells appear to just die off. This could explain why treatments aimed at reducing inflammation and altering the function of attacking cells, do not appear to affect these progressive forms of MS as much as they do the relapsing forms. Research into preventing apoptosis in these vital cells may provide exciting new treatments in the future. Combination therapies with anti-inflammatory drugs may produce even better results.
This area of research looks at the targets that are attacked by the immune system and may use natural, altered, or synthetic versions of the target in an attempt to alter the immune response. This type of immunotherapy works in the same manner as a vaccine, and the ultimate goal is to induce a tolerance to the target, thereby stopping the attack. Myelin basic protein (MBP) is a major target for destruction in MS, so much research is directed toward altering the attack through administering a version of the MBP.
Research into native myelin peptides for the treatment of MS uses the naturally occurring protein structure of myelin to induce a very specific response in the immune system. Peptides are molecules consisting of two or more amino acids, which are the fundamental elements of a protein.
Given the fact that MS appears to be an autoimmune disease where the body's own immune system attacks the myelin, researchers hope to alter this process by injecting myelin-derived peptides into the body. Similar to vaccines, these peptides are delivered through genetically engineered viruses.
A recombinant vaccinia virus is used to carry in these self-antigens (MBP in this case). Vaccinia is the cowpox virus, and when combined with antigenic material, is the standard method of immunization against any disease.
Once
these native myelin peptides have entered the body through an injected
virus, they are perceived as antigens (foreign substances), even though
they have the same makeup as myelin. The immune system may become activated
and launch an attack on these myelin peptides – possibly diverting
the attack away from the body's own myelin. Alternately, the antigen
may be tolerated by the immune system, and this tolerance may carry
over to the body's own myelin, possibly stopping the autoimmune response.
Although high doses of MBP given intravenously have inhibited EAE,
research has not confirmed why this occurs. Animal studies suggest that
T-cells could be killed off through apoptosis caused by the antigen
(MBP). Another possibility is an increase in Th2 cells that suppress
an immune response, or the antigen-presenting cells could keep damaging
cells from reaching certain receptors necessary to perpetuate the disease
process.
MP4 (Apogen®) is a chimeric, recombinant polypeptide containing
human MBP and human proteolipid protein epitopes. In studies with marmosets
(primates), MP4 prevented clinical symptoms of the animal model of MS,
and did not cause a worsening of the disease. This agent may be useful
in the future for the treatment of MS.
Using a synthetic MBP peptide, researchers gave intrathecal and intravenous inoculations to individuals with MS in a phase I trial. In the CSF, free anti-MBP antibodies (those that target the myelin) were temporarily neutralized, but participants experienced no reduction in relapses.
More desirable results may be attained through the use of altered peptide
ligands (APLs). A ligand is a binding molecule, and with APLs, the
amino acid sequence is slightly changed, so an APL is very similar
but not identical to the peptide it resembles.
This slight alteration in design could lower the risk of promoting
a more severe autoimmune response and could increase the potential
for bringing about tolerance, although this is not always the case.
In animal studies, success with APLs may be attributed to a shift from
a predominance of Th1 (pro-inflammatory) cytokines to Th2 (anti-inflammatory)
cytokines.
One APL that was in a phase II trial for MS was CGP 77116, which is a small protein similar to the protein in myelin. The dose tested was poorly tolerated and the trial had to be discontinued. Studies in MS have not been successful but more work is underway.
The T-cell antigen receptor (TCR) is a component in T-cell antigen recognition, so it is needed to help a T-cell identify its target. The TCR complex is one of the candidate genes thought to be involved in the development of MS and is linked to either the immune system or myelin.
Through animal studies, researchers have found that only very specific T-cell clones could cause EAE (animal model of MS) or MS. In CSF studies from individuals with MS, cultures produced an excess of certain TCR gene families. This is enabling researchers to identify a specific TCR region that can be targeted in a disease-modifying therapy.
During an immune reaction, T-cells are produced that recognize specific regions of the TCRs. These T-cells have the ability to suppress an immune response.
Researchers hope to activate the TCR's ability to inhibit an immune response by using specific TCR vaccines. If successful, such a vaccine could potentially activate down-regulating mechanisms to stop the immune system's attack on the CNS as soon as it begins.
Phase I trials have begun with TCR vaccines given to individuals with MS. Initial findings show an increase in the TCR peptide-specific T-cells that limit an immune response, as well as a lowered lymphocyte response to MBP in vitro (in the lab versus in the body). Some participants may have experienced some clinical benefit. Additional studies with TCR vaccines are in progress and planned for the future.
Positive results were also seen with a phase I trial using whole T-cell therapy. In this study, eight people with MS were vaccinated with irradiated MBP-reactive T-cells. Five of the eight showed a significant decrease in the number of exacerbations, a smaller increase in MRI lesion size, and a modest reduction in disability scores. The three who worsened showed evidence (in vitro) suggesting a shift in T-cell recognition.
This area of research includes antibiotics (which treat bacterial infections) and antiviral agents (which treat virus infections). The theory behind using such therapies is the idea that a dormant or slow-acting infection could be involved in the development of MS.
Evidence of viral antibodies, viral particles, and other signs of viral
infection have been found in individuals with MS. Measles, herpes, human
T-cell lymphoma, and Epstein-Barr viruses have been of particular interest
to MS investigators. Human herpesvirus-6 (HHV-6) and chlamydia pneumoniae
have received recent attention.
Antiviral agents that are under consideration for treating MS include acyclovir (Zovirax®) and valacyclovir. Both medications were developed to treat herpes infections. A randomized, double-blind study with 60 participants diagnosed with RRMS resulted in a one-third reduction in the annual relapse rate for those taking Zovirax® as compared to placebo. In a randomized, double-blind study with valacyclovir, a subgroup of RRMS patients with high levels of disease activity experienced a reduced number of new, active lesions as seen on MRI studies, as well as an increased number of scans that were free of new, active lesions. Antibiotic trials using agents that treat chlamydia pneumoniae are underway, but results are not yet available.
With the newly found availability of five approved long-term treatments for MS, investigators, physicians, and patients alike are tempted to see if combining these treatments would increase the effectiveness. In vitro, combining glatiramer acetate with one of the interferons has yielded encouraging results.
Recently, scientists have paired glatiramer acetate and one of the interferons, as well as adding an immunosuppressive or chemotherapeutic agent to an interferon. These combinations do not appear to increase toxicity and show some indication of effectiveness. Combination therapy, however, could be risky. Trials to test for the safety and efficacy of such combinations are underway.
One of the most exciting areas of MS research today is the discovery of agents to promote remyelination. For many individuals with MS, a remyelinating therapy could mean a partial return of lost function. This would truly be one of the best possible treatment outcomes.
According to research with animals and humans, remyelination can only be mediated by mature oligos not lost to disease, and newly developed oligos from precursor cells (such as stem cells). Large numbers of oligo precursor cells are present in chronic MS lesions, but for some reason, they become inactive.
Transplanting oligos or their progenitors into the CNS has yielded excellent results in rodent and dog studies. A trial with MS patients is now underway to see if transplanting myelin-producing cells from the peripheral nervous system (PNS) will benefit individuals with MS. Myelin-producing cells from the PNS are called "Schwann cells."
In the first of five individuals expected to undergo the procedure in this trial, Schwann cells were removed from a woman's ankle and transplanted into her brain. MRI was used to guide the doctor, who used a needle to inject these cells directly into a previously identified MS lesion.
Growth factors are peptides which are secreted locally and assist with the development of different cells and tissues. Growth factors are thought to affect oligos and may have the ability to promote remyelination. The four types of growth factors are:
Insulin-like growth factor (IGF-I) – promotes remyelination and reduces disease activity in animal studies. Pilot trials with individuals with MS are currently being conducted.
Nerve growth factor (NGF) – increases in the CSF with relapses and decreases when the flare-up subsides. Increased levels are also found in animals with EAE.
Fibroblast growth factor (FGF-II) – causes several positive changes when exposed to older oligos.
Ciliary neurotrophic factor (CNF) – appears to protect cultured oligos from some factors causing apoptosis, but does not protect them from CD4+ T-cells.
Fibroblast growth factor-II (FGF-II) gene therapy has shown positive effects in mice, including production of FGF-II in the CNS, a significant decrease in the number of T-cells and macrophages, and a significant increase in the number of myelin-producing cells. These results indicate that such therapy may provide a new option for treating MS in the future.