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Contents
Introduction
"The structure [of DNA] is a thing of transcendent beauty and explanatory power. Perfectly parsimonious, it shows at a glance how genes replicate, passing down the generations, and how they are expressed, dictating the construction of proteins."
Horace Freeland Judson, 2004 5
The year 2003 was widely celebrated as the fiftieth anniversary of the discovery of DNA's structure by Francis Crick and James Watson. Crick then went on to work out the "central dogma" of molecular biology -that information flows from the DNA in the nucleus to the outer parts of the cell where it is used to assemble proteins. These stunning accomplishments triggered a renaissance of investigation into basic biology which is finally beginning to yield remarkable new treatments for human disease.
No where are the new medications more urgently needed than for multiple sclerosis (MS), the most common CNS demyelinating disease in the world, affecting approximately 350,000 people in North America and more than million individuals worldwide. Like other auto-antibody-dependent autoimmune diseases (such as rheumatoid arthritis and lupus erythematosus) women are at far greater risk of developing MS than men. Why? Because female hormones amplify antibody responsiveness to ensure the successful transfer of immunological experience from mother to offspring. 9,16,17
Although there is some controversy about its pathogenesis, the intimate involvement of agitated B cells implicates an inflammatory cause of MS --a belief that is reinforced by the fact that steroids make patients feel better. This is a research advantage, because inflammation involves a number of potential targets for immune therapy: B cells, of course, but also invading T cells, dendritic cells, macrophages and microglia to name a few. 14,16,17
The majority of patients with MS --approximately 85%-- begin with the relapsing-remitting disease form, characterized by attacks (exacerbations) followed by periods of apparent quiescence. However, despite appearances to the contrary, MS is usually a steadily progressive illness. And while remyelination can occur during the early inflammatory phase, axons die in later stages and the damage becomes irreversible. Thus, the expert consensus is that all patients with MS should be aggressively treated as early in their disease as possible. 11,16
The introduction of immunomodulating therapy in the early 1990s provided the first way to decrease exacerbation frequency in MS patients and, perhaps, to slow disease progression. Indeed, beta-1b (Betaseron®), interferon beta-1a (Avonex®) and glatiramer acetate (Copaxone®) transformed MS into a manageable illness.4 But these breakthrough immunotherapies are fast becoming yesterday's medicines as newer, more effective and better tolerated MS treatments emerge.
One new and very elegant immunotherapy, natalizumab (Antegren®), a recombinant monoclonal antibody that blocks the egress of pathogenic T cells into the CNS, is in its final stages of clinical testing. A new benchmark efficacy rate of 50% was recently established by this α4- integrin blocker in a 6-month study. If longer-term trials confirm the same level of efficacy, Antegren will have a major impact on the care of patients in early stages of MS. 6,15
What follows is a short review of MS treatment, from the very bleak prognosis the disease incurred less than a decade ago to the great promise of precisely targeted immunotherapies about to emerge from a rich research pipeline.
Past
William Moxon and William Osler referred to this peculiar disease as "insular sclerosis," a name that stuck for many decades. The British called it "disseminated sclerosis." Eventually all other names were replaced by "multiple sclerosis" from the German multiple sklerose.
The first report of an unmistakable relapsing-remitting MS was published in the early 1800s by Charles Prosper Ollivier d'Angers who surmised that the cause was an infection. The patient was a young man who, remarkably, remained cheerful despite advancing disability and his treatment (which consisted of bleeding and a liberal application of leeches over the thoracic area). 13
Jean-Martin Charcot accurately described the nature of MS with the help of Edme Feliz Alfred Vulpian, who coined the term sclιrose en plaque diseminι. It was Charcot though who combined the clinical science and pathology of MS into a unified clinical concept in the l860s --which enabled clinicians to recognize what they were seeing in their offices, wards, and clinics.
MS has traditionally been thought to be either caused or triggered by an infection. Spirochetes and "slow" virus (now known to be prokaryotes called Mycoplasmas, the smallest known free-living organisms) were just two of the accused microbial perpetrators. A prominent German neurologist even tried to prove Koch's postulates by transmitting the illness from MS patients to a healthy subjects during World War II (the Schaltenbrand experiments). 7
But the absence of proof is not proof of absence. There is still suspicion of microbial involvement in MS and strong evidence that any one of several different viruses, acquired during childhood or adolescence, contribute to its susceptibility.16
Eventually the experts concluded that none of these treatments was any more successful than the improvement that occurred spontaneously.7
Present
Glatiramer acetate (Copaxone), a collection of random peptides, was originally developed to investigate immunologic mechanisms in experimental allergic encephalomyelitis (EAE). It eventually became apparent that the drug prevented or modified EAE in several species, including non-human primates. Copaxone entered clinical trials in the early 1990s and was released for clinical use shortly thereafter. 9
The choice of which agent to use depends on efficacy, tolerability and a patient's lifestyle. Interferons are generally considered more effective than Copaxone. However, the effects of neutralizing anti-IFN antibodies (Nabs) also have to be taken into consideration when choosing which interferon to use.
Until now the effects of Nabs on therapy was unclear. None of the phase III studies showed a relationship between Nab development and clinical efficacy. However, re-evaluation of these results in conjunction with longer-term observations disclosed that Nabs do interfere with efficacy and testing for these antibodies should be performed routinely with standardized assays at least 1 and 2 years after the start of treatment. Unfortunately though, Nabs are cross-reactive and once a patient mounts antibodies against one interferon all others will be similarly effected. So it may be best to initiate therapy with the interferon least likely to provoke an antibody response. 12
| Agent | Dose | Known or Possible Treatment Benefits |
| Interferon beta-1a (Avonex®) |
30 µg IM once weekly |
|
| Interferon beta-1a (Rebif®) |
22 or 44 µg SQ every other day |
|
| Interferon beta-1b (Betaseron®) |
8 million IU SQ every other day |
|
| Glatiramer acetate (Copaxone®) |
20 µg SQ every day |
|
| Adapted from Noseworthy JH et al. NEJM 2000;343:938-952. 8 | ||
Even though there is ample proof that the interferons and Copaxone reduce the frequency of exacerbations, relapses are inevitable. These signal disease reactivation and acute intervention with immunosuppressive therapy. Breakthrough disease is quite another matter. MS is a heterogeneous illness and single-drug therapy may not effect long-lasting remission. Because patients respond in variable degrees to different medications, combination therapy may be warranted. However, clinical studies are still needed to show which agents provide synergistic or additive effects and which are antagonize one another.
| __________________________side bar__________________________ Definition of "Breakthrough Disease" |
|
| ___________________________________________________________ |
| Agent | Advantages | Drawbacks |
| Glucocortico-steroids (GCSs) | The standard treatment for MS relapses. May hasten recovery from an acute exacerbations. High doses provide better results. Prolonged treatment with pulsed IV methylprednisolone (IVMP) may slow development of T1 black holes, prevent or delay whole-brain atrophy, and prevent or delay disability progression. |
Short-term complications usually resolve quickly and include GI upset, fluid retention, taste perversion, insomnia, irritability and anxiety. Long-term complications are potentially serious including osteoporosis and aseptic necrosis of the hip or shoulder, diabetes, hypertension, glaucoma, cataract and peptic ulcer. 18 |
| Methotrexate | Provides immunosuppressive, anti-inflammatory and immunoregulatory activity and provides a relatively well-tolerated treatment option for some MS patients. | Can cause ulcerative stomatitis, leukopenia, nausea, diarrhea and increased sun sensitivity. 3 |
| Azathioprine (Imuran®) |
A "pro drug," that slowly liberates 6-mercaptopurine and 6-thioinosinic acid which alter antibody production. Tumor necrosis factor (TNF)-α levels may also be reduced and suppressor-inducer T-cell subsets increased. |
The immunosuppressive effect of azathioprine requires three to six months of daily use, putting patients at increased risk for infection and malignancies. 3 |
| Mycophenolate-mofetil (MMF; CellCept®) | Inhibits inosine monophosphate dehydrogenase, without which lymphocytes cannot synthesize purines. A preliminary investigation with five patients suggests this immunosuppressive agent halts MS progression. | Studies in patients with MS are ongoing.1 |
| Cyclo-phosphamide |
Provides both cytotoxic and immunosuppressive effects. Monthly administration in doses ranging from 1000 to 2000 mg2 of body surface profoundly reduces the number of T helper or T inducer cells. Less striking, but also important, is the agent's ability to decrease suppressor cytotoxic cells in patients with MS. Cyclophosphamide pulsed therapy was recently used to "rescue" 47 relapsing-remitting MS patients. treatment halted progression of disease in 78% (as measured by EDSS) and MRI activity was stabilized by 75%. The investigators consider pulse cyclophosphamide a therapeutic option in MS patients unresponsive to interferons or Copaxone alone. 2 |
As would be expected, this potent drug is not without risks including menstrual irregularity, menopause and infertility. Potentially myelotoxic and carcinogenic.3 |
| Mitoxantrone |
An antineoplastic drug that suppresses humoral immunity, reduces T cell numbers, abrogates helper cell activity and enhances suppressor cell function. The agent has been used in 12 MS trials with good results. Infrequent administration (once every three weeks) provided significant improvement in EDSS scores and reductions in the number of relapses. |
Side effects include leukemias and cardiomyopathies which limit the duration of mitoxantrone usefulness.3 |
Despite the fact that available treatments dramatically lessen the impact of MS, most patients still progress. Thus, the importance of continued research and the hope provided by a full pipeline of more effective therapies, less toxic and easier to use medications for this disease.
In The Pipeline
As an integrin inhibitor, at least part of natalizumab (Antegren®) efficacy is achieved by blocking the egress of pathogenic T cells into the CNS. Preventing T-cell entry into the CNS is important because once inside they can precipitate an inflammatory cascade, resulting in new MS lesions. 10,15,16
Results of a randomized, double-blind preliminary trial of Antegren in patients with relapsing-remitting or relapsing secondary progressive MS (n=213) clearly showed MRI evidence of suppressed formation of gadolinium-enhancing inflammatory brain lesions in the patients receiving Antegren.
Although the intent of this 6-month study was not to demonstrate an effect on clinical outcome, a significant reduction in relapse frequency and an increased perception of well being occurred in the patients who were infused with Antegren. The authors conclude that selective inhibition of α4 integrin-mediated adhesion and migration of leukocytes is an effective approach to treating patients with MS.6
Monthly infusions of Antegren were also well tolerated. The only cause for concern was a trend towards an increased rate of infection, which is being carefully monitored in longer-term trials.6
| Agent | Dose | Treatment Benefits |
| Natalizumab (Antegren®)* |
3 or 6 mg by infusion Every 28 days |
|
| Major Target | Description | Advantages |
| Inflammation | Dual α4 integrin antagonist (VLA4) |
|
| Inflammation | Dual-acting COX-2 inhibitor |
|
| Inflammation | LFA3TIP human fusion protein |
|
| Inflammation | LTβ-receptor blockers |
|
| Inflammation | Rituximab (Rituxan®) |
|
| Inflammatory Consequences |
CB2 Agonist |
In EAE, CB2 agonism modifies diseases and reduces:
|
| Inflammatory consequences |
MAG-specific mAb |
Human MS plaques show preferential loss of MAG
|
| Neuroprotective | Nogo-A-specific mAb |
|
|
APC = Antigen Presenting Cells CB = Cannabinoid Receptor Mag = Myelin-Associated Glycoprotein Nogo-A =A CNS-myelin associated protein PPAR = Peroxisome Proliferator-Activated Receptor |
||
Summary and Conclusion
Available immune modulating agents, interferons in particular, decrease the frequency of exacerbations, reduce disability and appear toslow disease progression. At present, these agents, along with Copaxone, provide the platform therapies for MS. An impressive range of immunosuppressive therapies are available for the acute intervention of relapses and/or breakthrough disease. But even though these therapies dramatically lessen the clinical impact of MS, imaging and MRI spectroscopy reveal ongoing CNS damage of significant magnitude.As the immunopathology of MS becomes better understood, treatments with greater specificity are emerging. The preferred therapeutic targets are 1) mediators of lymphocyte migration and adhesion, 2) molecules critical for presentation of self-antigens and autoaggressive T-cell activation, and 3) cells that secrete the destructive cytokines involved in neuronal damage.14
The first new agent for MS in many years, an antibody designed to prevent T-cell entry into the CNS by blocking 4-integrin, is on the verge of approval by FDA. A number of other pipeline molecules appear even more promising; for example, an oral α4-integrin blocker and least one molecule with neuroprotective activity are already in clinical testing.
However, the true potential of any disease-modifying agent can only be realized if a patient uses it, perhaps for a lifetime. It is important, therefore, that many the new medications are better tolerated and easier to use than existing MS treatments. Antegren and Rituxan, for example, are given by monthly infusion, which patients seem to find far more acceptable than daily or weekly injection. An oral version of any effective medication would be widely applauded by doctors and patients alike. And there are a few of these in the pipeline as well.
In recent years, synergy between the powerful disciplines of immunology and molecular genetics have helped define the immunopathology of MS and give scientists the tools they need to conceive and generate new therapies. It is fitting, therefore, that the premier theorist of molecular biology and one of the men who began it all -Francis Crick-took his 1962 Nobel prize in physiology and used it to investigate the workings of the brain. He made the study of consciousness respectable because, as one neurologist said: "If Crick found it important, we'd better pay attention."5
- Ahrens N., Salama A., and Haas J. (2001) Mycophenolate-mofetil in the treatment of refractory multiple sclerosis. J Neurology 248, 713-714.
-
Gauthier S.A., Bharanidharan P., Stazone L., and et al. Treatment of Relapsing Remitting Interferon/Glatiramer Acetate Unresponsive Patients with Pulse Cyclophosphmide. PO2.130, A148. 2003. NEUROLOGY.
Ref Type: Report - Goodkin D.E. (2000) Treatment of Progressive Forms of Multiple Sclerosis. In Multiple Sclerosis: Diagnosis, Medical Management and Rehabilitation (ed. Burks J.S. and Johnson K.P.), pp. 177-192. Demos, New York.
- Holland N., Wiesel P., Cavalio P., and et al (2001) Adherence to Disease-Modifying Therapy in Multiple Sclerosis: Part I. Rehabilitation Nursing 26, 172-176.
- Judson H.F. (2004) First among Equals --Francis Crick. New England Journal of Medicine 351, 858.
- Miller D.H., Khan O.A., Sheremata W.A., Blumhardt L.D., Rice G.P., Libonati M.A., Willmer-Hulme A.J., Dalton C.M., Miszkiel K.A., O'Connor P.W., and International Multiple Sclerosis Trial Group (2003) A controlled trial of natalizumab for relapsing multiple sclerosis. New England Journal of Medicine 348, 15-23.
- Murray T.J. (2000) The History of Multiple Sclerosis. In Multiple Sclerosis: Diagnosis, Medical Management, and Rehabilitation (ed. Burks J.S. and Johnson K.P.), pp. 1-32. Demos, New York.
- Noseworthy J.H., Lucchinetti C., Rodriguez M., and Weinshenker B.G. (2000) Multiple Sclerosis. New England Journal of Medicine 343, 938-952.
- Pender M.P. (2000) Neurology.4:Multiple sclerosis. Med J Australia 172, 556-562.
- Ridley A.J., Schwartz M.A., Burridge K., Firtel R.A., Ginsberg M.H., Borisy G., Parsons J.T., and Horwitz A.R. (2003) Cell Migration: Integrating Signals from Front to Back. Science 302, 1704-1709.
- Rudick R.A. (2001) Evolving concepts in the pathogenesis of multiple sclerosis and their therapeutic implications. Neuroophthalmology 21, 279-283.
- Sorensen P.S. (2004) Antibodies to IFN-beta: The Danish National IFN-beta Project. Neurology 61, S27-S28.
- Spillane J.D. (1981) The doctrine of the nerves. Oxford University Press, New York.
- Steinman L. (2004) Immune Therapy for Autoimmune Diseases. Science 305, 212-216.
- von Andrian U.H. and Engelhardt B. (2003) alpha4 Integrins as Therapeutic Targets in Autoimmune Disease. New England Journal of Medicine 348, 68-72.
- Zamvil S.S. and Steinman L. (2003) Diverse targets for intervention during inflammatory and neurodegenerative phases of multiple sclerosis. Neuron 38, 685-688.
- Zinkernagel R.M. (2003) Understanding Microbial Pathogenesis as a Basis for Vaccine Design. In The Vaccine Book (ed. Bloom B. and Lambert P.-H.), pp. 149-163. Academic Press, New York.
- Zivadinov R., Rudick R.A., DeMasi R., and et a (2001) Effects of IV methylprednisolone on brain atrophy in relapsing-remitting MS. Neurology 57, 1239-1247.