In view of the potential severe side effects of new immune therapies for multiple sclerosis (MS), research is now focused on the optimized use of established drugs with known side effect profiles. Neurologists in Bochum, working under the auspices of Associate Prof. Andrew Chan (RUB Clinic for Neurology, St. Josef Hospital, Director: Prof. Ralf Gold) are pursuing a pharmacogenetic approach.
They were able to prove that the genetic blueprint of specific transporter proteins allows one to draw conclusions on the effectiveness and risk of side effects of the potent agent mitoxantrone. They hope to be able to develop personalized treatment plans for each individual patient. The results of this study have been published in BRAIN.
Mitoxantrone: highly efficient escalation therapy in multiple sclerosis
According to data supplied by the German Multiple Sclerosis Society's national MS register (DMSG - Deutsche Multiple Sklerose Gesellschaft), up to 10% of German MS patients have been treated with mitoxantrone in the past few years. Numerous studies have shown that it is highly efficient in suppressing disease activity. It is administered as so-called escalation therapy when other medication no longer suffices and in extremely severe courses of the disease. The high therapeutic efficacy of this substance, which originates from oncology, is coupled with potential, in part dose-dependent side effects on the heart, reproductive organs but also on the bone marrow, thus the pros and cons of its administration must be weighted. Prof. Gold stated that, for this very reason, a lifetime maximum dose of mitoxantrone of 140 mg per m2 body surface may not be exceeded.
Signs of the involvement of drug carriers in the effectiveness
Former studies carried out by Dr. Chan and Prof. Gold and their research team had already shown that diverse immune cells respond differently to mitoxantrone. This led to the hypothesis that specific drug carriers - proteins that eliminate mitoxantrone from the cells - have different influences on different cells as well as on the effectiveness of the drug in different patients. The so-called ATP-binding cassette transporters = ABC transporters, thus became the most interesting aspect. The researchers assumed that less potent transporters are accompanied by a higher mitoxantrone concentration within the cells and thus higher effectiveness, and vice versa, that highly functional transporters reduce the effectiveness of the drug.
Genetic blueprint of the transporter influences the effectiveness
They went on to test this hypothesis on a group of MS patients from all over Europe (cooperation with clinics in Dresden, Berg, Göttingen, and Barcelona). It was shown that the differing genetic blueprints of ABC-transporters are indeed linked to the therapeutic response to mitoxantrone. The probability of the patient group with a genetic disposition to low transporter activity responding positively to mitoxantrone is 3,5 times higher than in the group with genetically caused higher transporter activity. Moreover, the functional effects of these genotypes were also confirmed in cell culture experiments and in the MS animal model. Dr. Chan pointed out that the first data gained is also indicative of a correlation between the genetic blueprint of the transporter protein and the side effects of mitoxantrone, for example in isolated cases with cardiac side effects.
Extensive study in the competence network MS should confirm results
Dr. Chan explained, "These results furnish hope for personalized mitoxantrone therapy schedules, for example with adapted single doses. This could also result in longer-term total therapy times being possible, a factor which is particularly important because corresponding follow-up therapy periods have not yet been clearly established." The results of the retrospective study must however first be confirmed in a prospective manner on a large group of patients. The corresponding study within the frameworks of the nation-wide competence network MS, which is subsidized by the Federal Ministry of Education and Research (BMBF - Bundesforschungsministerium), will moreover also investigate further potential pharmacogenetic markers in correlation with mitoxantrone treatment. Prof. Gold and Dr. Chan explained that their primary target is the establishment of a personalized MS treatment strategy for every patient taking the individual aspects of the patient into consideration. These investigations may make it possible to incorporate individual genetic patterns in the decision on the therapy.
Cotte S, von Ahsen N, Kruse N, Huber B, Winkelmann A, Zettl UK, Starck M, König N, Tellez N, Dörr J, Paul F, Zipp F, Lühder F, Koepsell H, Pannek H, Montalban X, Gold R, Chan A: ABC-transporter gene-polymorphisms are potential pharmacogenetic markers for mitoxantrone response in multiple sclerosis. In: Brain, epub ahead of print, Jul 15, doi:10.1093/brain/awp164
Associate Professor Dr. Andrew Chan, Neurological Clinic at the Ruhr-University Bochum in St. Josef Hospital, Gudrunstraße 56, 44791 Bochum, Tel.: 0234/509-2411, Fax: 0234/509-2414, E-Mail: Andrew.Chan@rub.de
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