Novel treatment to stop progressive neuropathy and muscle weakness in multifocal motor neuropathy
Dr. Ruben Herrendorff, Pharmazentrum, University of Basel
Abstract (Lay summary see below)
The aim of the proposed translational project is to develop a promising new treatment for multifocal motor neuropathy (MMN). MMN is a disabling neuromuscular disease that affects 1-2 individuals per 100’000. The disorder shows a similar clinical picture as amyotrophic lateral sclerosis and is often misdiagnosed. Nonetheless, MMN is a pure motor neuropathy, which causes predominantly asymmetric weakness in the upper extremities. Recent studies have shown that antiganglioside autoantibodies (anti-GM1 IgM) are crucial in the pathophysiology. The binding of anti-GM1 antibodies to the GM1 epitope in the peripheral nervous system leads to complement activation and to disruption of the sodium channel clusters at the nodes of Ranvier. This causes multiple motor neuron conduction blocks, axonal degeneration, muscle fasciculations, and muscle atrophy leading to the loss of motor function in the hands and the legs. These considerable impairments make it hardly impossible for patients to cope with daily life. The treatment of MMN is currently limited to unselective immunosuppression and expensive immunoglobulins (IVIg). Both of these therapeutic options can, however, halt the motor decline only transiently and they fail to stop disease progression in the long-term.
Our therapeutic approach is radically different from the current immunosuppressive- and IVIg treatments. We are leveraging the potential of glycobiology- and chemistry to develop a promising new therapy. Based on the structure of the natural GM1 glycoepitope, we design glycomimetic antibody-scavengers that allow for efficient and selective in vivo removal of pathogenic anti-GM1 antibodies. Based on data from previous projects we can reasonably assume that such glycomimetics would in addition selectively reduce the anti-GM1 antibody production in patients. We conclude that an optimized glycomimetic could provide the first MMN-treatment which enables sustainable improvement in the health condition of patients.
Lay summary
Austricksen schädlicher Antikörper - Glykomimetika zur Behandlung der Multifokalen Motorischen Neuropathie
Die krankheitsauslösenden Autoantikörper werden gegen bestimmte Kohlenhydratstrukturen der motorischen Nerven gebildet. Der Angriff dieser Antikörper an den motorischen Nerven bewirkt eine Autoimmunreaktion mit fatalen Folgen. Die Signalübertragung an den Ranvierschen Schnürringen und das angrenzende schützende Myelin werden beeinträchtigt. Dadurch können Signale nicht mehr richtig vom Hirn zum Muskel geleitet werden. Es kommt zu unwillkürlichen Bewegungen kleiner Muskelgruppen (Faszikulationen), Muskelabbau (Atrophie) und Lähmungserscheinungen (Paresen).
Die heutzutage eingesetzten Medikamente führen meist nur kurzfristig zur Besserung, und bringen teilweise schwerwiegende Nebenwirkungen mit sich. Diese Therapien haben gemeinsam, dass sie sehr unspezifisch das Abwehrsystem schwächen. Unser Ziel ist es, mit einem komplett neuen Ansatz ganz gezielt nur die krankheitsauslösenden Antikörper zu neutralisieren, ohne dabei das restliche Immunsystem zu schwächen. Wir synthetisieren hierfür Imitate der angegriffenen Zuckerstrukturen (Glykomimetika). In ersten Vorversuchen konnten wir zeigen, dass solche Glykomimetika die schädlichen Antikörper hochselektiv binden und neutralisieren. Deshalb sind wir überzeugt, dass es basierend auf unserem Ansatz erstmals möglich ist, eine sichere und hochwirksame Therapie zu entwickeln, sodass Patienten in Zukunft auch nach langer Krankheit noch praktisch symptomfrei leben können.
Progetti
- Nuovi progetti di ricerca dal 2024
- L'importanza della ricerca
- Progetti finanziati
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- SEAL Therapeutics AG
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