Publication date: Available online 28 February 2019
Source: Clinical Neurophysiology
Author(s): Anna Kutschenko, Jasmin Weisemann, Katja Kollewe, Thiemo Fiedler, Sascha Alvermann, Sebastian Böselt, Claus Escher, Niklas Garde, Stefan Gingele, Stefan-Benno Kaehler, Ralf Karatschai, Tillmann H.C. Krüger, Stefan Sikorra, Pawel Tacik, Florian Wegner, Johannes Wollmann, Hans Bigalke, Kai Wohlfarth, Andreas Rummel
Abstract
Objectives
Botulinum neurotoxin serotypes A and B (BoNT/A & B) are highly effective medicines to treat hyperactive cholinergic neurons. Due to neutralizing antibody formation, some patients may become non-responders. In these cases, the serotypes BoNT/C-G might become treatment alternatives. BoNT/D is genetically least related to BoNT/A & B and thereby circumventing neutralisation in A/B non-responders. We produced BoNT/D and compared its pharmacology with BoNT/A ex vivo in mice tissue and in vivo in human volunteers.
Methods
BoNT/D was expressed recombinantly in E. coli, isolated by chromatography and its ex vivo potency was determined at mouse phrenic nerve hemidiaphragm preparations. Different doses of BoNT/D or incobotulinumtoxinA were injected into the extensor digitorum brevis (EDB) muscles (n=30) of human volunteers. Their compound muscle action potentials were measured 11 times by electroneurography within 220 days.
Results
Despite a 3.7-fold lower ex vivo potency in mice, a 110-fold higher dosage of BoNT/D achieved the same clinical effect as incobotulinumtoxinA while showing a 50% shortened duration of action.
Conclusions
BoNT/D blocks dose-dependently acetylcholine release in human motoneurons upon intramuscular administration, but its potency and duration of action is inferior to approved BoNT/A based drugs.
Significance
BoNT/D constitutes a potential treatment alternative for BoNT/A & B non-responders.
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