AI Article Synopsis
- - The study investigates Botulinum neurotoxin serotype D (BoNT/D) as a potential alternative treatment for patients who do not respond to the widely used BoNT/A and B due to the formation of neutralizing antibodies.
- - BoNT/D was produced in E. coli and tested for its efficacy in both mouse tissues and human volunteers, showing that while it's less potent, it can produce similar effects with a higher dosage and shorter action duration.
- - The findings suggest BoNT/D could be a viable option for patients who don't respond to other serotypes, despite its lower effectiveness compared to approved treatments.
Article 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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| http://dx.doi.org/10.1016/j.clinph.2019.02.007 | DOI Listing |
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