Abstract
With a prevalence of 15%, migraine is the most common neurological disorder and among the most disabling diseases, taking into account years lived with disability. Current oral medications for migraine show variable effects and are frequently associated with intolerable side effects, leading to the dissatisfaction of both patients and doctors. Injectable therapeutics, which include calcitonin gene–related peptide–targeting monoclonal antibodies and botulinum neurotoxin A (BoNT/A), provide a new paradigm for treatment of chronic migraine but are effective only in approximately 50% of subjects. Here, we investigated a novel engineered botulinum molecule with markedly reduced muscle paralyzing properties which could be beneficial for the treatment of migraine. This stapled botulinum molecule with duplicated binding domain—binary toxin-AA (BiTox/AA)—cleaves synaptosomal-associated protein 25 with a similar efficacy to BoNT/A in neurons; however, the paralyzing effect of BiTox/AA was 100 times less when compared to native BoNT/A following muscle injection. The performance of BiTox/AA was evaluated in cellular and animal models of migraine. BiTox/AA inhibited electrical nerve fiber activity in rat meningeal preparations while, in the trigeminovascular model, BiTox/AA raised electrical and mechanical stimulation thresholds in Aδ- and C-fiber nociceptors. In the rat glyceryl trinitrate (GTN) model, BiTox/AA proved effective in inhibiting GTN-induced hyperalgesia in the orofacial formalin test. We conclude that the engineered botulinum molecule provides a useful prototype for designing advanced future therapeutics for an improved efficacy in the treatment of migraine.
Highlights
IntroductionStudies in animal models have uncovered several brain networks that are involved in migraine pathophysiology, including the hypothalamus [6,7,8,9], the occipital cortex [7, 10,11,12,13], and the brainstem [7, 14, 15]
Mixing the two binding domains in the presence of light-chain translocation domain (LHn)–linker 3 led to the formation of an SDS-resistant protein, named here BiTox/AA, which exhibited higher molecular weight compared to native botulinum neurotoxin A (BoNT/A) due to the presence of the linking system and the additional binding domain (Fig. 1b)
The precise molecular events that initiate migraine are not fully understood; it is generally agreed that inhibition of the peripheral trigeminal fibers is of pivotal importance in the treatment of migraine
Summary
Studies in animal models have uncovered several brain networks that are involved in migraine pathophysiology, including the hypothalamus [6,7,8,9], the occipital cortex [7, 10,11,12,13], and the brainstem [7, 14, 15] It remains unclear which molecular events initiate migraine attacks, there is a general agreement that a successful treatment strategy will involve inhibition of the peripheral trigeminal fibers innervating pain-producing extracranial and intracranial structures. The clinical efficacy and minimally invasive injections every 3 months have made BoNT/A an important treatment option for patients with chronic migraine
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