Botulinum neurotoxins: Future innovations

Botulinum neurotoxins (BoNTs) are multi-domain proteins whose potent and selective actions on nerve endings have led to innovations in both basic and clinical science. The various BoNT domains are responsible for binding to gangliosides and proteins associated with nerve cell membranes, internalization into the cell, and cleavage of one or more SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) proteins necessary for vesicle docking and fusion. Novel modifications to BoNT molecules, such as the creation of chimeras, helped identify the protein domains responsible for various aspects of BoNT action, such as localized effects. Other molecular modifications have been introduced in attempts to increase the specificity of BoNTs for autonomic or sensory neurons, with the ultimate goal of optimizing therapeutic selectivity. This research, in turn, has led to the development of BoNT-based proteins that can target non-SNARE substrates such as phosphatase and tensin homolog (PTEN). Still others are developing different BoNT serotypes, subtypes, or variants that are longer- or shorter-acting or have faster onset for various clinical purposes. New formulations of BoNTs that provide convenience for both patients and physicians are under investigation. Novel clinical uses are being evaluated for onabotulinumtoxinA, including in the prevention of post-operative atrial fibrillation. All these innovations capitalize on the unique properties of BoNTs, which continue to intrigue scientists and clinicians across numerous fields of study.