NRB‑1A: In Silico Design for Five‑Minute Migraine Intervention
Abstract
Background Migraine pain escalates through rapid activation of calcitonin gene–related peptide signaling within trigeminal pathways, driving vasodilation, neurogenic inflammation, and nociceptor sensitization that can amplify within minutes of attack onset (Edvinsson, 2015; Goadsby et al., 2017). The superior nasal compartments, including the superior turbinates’ and olfactory cleft, are closely opposed to olfactory epithelium and trigeminal nerve endings, creating a short diffusional path for locally acting biologics to intercept CGRP or its receptor near the origin of pain signaling (Illum, 2003; Djupesland, 2013; Thorne, Pronk, Padmanabhan, & Frey, 2004). This route must overcome nasal physiology constraints such as mucociliary clearance and protease activity that can reduce residence time and degrade proteins, making compact, high affinity, fast on rate antagonists biologically attractive for minute scale action (Illum, 2003; Wang, 2005; von Mentzer et al., 2020). Objective Evaluate, in silico only, whether intranasal delivery of a preformed, humanized, Fc‑less nanobody or single chain variable fragment in the 12 to 30 kDa range can achieve biologically plausible and clinically meaningful CGRP axis inhibition within five minutes, sustain several hours of localized suppression governed by nasal physiology and target kinetics, and return toward baseline within 24 to 48 hours. Additionally, parameterize a short duration adeno associated virus secretion fallback that extends…
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