Can pharmacological connexin-43 upregulation achieve therapeutic benefit without causing seizures or arrhythmias?

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Description

The safety concerns about excessive gap junction coupling creating seizures and cardiac issues were raised but not resolved. Determining the therapeutic window is critical for clinical translation of connexin-43 modulators.

Source: Debate session sess_SDA-2026-04-01-gap-20260401231108 (Analysis: SDA-2026-04-01-gap-20260401231108)

Resolution criteria

Resolution requires: (1) In vivo dose-response of Cx43 upregulator (e.g., rotigaptide analogue, AAV-Cx43) in rodents: EEG monitoring over >=4 weeks identifies seizure threshold (minimum dose causing IED or clinical seizure) and cardiac telemetry identifies arrhythmia threshold, establishing a safety window defined as the ratio of therapeutic dose to first adverse event dose (TI>=3); (2) Therapeutic efficacy confirmed in a neurodegeneration model (5xFAD, stroke, TBI) at doses <50% of seizure/arrhythmia threshold, showing >=20% improvement in neuronal survival or functional outcome; (3) Mechanistic basis of adverse events: siRNA knockdown of Cx43 in cardiac tissue or hippocampus demonstrates whether seizures/arrhythmias are on-target effects of Cx43 upregulation, guiding tissue-specific delivery strategies. In vitro gap junction coupling assays without safety pharmacology data in vivo are insufficient.

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