Sustained Relief of Chronic Pain via a Nav1.7-Targeting ASO-siRNA Conjugate in Rats.

Chronic pain affects a large global population, yet safe, long-acting analgesics remain limited. Nav1.7 is a genetically validated pain target, but conventional small-molecule approaches have had limited success. Therapeutic oligonucleotides-antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs)-offer selective and durable gene silencing. Here, we developed N02C0702, an ASO-siRNA conjugate (ASC) that achieves efficient Nav1.7 knockdown and demonstrates greater activity than the individual ASO (N02A114) and siRNA (N02S154) components at both mRNA and protein levels, without requiring additional delivery systems. In rat models, N02C0702 was associated with reduced pain behaviors in both complete Freund's adjuvant-induced inflammatory pain and spinal nerve ligation-induced neuropathic pain. A single intrathecal administration produced effects lasting up to 28 and 56 days in the respective models. These findings support Nav1.7 as a relevant analgesic target and suggest that the ASC platform may offer a promising approach for chronic pain and other CNS-related conditions.