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Selective reduction of Nav1.7 with divalent small interfering RNA delivers strong and durable analgesia in thermal and pinprick models of acute pain

ABSTRACT: Humans missing the SCN9A gene encoding the Nav1.7 sodium ion channel are wholly insensitive to pain, but inhibitors of Nav1.7 tested clinically have not produced strong analgesia. Here we investigated whether pharmacological challenges of selectivity, CNS distribution, and target engagement might be addressed by transcript knockdown with divalent small interfering RNA (di-siRNA), a modality with efficient distribution in the brain following dosing into cerebrospinal fluid. SCN9A_2544 di-siRNA sequence catalyzing SCN9A transcript cleavage was identified by in-vitro screening. Following intrathecal dosing in rats, di-siRNA was internalized into over 90% of neuronal cell bodies within the dorsal root ganglion, knocked down cytoplasmic transcript with no detectable off-target knockdown, and reduced Nav1.7 protein up to 75% in DRG and up to 85% in spinal cord. Results show that SCN9A_2544 di-siRNA reduces Nav1.7 function in vivo selectively and to a level that produces powerful analgesia.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE302419 | GEO | 2026/05/01

REPOSITORIES: GEO

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The molecular basis of analgesia in congenital insensitivity to pain associated with loss of Nav1.7 function

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