423) Distribution and efficacy of centrally and systemically administered antisense oligonucleotides in the pain system

Chronic pain remains a large unmet clinical need due to limited efficacy of available therapies. Antisense oligonucleotides (ASOs) are stable single strands of DNA that bind to their complementary target RNA and direct its catalytic degradation through the action of RNase H, an endogenous enzyme present in most mammalian cells. Thirty years of ASO optimization has led to second generation ASOs with characteristics amenable to the treatment of neurodegenerative diseases and are currently being tested clinically. We aim to determine if inflammatory and neuropathic pain are amenable to treatment with ASOs. First, we set out to examine the distribution, suppression of target RNA, and duration of effect of ASO delivered via repeat subcutaneous injections or a single intrathecal (IT) bolus injection in areas involved in pain processing, namely the dorsal root ganglia (DRG), trigeminal ganglia and spinal cord. We have previously reported with systemic administration, robust reductions in target RNA in peripheral ganglia, but not the spinal cord. ASOs are soluble in cerebrospinal fluid (CSF) and are distributed throughout the CNS when administered intrathecally. We demonstrate here that IT administration of ASOs into the CSF is sufficient to reduce expression of target RNA throughout the rodent CNS, including spinal cord, trigeminal and DRG. Due to the remarkably long half-life of ASOs in the CNS, a single injection of ASO into the CSF led to reductions in target RNA that persisted for more than 2 months. Thus, by multiple routes of administration, ASOs are able to target the tissues involved in pain processing and ASO-mediated gene suppression may be a feasible treatment for various forms of pain. All authors are employees of Isis Pharmaceuticals.