Application of RNA Interference to Treat Conditions Associated with Dysregulation of Transient Receptor Potential Vanilloid 1 Channel

Abstract

Transient receptor potential vanilloid 1 (TRPV1) is a member of the transient receptor potential (TRP) family of proteins and is most notably the target of capsaicin, the active ingredient of “hot” pepper such as jalapeno and habanero. The channel is expressed primarily in small diameter neurons (Aδ and C fibers) within sensory ganglia comprising the pain pathway but expression is observed in larger diameter neurons under conditions of inflammation. TRPV1 is a nonselective cation channel, which responds to heat (activation threshold ∼43°C) and transmits pain sensations in response to noxious heat. It is also expressed in nonneuronal tissue such as keratinocytes, bladder uroepithelium, knee joints, the gastrointestinal tract and the cochlea, suggesting additional physiological roles of channel activation. Several disease states associated with dysregulation of TRPV1 include visceral and peripheral inflammatory pain observed in irritable bowel disease, bone cancers, arthritis and bladder inflammation. Other conditions include diabetic peripheral neuropathy, obesity, and drug-induced hearing loss. Animal studies have shown beneficial effects of targeting TRPV1, using both agonist and antagonist drugs, in the treatment of some of these conditions. However, the propensity of TRPV1 antagonists to produce hyperthermia could limit their future application. Such problems might be resolved by the focal administration of short interfering (si) RNA to the affected organ in order to reduce TRPV1 expression. While demonstration of TRPV1 knockdown by RNA interference (RNAi) is widely used in vitro, results obtained from a limited number of in vivo studies suggest that RNAi could be applied to the treatment of diseases associated with TRPV1 hyperactivity. To date, RNAi has proven beneficial in reducing inflammatory pain and in treating hearing loss associated with cisplatin chemotherapy. This review will focus on the current progress of RNAi in the treatment of diseases associated with TRPV1 dysfunction, discuss potential future applications of this technology, and highlight factors that could affect its use clinically.