Neuron-specific block of T-type calcium channels

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DESCRIPTION (provided by applicant): Pain is a leading health problem in the United States with 1 in 10 Americans suffering from moderate to severe pain. Yet, the treatment of chronic pain remains a clinical challenge, with only half of patients receiving adequate pain relief. Therefore, the development of novel analgesics without abuse potential and side effects would have significant impact on the treatment of pain. The hypothesis guiding these exploratory studies is that chronic pain can be treated by inhibiting ion channels in nociceptors such as the Cav3.2 T-type voltage-gated calcium channel. T-currents are upregulated in animal models of chronic constrictive nerve injury and diabetic neuropathy, and Cav3.2 directed antisense oligonucleotides reverse the mechanical hyperalgesia and allodynia observed in these animals. Importantly, Cav3.2 is important for pain signaling in both rodents and humans, since the clinically relevant analgesic, lipoic acid, blocks human Cav3.2 currents in vitro yet is ineffective in Cav3.2 knockout mice in vivo. These studies will develop short hairpin RNAs (shRNA) that inhibit the expression of mouse and human Cav3.2 channels. In contrast to chemically synthesized siRNA, delivery of DNA-based shRNA can be specifically targeted to neuronal subtypes using gene promoters. The present study will explore the use of the sodium channel promoter Scn10a, whose expression is largely limited to nociceptors. An important feature for clinical use is the ability to regulate gene therapy. This will be accomplished using a newly developed version of the tetracycline repressor, which requires drug for activation (doxycycline-ON). Recombinant adeno-associated virus (rAAV) has emerged as the top choice for human gene therapy. AAV particles can be produced with protein coats that effectively infect sensory neurons and are retrogradely transported to the nucleus (e.g. serotype 8). The goal of these studies is to develop rAAV targeting vectors that direct shRNA- mediated knockdown of Cav3.2, use this to prepare viral particles, and then test for nociceptor- specific expression in rats with neuropathic pain. The research team includes Dr. Edward Perez- Reyes, a T-channel expert, Dr. Guanping Gao, an AAV expert, and Dr. Hui-Lin Pan, a neuropathic pain expert. PUBLIC HEALTH RELEVANCE: Project Narrative Chronic pain affects over 10% of the population, resulting in lowered productivity and quality of life. The present proposal is focused on developing a novel treatments of pain that can provide long-term treatment without abuse potential. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.