Human Apyrase Therapy for Diabetic Neuropathic Pain

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 DESCRIPTION (provided by applicant): Neuropathic pain such as diabetic neuropathic pain (DNP) can be difficult to treat with only 30-40% of patients achieving meaningful (>40-50%) pain relief. Current therapies (e.g. duloxeline) mainly address symptoms by focusing on blocking neurotransmission in the pain pathway with limited efficacy, potentially severe side effects and narrow therapeutic index. Hence, novel therapies are needed to safely manage symptoms and also target the underlying pathophysiological mechanisms that will improve the functional status and life quality of affected patients. APT102, an optimized human apyrase, selectively scavenges excess pro-inflammatory and algogenic extracellular ATP (eATP) and ADP (eADP) and metabolizes them to eAMP, thereby attenuating vascular or central inflammation and pain. Ubiquitous CD73 further metabolizes eAMP to adenosine, which has been shown to reduce neuropathic pain in animals and humans. It has been shown that administration of APT102 exhibited a long-lasting (days) anti-hyperalgesic effect in the model of Complete Freud's Adjuvant-induced inflammatory pain with no noticeable side effects. In the proposed studies, we will evaluate the dose-response of APT102 in both the chronic constriction injury (CCI) model of neuropathy and the model of STZ-induced diabetic neuropathy. We also will determine the potential side effects of APT102 using the rotarod and functional observational battery assays in healthy rats. Specific Aim 1. To determine whether APT102 (s.c.) will abrogate neuropathic pain in the CCI model in rats without behavioral side effects. Specific Aim 2. To determine whether APT102 (s.c.) will abrogate neuropathic pain in the STZ-induced diabetic model in rats without significant side effects. The long-term goal is to develop APT102 as a safe and disease-modifying analgesic therapy. Weekly or monthly dosing will provide sustained pain relief for neuropathic pain patients without significant side effects, tolerance or addiction.