Human Apyrase Therapy for Diabetic Neuropathic Pain

 描述(由申请人提供)：神经性疼痛，如糖尿病神经病理性疼痛(DNP)可能很难治疗，只有30%-40%的患者获得有意义的(&gt；40%-50%)疼痛缓解。目前的治疗方法(如度洛林)主要是通过阻断疼痛通路中的神经传递来治疗症状，疗效有限，副作用可能严重，治疗指数较窄。因此，需要新的治疗方法来安全地管理症状，并针对潜在的病理生理机制，以改善受影响患者的功能状态和生活质量。APT102是一种优化的人类apyrase，它选择性地清除过量的促炎和致过敏细胞外ATP(EATP)和ADP(EADP)，并将它们代谢成eAMP，从而减轻血管或中枢炎症和疼痛。无处不在的CD73进一步将eAMP代谢成腺苷，腺苷已被证明可以减轻动物和人类的神经病理性疼痛。在完全弗洛伊德佐剂诱导的炎性疼痛模型中，APT102表现出持久(数天)的抗痛敏作用，且无明显副作用。在拟议的研究中，我们将评估APT102在慢性狭窄损伤(CCI)神经病变模型和STZ诱导的糖尿病神经病变模型中的剂量反应。我们还将使用旋转棒和功能观察电池测试来确定APT102在健康大鼠中的潜在副作用。具体目标1.确定APT102(S.C.)将消除大鼠CCI模型中的神经病理性疼痛，而没有行为副作用。具体目标2.确定APT102(S.C.)将消除STZ诱导的糖尿病大鼠模型中的神经病理性疼痛，而没有明显的副作用。长期目标是开发APT102作为一种安全和改善疾病的止痛疗法。每周或每月给药将为神经性疼痛患者提供持续的疼痛缓解，没有明显的副作用、耐受性或成瘾。

 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.