Human Apyrase Therapy for Diabetic Neuropathic Pain

人腺苷三磷酸双磷酸酶治疗糖尿病神经性疼痛

• 批准号: 8976658
• 负责人: RIDONG CHEN
• 金额: $ 29.98万
• 依托单位: APT THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8976658
• 关键词: Address; Adenosine; Adjuvant; Adverse effects; Affect; Agonist; Analgesics; Animal Model; Animals; Anticonvulsants; Antidepressive Agents; Apyrase; Attenuated; Behavioral; Biological Assay; Blood Glucose; Blood Vessels; Bolus Infusion; Clinical Trials; Data; Diabetic Neuropathies; Disease; Dose; Exhibits; Family; Goals; Hormones; Human; Hyperglycemia; Inflammation; Inflammatory; Injection of therapeutic agent; Lidocaine; Mechanics; Modeling; Nerve; Neuropathy; Nociception; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Opioid Analgesics; P2X-receptor; Pain; Pathway interactions; Patients; Phase; Principal Investigator; Prostate carcinoma; Quality of life; Rattus; Refractory; Reporting; Safety; Serotonin; Signal Transduction; Streptozocin; Suramin; Symptoms; Tactile; Testing; Therapeutic Index; Tramadol; United States; Weight Gain; Work; addiction; allodynia; chronic constriction injury; db/db mouse; diabetic; duloxetine; extracellular; functional status; gabapentin; improved; inflammatory pain; inhibitor/antagonist; nerve injury; neurotransmission; novel; pain behavior; painful neuropathy; preclinical safety; pregabalin; programs; prostatic fraction Acid phosphatase isoenzyme; public health relevance; receptor; response; reuptake; spared nerve; transmission process

 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.

 描述（由申请人提供）：神经性疼痛，例如糖尿病神经性疼痛 (DNP) 可能很难治疗，只有 30-40% 的患者能够实现有意义的 (>40-50%) 疼痛缓解，目前的治疗方法（例如度洛西林）主要解决这一问题。通过专注于阻断疼痛通路中的神经传递来缓解症状，但疗效有限、可能存在严重的副作用和狭窄的治疗指数，因此需要新的疗法来安全地控制症状并针对潜在的症状。 APT102 是一种优化的人腺苷三磷酸双磷酸酶，可选择性清除过量的促炎性和致痛性细胞外 ATP (eATP) 和 ADP (eADP)，并将其代谢为 eAMP，从而减弱血管或神经损伤。无处不在的 CD73 进一步将 eAMP 代谢为腺苷，这已被证明可以减轻神经性疼痛。动物和人类的研究表明，在完全弗洛伊德佐剂诱发的炎症性疼痛模型中，APT102 的给药表现出持久（数天）的抗痛觉过敏作用，并且没有明显的副作用。我们还将确定 APT102 在慢性压迫性损伤 (CCI) 神经病模型和 STZ 诱导的糖尿病神经病模型中的剂量反应。 APT102 在健康大鼠中使用转棒和功能性观察电池测定。 具体目标 1. 确定 APT102 (s.c.) 是否会消除大鼠 CCI 模型中的神经性疼痛，而不会产生行为副作用。将消除 STZ 诱导的大鼠糖尿病模型中的神经性疼痛，且没有明显的副作用。长期目标是开发。 APT102 作为一种安全且缓解疾病的镇痛疗法，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，而不会产生明显的副作用、耐受性或成瘾性。