Immunomodulatory Therapy for Neuropathic Pain

神经性疼痛的免疫调节疗法

基本信息

批准号：
10378231
负责人：
RIDONG CHEN
金额：
$ 99.64万
依托单位：
APT THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378231
关键词：
Address Affect Affinity Aldesleukin American Analgesics Animal Model Anti-Inflammatory Agents Anticonvulsants Antidepressive Agents Attenuated Autoimmune Autoimmune Diseases Benefits and Risks Binding Binding Sites Blood Glucose Blood Vessels CD8-Positive T-Lymphocytes Cell Count Cell physiology Cells Cessation of life Chimeric Proteins Clinical Research Cyclic GMP Data Development Diabetic Neuropathies Disease Dose Escherichia coli FOXP3 gene Functional disorder GTP-Binding Proteins Generations Goals Half-Life Homeostasis Human IL2 gene IL2RA gene Immune In Vitro Infection Injections Insulin-Dependent Diabetes Mellitus Interferons Interleukin-2 Kidney Lesion Lidocaine Maintenance Malignant Neoplasms Mammalian Cell Mechanics Mediating Memory Modeling Mononeuropathies Mutation NK Cell Activation Natural Killer Cells Nervous system structure Neurons Norepinephrine Opioid Pain Pathogenicity Pathway interactions Patients Peripheral nerve injury Pharmaceutical Preparations Pharmacology Phase Phenotype Plasma Polyneuropathy Postherpetic neuralgia Prevention strategy Principal Investigator Quality of life Rattus Reaction Recombinant Proteins Regulatory T-Lymphocyte Renal carcinoma Reporting Safety Self Tolerance Sensory Ganglia Serotonin Serum Albumin Severities Site Streptozocin Symptoms Syndrome Th1 Cells Therapeutic Therapeutic Index Thymus Gland Toxic effect Trigeminal Neuralgia United States Variant Work addiction allodynia analog base chronic constriction injury chronic pain cytokine design diabetic diabetic rat drug candidate drug development duloxetine effector T cell eosinophil experience functional status gabapentin immunomodulatory therapies improved inhibitor/antagonist innovation macrophage manufacturing process mechanical allodynia melanoma molecular size neuroinflammation neurotransmission non-opioid analgesic novel novel strategies novel therapeutics opioid epidemic opioid overdose pain relief painful neuropathy phase 1 study post stroke pain pregabalin prevent programs receptor response restoration reuptake sciatic nerve side effect somatosensory symptom management symptom treatment type I diabetic

项目摘要

Principal Investigator/Program Director (Last, First, Middle: Ridong Chen Project Summary More than 25 million Americans suffer from chronic pain. Due to the lack of other treatments, there has been an overreliance on opioids, contributing to an alarming epidemic of opioid overdose addictions and deaths. Neu- ropathic pain is difficult to treat, with only 30-40% of patients achieving meaningful (>40-50%) pain relief. Current therapies (e.g., duloxeline and gabapentin) mainly address symptoms by focusing on blocking neurotransmis- sion in the pain pathway with limited efficacy, severe side effects, and narrow therapeutic indices. Hence, novel non-opioid therapies are urgently needed to safely manage symptoms and also target the underlying pathophys- iological mechanisms that will improve the functional status and quality of life of affected patients. It has been recently shown that CD4+ Th1 is a major player for neuropathic pain development. Interleukin-2 (IL-2) is the key cytokine for the generation, survival, and function of regulatory T cells by direct binding to its high affinity receptor. Treatment with low-dose rIL-2 increased anti-inflammatory regulatory T cells and M2 type macrophages and inhibited pathogenic interferon- secreting T helper type 1 cells. This rIL-2 treatment was efficacious in human clinical studies for autoimmune diseases without complications or infections. Hence, resto- ration or enhancement of regulatory T cells with low-dose IL2 may offer a novel strategy for prevention and treatment of neuropathic pain. However, several drawbacks exist for current low-dose rIL2 therapy, including a short half-life, propensity for in vitro aggregation causing adverse local reaction at injection sites, and a potential narrow therapeutic window. We have designed proprietary IL2-based variants that will enable selective stimu- lation of Tregs with an extended half-life and a broad therapeutic window. In the Phase I study, we successfully identified the variant, designated APT603, which selectively stimulates regulatory T cells and provides robust analgesic efficacy in the chronic constriction injury model of mononeuropathy in rats with an excellent safety profile. With an experienced drug development team, we propose to determine dose responses in two well es- tablished models of neuropathic pain with distinct pathophysiology and to conduct critical activities necessary to enable IND filing for APT603.  Specific Aim 1: Determine the therapeutic index of APT603 for abrogating neuropathic pain in STE- induced (T1D) diabetic rats and in a rat model of sciatic nerve chronic constriction injury (CCI).  Specific Aim 2: Manufacture cGMP (Current Good Manufacturing Practice) grade APT603.  Specific Aim 3: Evaluate the nonclinical safety of APT603. The long-term goal is to develop the drug candidate as a safe and disease-modifying analgesic therapy. Weekly or bi-weekly dosing will provide sustained neuropathic pain relief for patients without inducing significant side effects, tolerance, or addiction.

首席研究员/项目主任（后、一、中：陈日东项目概要超过2500万美国人患有慢性疼痛，由于缺乏其他治疗方法，一直存在。对阿片类药物的过度依赖，导致阿片类药物过量成瘾和死亡的惊人流行。神经性疼痛很难治疗，目前只有 30-40% 的患者（>40-50%）实现有效的疼痛缓解。治疗（例如度洛西林和加巴喷丁）主要通过阻断神经传递来解决症状其在疼痛途径中的作用有限，副作用严重，且治疗指标狭窄。迫切需要非阿片类药物疗法来安全地控制症状并针对潜在的病理学将改善受影响患者的功能状态和生活质量的生物学机制。最近表明 CD4+ Th1 是神经性疼痛发展的主要参与者 Interleukin-2。 (IL-2) 是调节性 T 细胞的生成、存活和功能的关键细胞因子，通过直接与其结合高亲和力受体。低剂量rIL-2治疗增加抗炎调节T细胞和M2型。 rIL-2 治疗可抑制巨噬细胞和抑制致病性干扰素 γ 分泌 T 辅助细胞。在自身免疫性疾病的人体临床研究中有效，无并发症或感染。用低剂量 IL2 定量或增强调节性 T 细胞可能会提供一种新的预防和治疗策略。然而，目前的低剂量 rIL2 疗法存在一些缺点，包括半衰期短，体外聚集的倾向导致注射部位局部不良反应，以及潜在的我们设计了基于 IL2 的专有变体，可以实现选择性刺激。在 I 期研究中，我们成功地开发了具有延长半衰期和宽治疗窗的 Tregs。鉴定出该变体，命名为 APT603，它选择性地刺激调节性 T 细胞并提供强大的在大鼠单神经病慢性压迫性损伤模型中的镇痛效果具有良好的安全性凭借经验丰富的药物开发团队，我们建议确定两个井中的剂量反应。建立了具有独特病理生理学的神经性疼痛模型，并进行必要的关键活动启用 APT603 的 IND 备案。  具体目标 1：确定 APT603 消除 STE 神经病理性疼痛的治疗指数诱导（T1D）糖尿病大鼠和坐骨神经慢性缩窄损伤（CCI）大鼠模型。  具体目标 2：生产 cGMP（现行良好生产规范）等级 APT603。  具体目标 3：评估 APT603 的非临床安全性。长期目标是将候选药物开发为安全且缓解疾病的镇痛疗法。每周或每两周一次给药将为患者提供持续的神经性疼痛缓解，而不会引起明显的疼痛。副作用、耐受性或成瘾性。