Disease Modifying Analgesia with CA8 Gene Therapy

CA8 基因治疗的疾病修饰镇痛

• 批准号: 10710264
• 负责人: ROY C. LEVITT
• 金额: $ 110.94万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-16 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710264
• 关键词: Disease; Modifying; Analgesia; CA8; Gene

Chronic pain costs about $650 billion annually,1,2 and most chronic noncancer pain remains inadequately treated.3 In the absence of suitable analgesic alternatives, an epidemic of opioid overuse, abuse, and life- threatening complications has occurred.4 To address this unmet need, we set out to identify novel nonopioid analgesics and discovered that dorsal root ganglion (DRG) carbonic anhydrase-8 (CA8) expression regulates analgesic responses.5 CA8 delivered using gene therapy via clinically relevant routes of administration acts as a ‘local anesthetic’ transducing DRG to produce profound long lasting analgesia (equivalent >200mg of oral morphine in 60kg adult), without motor blockade or clinical pathology in chronic animal pain models.6-9 Prior NIH funding supported the creation, characterization and validation of replication defective HSV (rdHSV) CA8 expressing biotherapeutics (vHCA8) using gene therapy candidates. This HEAL UG3/UH3 Proposal (NS-21- 010) includes 6 Projects designed to optimize and develop through an IND-in effect for a novel non-opioid analgesic lead candidate with the goal of treating chronic knee osteoarthritis (OA) pain. UG3 Program: PROJECT 1: Conduct dose-ranging, safety (NOAEL), efficacy (analgesia) and neuronal specificity for each promoter construct (e.g., pCMV, pAdvillin, pTrkA) using clinically relevant routes of administration. MILESTONE 1: Define the safety and efficacy (including PD, biodistribution, histopathology, etc.) of each vHCA8 construct and select the least invasive route of administration and the safest most effective vHCA8 promoter construct for further development. PROJECT 2: Determine the safety and efficacy (analgesia) of the lead vHCA8 promoter construct as a treatment for chronic OA pain. MILESTONE 2: Demonstrate the lead vHCA8 biotherapeutic candidate treats chronic OA pain that produces persistent analgesia and anti-hyperalgesia without toxicity. UH3 Program: In collaboration with LDT: PROJECT 3: Engage NIH Contract Development and Manufacturing Organization (CDMO); establish process and analytical methods development supporting characterization of vHCA8 drug substance (DS) and drug product (DP); manufacture DS for GLP Toxicology studies (Tox); develop DP formulation; run stability; and complete CM&C IND sections. MILESTONE 3: Complete manufacturing process and analytical development to support IND; manufacture DS for GLP Tox and write IND CM&C sections. PROJECT 4: Engage NIH contracted clinical CRO, develop initial clinical protocol, conduct Pre-IND Meeting. MILESTONE 4: Define regulatory path. PROJECT 5: Engage NIH contracted CRO with required Tox capabilities; conduct GLP Tox; integrate all preclinical data into IND, submit IND. MILESTONE 5. IND in-effect. PROJECT 6: Establish NewCo; in-license IP. MILESTONE 6: NewCo controls IP protecting commercial opportunities; establish freedom-to- operate (FTO). Timeline: Years 1 - 5. SUMMARY: At the end of these UG3/UH3 Programs, one vHCA8 biotherapeutic candidate will be ready for Phase 1 clinical studies as a novel non-opioid long-acting analgesic delivered as a first-in-class local anesthetic with disease-modifying potential.

慢性疼痛每年花费约 6500 亿美元，1,2 大多数慢性非癌性疼痛仍未得到充分治疗。3 在缺乏合适的镇痛替代品的情况下，阿片类药物过度使用、滥用和危及生命的并发症已经流行。4根据需要，我们着手鉴定新型非阿片类镇痛药，并发现背根神经节 (DRG) 碳酸酐酶 8 (CA8) 表达可调节镇痛反应。 5 CA8通过临床相关的给药途径使用基因疗法传递，作为“局部麻醉剂”转导DRG，产生深度持久的镇痛作用（相当于60公斤成人口服>200毫克吗啡），在慢性动物疼痛模型中没有运动阻滞或临床病理。 6-9 之前的 NIH 资金支持使用候选基因疗法创建、表征和验证复制缺陷型 HSV (rdHSV) CA8 表达生物治疗药物 (vHCA8)。 UG3/UH3 提案 (NS-21-010) 包括 6 个项目，旨在通过 IND 效果优化和开发一种新型非阿片类镇痛药主要候选药物，其目标是治疗慢性膝骨关节炎 (OA) 疼痛 UG3 项目：项目 1：对每个启动子构建体（例如， pCMV、pAdvillin、pTrkA）使用临床相关的给药途径 里程碑 1：定义每个 vHCA8 构建体的安全性和有效性（包括 PD、生物分布、组织病理学等），并选择侵入性最小的给药途径和最安全、最有效的 vHCA8。用于进一步开发的启动子构建体：确定主要 vHCA8 启动子构建体作为慢性病治疗的安全性和有效性（镇痛）。 OA 疼痛。 里程碑 2：展示领先的 vHCA8 生物治疗候选药物可治疗慢性 OA 疼痛，产生持久镇痛和抗痛觉过敏，且无毒性。 UH3 计划：与 LDT 合作：项目 3：与 NIH 合同开发和制造组织 (CDMO) 合作；支持 vHCA8 原料药 (DS) 和药品 (DP) 表征的工艺和分析方法开发；为 GLP 毒理学研究制造 DS； (Tox)；开发 DP 配方；并完成 CM&C IND 部分：完整的生产工艺和分析开发，以支持 IND；为 GLP Tox 生产 DS 并编写 IND CM&C 部分：与 NIH 签约的临床 CRO。制定初始临床方案，进行 IND 前会议：确定监管路径 5：让 NIH 签约 CRO 具备所需的 Tox 能力；进行 GLP Tox；将所有临床前数据纳入 IND，提交 IND 项目 6：建立新公司；里程碑 6：新公司控制知识产权，保护商业机会； FTO）。 时间线：第 1 - 5 年。 摘要：在这些 UG3/UH3 计划结束时，出现了一种 vHCA8 生物治疗候选药物作为一种新型非阿片类长效镇痛药，作为具有改善疾病潜力的一流局部麻醉剂，将准备进行一期临床研究。