Disease Modifying Analgesia with CA8 Gene Therapy

慢性疼痛每年花费约6500亿美元，而且大多数慢性非癌性疼痛仍未得到充分治疗由于缺乏合适的镇痛药替代品，阿片类药物的过度使用、滥用和危及生命的并发症已成为一种流行病为了解决这一未满足的需求，我们开始寻找新的非阿片类镇痛药，并发现背根神经节（DRG）碳酸酐酶-8 （CA8）的表达调节镇痛反应在慢性动物疼痛模型中，通过基因治疗通过临床相关的给药途径给药CA8作为“局部麻醉剂”转导DRG，产生深刻持久的镇痛作用（相当于60公斤成人口服吗啡200毫克），没有运动阻滞或临床病理。先前的NIH资助支持使用基因治疗候选物创建、表征和验证表达复制缺陷HSV (rdHSV) CA8的生物疗法（vHCA8）。该HEAL UG3/UH3提案（NS-21- 010）包括6个项目，旨在优化和开发一种新型非阿片类镇痛药的内效，目的是治疗慢性膝骨关节炎（OA）疼痛。项目1：采用临床相关给药途径，对每个启动子构建体（如pCMV、pAdvillin、pTrkA）进行剂量范围、安全性（NOAEL）、有效性（镇痛）和神经元特异性研究。里程碑1：明确每种vHCA8构建物的安全性和有效性（包括PD、生物分布、组织病理学等），选择侵入性最小的给药途径和最安全最有效的vHCA8启动子构建物进行进一步开发。项目2：确定vHCA8先导启动子构建物治疗慢性OA疼痛的安全性和有效性（镇痛）。里程碑2：证明领先的vHCA8生物治疗候选药物治疗慢性OA疼痛，产生持久的镇痛和抗痛觉过敏，没有毒性。UH3计划：与LDT合作；项目3：聘请NIH合同开发和制造组织（CDMO）；建立vHCA8原料药（DS）和制剂（DP）的工艺流程和分析方法开发；生产用于GLP毒理学研究的DS (Tox)；开发DP配方；稳定运行;并完成CM&C IND部分。里程碑3：完整的制造工艺和分析开发以支持IND；制作GLP Tox的DS，并编写IND CM&C部分。项目4：参与NIH签约临床CRO，制定初步临床方案，召开Pre-IND会议。里程碑4：定义监管路径。项目5：与NIH签约的CRO合作，提供所需的Tox能力；进行GLP Tox；将所有临床前数据整合到IND中，提交IND。实际上。项目六：成立新公司；许可证而IP。里程碑6:NewCo控制知识产权保护商业机会；建立自由操作（FTO）。时间：1 - 5年级。总结：在UG3/UH3项目结束时，一种vHCA8生物治疗候选药物将作为一种新型非阿片类长效镇痛药，作为一种具有改善疾病潜力的一流局部麻醉剂，进入i期临床研究。

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.