Disease Modifying Analgesia with CA8 Gene Therapy

慢性疼痛每年花费约6500亿美元，1，2，大多数慢性非癌症疼痛仍然没有得到充分治疗。3在缺乏合适的镇痛剂替代品的情况下，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为了解决这一未满足的需求，我们着手鉴定新型非阿片类镇痛药，发现背根神经节（DRG）碳酸酐酶-8（CA 8）通过临床相关的给药途径使用基因疗法递送的CA 8充当“局部麻醉剂”，转导DRG以产生深度持久的镇痛（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学。6 -9 NIH之前的资金支持了该模型的创建，使用基因治疗候选物的表达复制缺陷型HSV（rdHSV）CA 8的生物治疗剂（vHCA 8）的表征和验证。本HEAL UG 3/UH 3提案（NS-21- 010）包括6个项目，旨在通过IND生效优化和开发一种新型非阿片类镇痛药先导候选药物，目的是治疗慢性膝关节骨关节炎（OA）疼痛。UG 3计划：项目1：对每种启动子构建体进行剂量范围、安全性（NOAEL）、疗效（镇痛）和神经元特异性（例如，pCMV、pAdvillin、pTrkA）。里程碑1：定义安全性和有效性（包括PD、生物分布、组织病理学等）并选择最小侵入性的给药途径和最安全最有效的vHCA 8启动子构建体用于进一步开发。项目2：确定先导vHCA 8启动子构建体治疗慢性OA疼痛的安全性和有效性（镇痛）。里程碑2：证明主要vHCA 8生物素候选物治疗慢性OA疼痛，产生持续镇痛和抗痛觉过敏，无毒性。UH 3项目：与LDT合作：项目3：参与NIH合同开发和生产组织（CDMO）;建立支持vHCA 8原料药（DS）和制剂（DP）表征的工艺和分析方法开发;生产用于GLP毒理学研究（Tox）的DS;开发DP制剂;运行稳定性;并完成CM&C IND部分。里程碑3：完成生产工艺和分析开发以支持IND;生产GLP Tox用DS并编写IND CM&C章节。项目4：聘请NIH签约临床CRO，制定初始临床方案，召开IND前会议。里程碑4：项目5：与NIH签约的CRO进行必要的Tox能力合作;进行GLP Tox;将所有临床前数据整合到IND中，提交IND。IND生效。项目6：建立新公司;许可IP。里程碑6：新公司控制知识产权保护商业机会;建立自由经营（FTO）。时间轴：1 - 5年级。总结：在这些UG 3/UH 3项目结束时，一种vHCA 8生物素候选药物将作为一种新型非阿片类长效镇痛药，作为具有疾病改善潜力的一流局部麻醉剂，准备进行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.