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的治疗。3在缺乏合适的止痛药替代品的情况下，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为了解决这种未得到满足的需求，我们着手寻找新的非阿片类止痛药，并发现背根神经节(DRG)碳酸失碳酶-8(CA8)的表达调节止痛反应。5 CA8通过临床相关的给药途径使用基因治疗作为一种‘局部麻醉剂’转导DRG产生深刻而持久的止痛(相当于&GT；6-9 NIH之前的资助支持了复制缺陷单纯疱疹病毒(RdHSV)CA8表达生物疗法(VHCA8)候选基因的创建、表征和验证。这份Hear UG3/UH3提案(NS-21-010)包括6个项目，旨在通过IND-In效应优化和开发一种新的非阿片类止痛药候选药物，目标是治疗慢性膝骨性关节炎(OA)疼痛。UG3计划：计划1：使用临床相关的给药途径，对每个启动子构建体(例如，pCMV、pAdvilin、pTrkA)进行剂量范围、安全性(NOAEL)、有效性(止痛)和神经元特异性。里程碑1：确定安全性和有效性(包括PD、生物分布、组织病理学等)并选择创伤最小的给药途径和最安全、最有效的vHCA8启动子构建体进行进一步的研究。项目2：确定先导vHCA8启动子构建作为治疗慢性骨性关节炎疼痛的安全性和有效性(止痛)。里程碑2：展示领先的vHCA8生物治疗候选药物治疗慢性骨性关节炎疼痛，产生持久的止痛和抗痛觉过敏，且无毒性。UH3计划：与LDT合作：项目3：与NIH签约开发和制造组织(CDMO)合作；建立工艺和分析方法开发，支持vHCA8药物物质(DS)和药物产品(DP)的表征；为GLP毒理学研究(TOX)制造DS；开发DP配方；运行稳定性；以及完成CM和C IND部分。里程碑3：完成制造流程和分析开发以支持IND；为GLP Tox制造DS并撰写IND CM&C部分。项目4：聘请NIH签约的临床CRO，制定初始临床方案，召开IND前会议。里程碑4：确定监管路径。项目5：与NIH签约的CRO接洽所需的TOX能力；进行GLP TOX；将所有临床前数据整合到IND中，提交IND。里程碑5.IND效应。项目6：建立新公司；许可证内IP。里程碑6：Newco控制保护商业机会的知识产权；建立运营自由(FTO)。时间表：第1-5年。总结：在这些UG3/UH3计划结束时，一种vHCA8生物治疗候选药物将作为一种新型的非阿片类长效止痛剂用于第一阶段临床研究，作为一种具有改善疾病潜力的一流局部麻醉剂。

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.