HEAL: Development of Clinical Candidate Drugs for Pain, Addiction and Overdose

HEAL：开发治疗疼痛、成瘾和药物过量的临床候选药物

• 批准号: 10259369
• 负责人: Donald Lo
• 金额: $ 1029.92万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10259369
• 关键词: 3-Dimensional; ADME Study; Acids; Acute; Address; Alkaloids; Analgesics; Anatomy; Animal Model; Animals; Back; Binding; Biodistribution; Biological; Biological Assay; Biological Availability; Biological Response Modifier Therapy; Blood - brain barrier anatomy; Blood Chemical Analysis; Blood Pressure; Blood specimen; Brain; Brain imaging; Buprenorphine; CRISPR/Cas technology; Cardiac; Cardiopulmonary; Cavia; Cell model; Cell surface; Chronic; Clinical; Clinical Trials; Cocaine; Collaborations; Community Developments; Complement; Controlled Clinical Trials; Data; Development; Diagnostic Imaging; Dopamine; Dose; Drug Evaluation; Drug Kinetics; Electrophysiology (science); Emotions; Encapsulated; Endosomes; Enhancers; Enkephalins; Evaluation; Family suidae; Fetal Development; Formulation; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genes; Goals; Hand; Health; Hematology; Human; Human Activities; Human Biology; In Vitro; Infrastructure; Intervention; Investigational Drugs; Investigational New Drug Application; Lead; Leucine Enkephalin; Licensing; Life; Ligands; Location; Measures; Methadone; Methods; Miniature Swine; Mitragyna; Modality; Modeling; Molecular; Mothers; Motivation; Naltrexone; National Institute of Drug Abuse; Natural History; Neonatal Abstinence Syndrome; Nervous system structure; Neuraxis; Neurons; Newborn Infant; Nociception; Nose; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Antagonist; Opioid Receptor Binding; Organ; Overdose; Oxycodone; Pain; Pain Measurement; Pathologic; Pathway interactions; Patients; Penetration; Peripheral; Peripheral Nervous System; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Physiology; Polymers; Posterior Horn Cells; Potassium Channel; Pre-Clinical Model; Pregnancy; Pregnant Women; Process; Productivity; Property; Prosencephalon; Public Health; Records; Relapse; Research Contracts; Research Personnel; Resources; Rewards; Risk; Route; Science; Scientist; Self Administration; Sickle Cell Anemia; Signal Transduction; Spinal Cord; Spinal cord posterior horn; Substance Use Disorder; Symptoms; System; TACR1 gene; Technology; Testing; Therapeutic; Time; Tissue Microarray; Tissues; Toxicology; Translational Research; United States Food and Drug Administration; United States National Institutes of Health; Urine; Validation; Withdrawal; Withdrawal Symptom; Work; addiction; aprepitant; behavior measurement; bioprinting; chronic pain; clinical development; clinical investigation; delta opioid receptor; dopamine D3 receptor; drug candidate; drug craving; drug development; drug efficacy; drug of abuse; drug seeking behavior; effective therapy; efficacy study; efficacy testing; endogenous opioids; experience; fetal; fetal blood; first-in-human; gene therapy; high throughput screening; human model; improved; in utero; in vivo; induced pluripotent stem cell; innovation; lung imaging; mesolimbic system; molecular phenotype; mouse model; mu opioid receptors; naltrexol; nanoparticle; non-cancer chronic pain; novel; novel therapeutics; opioid abuse; opioid epidemic; opioid misuse; opioid use; opioid use disorder; opioid withdrawal; pain relief; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; preclinical efficacy; prevent; receptor; research and development; research clinical testing; safety assessment; safety study; side effect; small molecule; therapeutic development; translational model; transmission process

Characterization of a large-animal preclinical model of sickle cell disease Sickle Cell Disease (SCD) patients are in urgent need of improved pain therapeutics that optimize analgesic benefits in managing chronic and acute There is also a need for a large-animal model of SCD to attempt to address the aspects of SCD research and therapeutics development that traditional murine models have not been able to fully realize. The Yucatan mini-pig is nearly the same size as an average human allowing longitudinal sampling of blood and is likely to serve as a better translational model for human anatomy and physiology, notably for vasculature and pain transmission pathways. SCD pigs have been developed utilizing CRISPR / Cas9 technology for molecular and phenotypic characterization inclusive of a planned two year natural history study (NHS) and for subsequent colony expansion. The NHS is assessing, the pathological changes over time in hematologic parameters, urine and blood chemistry, electrophysiologic, pain and related behavioral measurements, diagnostic imaging of the brain and lungs as well as assessment of other cardiopulmonary functions culminating in a complete pathological analyses of tissues and organs.. The goal is to make SCD pigs, and NHS data, including pain assessments, widely available to the research and drug development community for a more complete assessment and validation of the model for SCD. Targeting endosomal GPCR (eGPCR) signaling platforms for the treatment of chronic pain Pain is transmitted through the nervous system via the activity of G-protein coupled receptors (GPCRs) found on neurons in the central and peripheral nervous systems including the brain and spinal cord. GPCRs can function at the surface of these cells, or in internalized compartments called endosomes. By specifically targeting eGPCRs, it is hypothesized that superior pain relief can be achieved via particular endosomal targets which have been demonstrated to be responsible for ongoing signaling in chronic pain and which, due to their compartmentalized location, may not have been optimally targeted by previous clinical agents. Selective delivery of small molecule antagonists can be achieved with encapsulation into an acid labile nanoparticle that breaks down inside the acidic compartment of the endosome to release the antagonist, specifically targeting the eGPCR signaling of the nociceptive transmission pathway. The FDA-approved small molecule aprepitant (AP) is encapsulated into DIPMA polymers and has been shown to target the endosomal NK1R signaling of the spinal cord dorsal horn neurons after intrathecal administration. The project team is providing proof of concept and testing efficacy and potential for side effects of the nanoparticle formulation. Fast, Centrally-Acting, Non-Addicting Novel Analgesic for Chronic Non-Cancer Pain Enkephalins, an endogenous opioid ligand, preferentially bind to delta-opioid receptors to produce analgesic benefits without the associated negative effects typically noted from mu-opioid receptor binding. Enkephalins have been well studied but not developed as drugs accessible to patients due to their rapid enzymatic degradation and poor brain permeation, even with the use of various penetration enhancers. Therefore, new methods of enkephalin delivery must be developed and investigated to devise novel, non-addictive pain-relieving therapies. To this end, Virpax Pharmaceuticals has developed NES100, a formulation of leucine-enkephalin (L-ENK) in an IP-protected Molecular Envelope Technology (MET) that enables the efficient delivery of L-ENK exclusively to the brain via the intranasal route with essentially no peripheral exposure. This collaborative project is aimed to support an IND application, this effort includes additional in vivo preclinical efficacy determination, PK-ADME studies, GMP manufacturing of L-ENK and MET and formulation of NES100 for nasal delivery, evaluation of abuse liability and toxicological and safety assessment. Development of D3 Antagonist for Substance Use Disorder Drugs of abuse share the ability to elevate dopamine in the nucleus accumbens shell, a key component of the reward system. The dopamine D3 receptor (D3R) expressed in the ventral forebrain mesolimbic dopamine system is thought to influence reward, emotion, and motivation and, by extension, drug seeking and relapse. D3R-selective antagonists decrease craving for drugs of abuse and drug-seeking behavior and have been investigated clinically with promising results. However, these efforts have been discontinued due to elevated blood pressure in a preclinical model when used in combination with cocaine. NIDA has developed highly selective dopamine D3 receptor antagonists that has demonstrated efficacy in multiple preclinical models of addiction including reduction in self-administration and reinstatement of oxycodone and, notably, did not alter activity of human cardiac potassium channels (hERG) in vitro at pharmacologically relevant concentrations. Braeburn and NIDA executed a license for these compounds to treat OUD. This collaboration is using the combined resources and expertise of NCATS, Braeburn, and NIDA to conduct IND-enabling preclinical development studies with the lead compound for the treatment of OUD. The team intends to conduct additional studies to identify a back-up compound for development. Evaluation of drug efficacy in a guinea pig model of neonatal opioid withdrawal syndrome Neonatal opioid withdrawal syndrome (NOWS) develops in utero following opioid abuse by a pregnant mother. This project involves the development of a selective neutral opioid antagonist, 6-beta-naltrexol (6BN), a metabolite of the FDA-approved opioid addiction treatment naltrexone. 6BN is hypothesized to have superior physicochemical and pharmacological properties to treat NOWS. One important aspect of 6BN is that it does not readily cross the blood brain barrier (BBB) into the maternal central nervous system but can cross the immature fetal BBB. In addition, 6BN has been demonstrated to prevent opioid dependence in animal models at low doses that do not block opioid analgesia nor cause withdrawal. These combined properties of 6BN would allow for concurrent administration of 6BN with methadone or buprenorphine in pregnant mothers, blocking deleterious effects of the opioids on the developing fetus, while not interfering with their ability to serve as an effective therapy for treating opioid use disorder in the mother. This collaborative project is evaluating drug efficacy of 6BN in reducing withdrawal symptoms and measuring the biodistribution and pharmacokinetics of 6BN to support the hypothesis that 6BN, when administered during pregnancy, can reduce newborn symptoms of opioid withdrawal without the risk of precipitated maternal and fetal withdrawal. Collaboration to Develop a Mitragynine Formulation and Conduct the First Rigorously Controlled Clinical Trials with a Kratom Alkaloid Extract Mitragynine (MG), the active component of Kratom, is popularly used as a treatment for opioid withdrawal although the DEA/HHS has indicated MG has a high abuse potential. Because no kratomderived product that meets the FDA standards for Investigational New Drugs currently exists, the DEA assertion has not been rigorously tested in humans. Further, counterclaims from kratom supporters that MG has significant value as a potential therapeutic for the treatment of chronic pain and opioid addiction have also not been tested in rigorous placebocontrolled clinical trials. This collaborative project will allow these claims to be empirically evaluated by generating a preclinical data package and sufficient clinical drug product.

镰状细胞疾病的大动物临床前模型的表征 镰状细胞疾病（SCD）患者迫切需要改善疼痛治疗剂，以优化镇痛作用在管理慢性和急性方面，还需要大型的SCD模型来试图解决SCD研究和疗法开发方面，以至于传统鼠模型无法完全实现。 Yucatan迷你木偶的大小几乎与普通人的大小相同，允许对血液进行纵向采样，并且很可能是人类解剖学和生理学的更好的翻译模型，特别是对于脉管系统和疼痛传播途径。 SCD猪已经利用CRIS / CAS9技术开发了分子和表型表征，包括计划的两年自然历史研究（NHS）以及随后的菌落扩张。 NHS正在评估，血液学参数，尿液和血液化学，电生理学，疼痛和相关行为测量，大脑和肺部的诊断成像以及其他心肺功能的评估临界范围的痛苦分析，使SCD的痛苦是痛苦的。研究和药物开发界进行了更完整的评估和SCD模型的验证。 靶向内体GPCR（EGPCR）信号平台用于治疗慢性疼痛 通过神经系统通过神经系统的活性（GPCR）在中枢和周围神经系统（包括脑和脊髓）的神经元上发现的活性通过神经系统传播疼痛。 GPCR可以在这些细胞的表面或称为内体的内部隔室中起作用。通过特异性靶向EGPCR，可以假设可以通过特定的内体靶标可以实现上疼痛的缓解，这些内体靶标被证明是造成慢性疼痛中持续信号传导的原因，并且由于其分室的位置，可能无法最佳地靶向以前的临床药物。可以将小分子拮抗剂的选择性递送到封装到酸不稳定的纳米颗粒中，该纳米粒子在内体的酸性隔室内分解以释放拮抗剂，专门针对伤害感受器透射途径的EGPCR信号。在胸腔内给药后，已将FDA批准的小分子座位（AP）封装在DIPMA聚合物中，并已显示针对脊髓背侧角神经元的内体NK1R信号传导。项目团队正在提供概念证明和测试功效，并提供纳米颗粒配方副作用的潜力。 快速，中心作用，无成名的慢性非癌症疼痛的新型镇痛药 内源性阿片类配体Enkephalins优先与三角洲阿片受体结合以产生镇痛益处，而没有通常从MU-Apioid受体结合中注意到的相关负面作用。 Enkephalins经过了很好的研究，但由于患者的快速酶促降解和大脑渗透不良，即使使用各种渗透促进剂，因此无法作为患者使用的药物开发。因此，必须开发和研究新的Enkephalin递送方法，以设计新型的非添加性疼痛疗法。为此，Virpax Pharmaceuticals开发了NES100，这是一种在IP保护的分子包膜技术（MET）中的亮氨酸 - 源石蛋白（L-ENK）的公式，该公式可以通过内部途径有效地通过内鼻途径将L-ENK独家传递给大脑，而本质上没有外周的暴露。该协作项目的目的是支持IND应用程序，这项工作包括额外的体内临床前疗效确定，PK-ADME研究，L-ENK的GMP制造和MET和MET和NES100的NES100，用于鼻输送，评估虐待责任，毒理学和毒理学和安全评估。 开发D3拮抗剂用于药物使用障碍 滥用药物具有提升奖励系统的关键组成部分伏伏壳中升高多巴胺的能力。在腹前脑前缘多巴胺系统中表达的多巴胺D3受体（D3R）被认为会影响奖励，情感和动机，并通过扩展，寻求和复发。 D3R选择性拮抗剂减少了对滥用和寻求药物行为的药物的渴望，并已在临床上进行了调查，结果有令人鼓舞的结果。但是，与可卡因结合使用时，由于临床前模型中的血压升高，这些努力已经停止。 NIDA已经开发了高度选择性的多巴胺D3受体拮抗剂，这些拮抗剂在多种临床前成瘾模型中表现出功效，包括减少自我给药和羟考酮的恢复，并且尤其没有改变人类心脏钾通道（HERG）在药理学相关浓度中的活性。 Braeburn和NIDA为这些化合物的治疗OUD执行了许可。这种合作利用NCAT，Braeburn和NIDA的合并资源和专业知识来进行促进的临床前开发研究，并使用铅化合物来处理OUD。该团队打算进行其他研究，以确定开发的备用化合物。 在新生儿阿片类药物戒断综合征的豚鼠模型中评估药物疗效 新生儿阿片类药物戒断综合征（Nows）在孕妇滥用阿片类药物后在子宫内发展。该项目涉及一种选择性中性阿片类药物拮抗剂6-β-奈特列蛋白（6亿），这是FDA批准的阿片类药物成瘾治疗纳曲酮的代谢产物。假设60亿只具有出色的物理化学和药理学特性来治疗现在。 6亿美元的一个重要方面是，它不容易将血脑屏障（BBB）越过母体中枢神经系统，而是可以越过未成熟的胎儿BBB。此外，已经证明了6亿只能防止低剂量的动物模型中阿片类药物的依赖性，而低剂量不会阻止阿片类镇痛或导致戒断。这些6亿美元的合并特性将允许在怀孕的母亲中同时使用美沙酮或丁丙诺啡同时给药，阻止阿片类药物对发育中的胎儿的有害影响，同时不干扰母亲治疗阿片类药物使用障碍的有效治疗能力。该协作项目是评估6亿次减少戒断症状的药物疗效，并测量6亿亿美元的生物分布和药代动力学，以支持以下假设：在怀孕期间服用60亿，可以减少阿片类药物戒断的新生儿症状，而不会降低产妇和胎儿戒断的风险。 合作开发Mitragynine配方，并使用Kratom生物碱提取物进行第一次严格控制的临床试验 Kratom的活性成分Mitragynine（MG）通常被用作阿片类药物戒断的治疗方法，尽管DEA/HHS表明MG具有很高的滥用潜力。由于目前存在符合FDA标准的Kratomdered产品，因此目前存在研究新药，因此在人类中尚未对DEA主张进行严格的测试。此外，KRATOM支持者的反诉讼称，在严格的安慰剂控制临床试验中，也没有对MG具有显着的治疗治疗慢性疼痛和阿片类药物成瘾的潜在治疗方法。该协作项目将允许通过生成临床前数据包和足够的临床药物来对这些主张进行经验评估。