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.

镰状细胞病大型动物临床前模型的表征