Novel therapeutic for HPA hyperactivity

HPA 过度活跃的新疗法

基本信息

批准号：
10602389
负责人：
Linda S Lloyd
金额：
$ 60.54万
依托单位：
STRESS THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10602389
关键词：
Adrenal Glands Affinity Alcohol abuse Alzheimer&apos s Disease Antibodies Area Automobile Driving Binding Biological Biological Products Biological Response Modifier Therapy Biological Sciences Bioreactors Cell Line Cells Chimeric Proteins Chinese Hamster Ovary Cell Chronic Circulation Clinical Clinical Trials Cloning Codon Nucleotides Core Facility Corticosterone Corticotropin Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Development Dissociation Dose Drug Kinetics Drug abuse Electroporation Endotoxins Ensure Evaluation Experimental Designs Fc Receptor Feedback Foundations Generations Glucocorticoid Receptor Glucocorticoids Half-Life Hormones Human Hydrocortisone Hyperactivity Hypothalamic structure IgG2 Immunoglobulin G Immunology Investigational Drugs Kinetics Lead Length Letters Life Mediating Medical Mental Depression Mineralocorticoid Receptor Mus Mutation Neuropharmacology Neurosciences Neurosecretory Systems Outcome Parkinson Disease Pathogenesis Pathologic Pathway interactions Peripheral Pharmaceutical Preparations Pharmacology Phase Pituitary Gland Plasma Printing Production Property Receptor Activation Recycling Research Research Contracts Research Institute Risk Safety Small Business Innovation Research Grant Stress System Testing Therapeutic Time Toxicology Work alcohol use disorder antagonist behavior measurement biological adaptation to stress cell bank clinical development corticotropin releasing factor-binding protein design experience first-in-human flasks flexibility gene cloning gene synthesis good laboratory practice hypothalamic-pituitary-adrenal axis neonatal Fc receptor novel novel therapeutics pharmacokinetics and pharmacodynamics professor receptor resilience response stable cell line therapeutic target

项目摘要

Summary. The hypothalamic pituitary adrenal (HPA) axis is the key neuroendocrine system that controls peripheral responses to stress. While the stress response is essential for survival, it can become dysregulated. Hyperactivity of the HPA characterizes a variety of illnesses including alcohol use disorder (AUD). HPA hyperactivity is characterized by higher production of corticotropin-releasing factor (CRF) and glucocorticoids. This Phase II SBIR aims to develop a novel biologic therapeutic aimed at normalizing pathologic HPA hyperactivity. Medications to modulate the HPA axis are currently sub-optimal. Therapeutic attempts to use glucocorticoid receptor (GR) antagonists have shown some promise in conditions like AUD and depression. However, chronically blocking GR-mediated effects can be counterproductive as, for instance, it interferes with glucocorticoid negative feedback, leading to increased cortisol levels and mineralocorticoid receptor activation. CRF receptor type 1 (CRF1) antagonists have been extensively explored, but thus far have proven disappointing, possibly because of the pharmacokinetics and pharmacodynamics properties of the existing drugs. Therefore, the identification of novel therapeutics to normalize hyperactivity of the HPA axis represents an area of significant unmet medical need. This proposal will optimize a lead validated in the Phase I SBIR and establish a stable cell line for the production of material for the eventual Investigational New Drug (IND)-enabling studies and clinical trials. Altogether, the present project will lay the foundations for the clinical development of a first-in-class therapeutic for AUD and potentially for other conditions characterized by HPA axis hyperactivity.

概括。下丘脑垂体肾上腺（HPA）轴是控制神经内分泌的关键系统对压力的外周反应。虽然压力反应对于生存至关重要，但它可能会变得失调。 HPA 过度活跃是多种疾病的特征，包括酗酒紊乱（澳元）。 HPA 过度活跃的特点是促肾上腺皮质激素释放量增加因子（CRF）和糖皮质激素。该 II 期 SBIR 旨在开发一种新型生物疗法，旨在使病理正常化 HPA 亢进。目前调节 HPA 轴的药物效果不佳。治疗性使用糖皮质激素受体 (GR) 拮抗剂的尝试已在以下情况中显示出一些希望：澳元和抑郁症。然而，长期阻断 GR 介导的效应可能会适得其反例如，它会干扰糖皮质激素的负反馈，导致皮质醇水平升高和盐皮质激素受体激活。 CRF 1 型受体 (CRF1) 拮抗剂进行了广泛的探索，但迄今为止证明令人失望，可能是因为现有药物的药代动力学和药效学特性。因此，使 HPA 轴过度活跃正常化的新疗法的鉴定代表了一个领域重大未满足的医疗需求。该提案将优化在 I 期 SBIR 中验证的先导药物，并建立稳定的细胞系为最终的研究性新药 (IND) 支持研究生产材料，以及临床试验。总而言之，本项目将为临床开发奠定基础用于治疗 AUD 以及可能治疗以 HPA 轴为特征的其他疾病的一流疗法多动症。