Safety and Efficacy Testing of FX101 in an SIV/NHP Model

SIV/NHP 模型中 FX101 的安全性和有效性测试

基本信息

批准号：
9254849
负责人：
Diane L. Bolton
金额：
$ 115.46万
依托单位：
JERICHO SCIENCES, LLC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-17 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9254849
关键词：
Acquired Immunodeficiency Syndrome Address Adherence Adverse effects Adverse event Affect Aftercare Analysis of Variance Animal Model Anti-Retroviral Agents Antiviral Agents Award Blood Blood Cells Bone Marrow Businesses Cardiovascular Diseases Caring Cerebrospinal Fluid Chronic Clinical Clinical Chemistry Clinical Trials Comorbidity Complete Blood Count Complex Data Development Disease Dose Economics Family Felidae Feline Immunodeficiency Virus Felis catus Flow Cytometry Funding Genetic Transcription HIV HIV Infections HIV therapy HIV-1 HIV-associated neurocognitive disorder Head Health Healthcare Systems Heart Highly Active Antiretroviral Therapy Human Human immunodeficiency virus test Immune Immune System Diseases Immune System and Related Disorders Immune response Immunology In Vitro Individual Infection Inflammation International Interruption Intervention Investigation Latent Virus Legal patent Lentivirus Infections Long-Term Effects Longevity Macaca mulatta Measures Mediating Methods Military Personnel Mission Modeling Monitor National Institute of Drug Abuse National Institute of Mental Health Neuraxis Neurology Nucleocapsid Nucleocapsid Proteins Outcome Pathogenesis Pathology Pathway interactions Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Phase Physiological Plasma Preclinical Testing Prevention Production Proviruses Quality of life Regimen Research Research Priority Research Support Risk Rodent SIV Safety Science Shock Small Business Innovation Research Grant Source Study models Subfamily lentivirinae Technology Testing Therapeutic Therapeutic Intervention Tissues Toxic effect Translating Treatment Efficacy United States National Institutes of Health Universities Urinalysis Validation Viral Viral Genome Viral load measurement Viral reservoir Viremia Virus Virus Diseases Virus Latency Virus Replication Whole Blood Withdrawal Withholding Treatment Work Zinc Fingers antiretroviral therapy cellular targeting clinical biomarkers clinical practice co-infection design drug development effective therapy efficacy testing experience gene therapy immune function immunotoxicity improved in vitro Model in vivo killings man medication compliance micronucleus neurotoxicity neutralizing antibody next generation nonhuman primate novel therapeutic intervention pill preclinical safety prevent programs purge safety testing simian human immunodeficiency virus skills small molecule social therapeutic target therapy adherence tool viral rebound virology

项目摘要

Abstract While highly active antiretroviral therapy (HAART) has significantly improved the health of individuals infected with human immunodeficiency virus-1 (HIV), available therapeutics largely target virus replication pathways such that treatment interruption results in the rapid resumption of viral replication and decline of immunologic function. Even despite successful therapeutic control of replication, chronic inflammation, HIV-associated neurocognitive disorders, cardiovascular disease and other comorbidities further threaten the health of an estimated 1.2 million HIV-infected people in the U.S. New therapeutic strategies capable of longer term virus suppression and reductions in the sources of persistent virus would relieve consequences of daily drug compliance and comorbidities for over 34 million HIV-infected people globally. Jericho Sciences’ investigational small molecule, FX101, is proposed to target the highly conserved zinc finger domains of lentiviral nucleocapsid (NC) proteins, a well-established therapeutic target for the treatment of HIV. FX101 has demonstrated preclinical safety and antiviral efficacy in multiple in vivo, ex vivo and in vitro models to support continuing translational testing. Zinc finger domains (ZFDs) of HIV nucleocapsid (NC) protein are highly conserved therapeutic targets shared across all lentiviruses, including feline, simian and human immunodeficiency viruses (FIV, SIV and HIV, respectively). Following eight monotherapeutic doses of FX101 over four weeks in chronically FIV-infected cats − one of the research models for HIV − blood plasma and cerebrospinal fluid viremia remained 85-95% below corresponding pretreatment levels up to 36 weeks following cessation of treatment, in the absence of observed or measured adverse events (p<0.0005; n=6; one-way ANOVA). These results are unprecedented in FIV-infected cats. Concurrently, integrated provirus in peripheral blood mononuclear cells continued to decrease by 95% from the normalized starting virus load (p<0.0001; n=6; one-way ANOVA). While we have yet to fully elucidate mechanistic implications of the nucleocapsid target profile, the most differentiating feature is the potential long term control of virus production in an apparent systemic reduction of virus replication setpoint. We propose here to conduct translational testing of FX101 in a simian immunodeficiency virus-infected nonhuman primate (SIV/NHP) model to establish the safety profile, therapeutic efficacy, and clinical biomarkers that may implicate this strategic candidate molecule’s potential utility toward a cotherapeutic functional eradication of HIV infection in humans. .

抽象的虽然高度活跃的抗逆转录病毒疗法（HAART）已显着改善了感染者的健康状况使用人类免疫缺陷病毒-1（HIV），可用的治疗在很大程度上靶向病毒复制途径这样的治疗中断会导致病毒复制的快速恢复和免疫学的下降功能。甚至绝望地成功控制复制，慢性炎症，与HIV相关的神经认知障碍，心血管疾病和其他合并症进一步威胁美国估计有120万艾滋病毒感染者的新治疗策略能够长期病毒持续病毒来源的抑制和减少将挽救每日药物的后果全球超过3400万名HIV感染者的合规性和合并症。耶利哥科学的研究性小分子FX101被提议针对高度组成的锌指慢病毒核蛋白酶（NC）蛋白的结构域，这是一个公认的HIV治疗靶标。 FX101在多个体内和体外模型中证明了临床前的安全性和抗病毒效率支持持续的翻译测试。 HIV核素（NC）蛋白的锌指域（ZFD）是在所有慢病毒中共享的高度保守的治疗靶标，包括猫科免疫缺陷病毒（分别为FIV，SIV和HIV）。在八个单一疗法剂量的FX101之后在慢性感染的猫中，超过四个星期 - HIV-血浆和脑脊液病毒血症仍低于36周的相应预处理水平85-95％停止治疗后，在没有观察到或测量的不良事件的情况下（p <0.0005; n = 6; 单向方差分析）。这些结果在FIV感染的猫中是前所未有的。同时，集成的病毒外周血单核细胞继续从归一化的起始病毒负荷下降95％（p <0.0001; n = 6;单向方差分析）。虽然我们尚未完全阐明 Nucleocapsid靶标轮廓，最不同的特征是病毒产生的潜在长期控制在明显的系统性减少病毒复制设定点中。我们在这里建议进行翻译测试在邻氨酸免疫缺陷感染的非人类灵长类动物（SIV/NHP）模型中的FX101以建立安全性概况，治疗效率和临床生物标志物，可能暗示该战略候选人分子对人类艾滋病毒感染的毒素功能放疗的潜在效用。。