An Antiviral to Treat Progressive Multifocal Leukoencephalopathy_(PML)

一种治疗进行性多灶性白质脑病 (PML) 的抗病毒药物

基本信息

批准号：
8906181
负责人：
Stacy Remiszewski
金额：
$ 22.5万
依托单位：
EVRYS BIO, LLC
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-02-05 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8906181
关键词：
Acquired Immunodeficiency Syndrome Address Adult Agonist Animal Model Anti-Inflammatory Agents Anti-Retroviral Agents Anti-inflammatory Antimalarials Antiviral Agents Area Astrocytes Autoimmune Diseases Autoimmune Process Biochemical Biodistribution Biological Assay Biological Markers Biological Sciences Blood - brain barrier anatomy Brain Brain Injuries Cell Culture Techniques Cells Central Nervous System Infections Cessation of life Cidofovir Clinic Clinical Crohn&apos s disease Cytarabine DNA-Directed DNA Polymerase Demyelinations Development Disabled Persons Disease Disease Progression Drug Kinetics Drug Targeting Enzymes Etanercept Excision Exhibits Functional disorder Genes Genetic Transcription Goals Growth Highly Active Antiretroviral Therapy Human Immune Immune system Immunocompromised Host Immunosuppression Immunosuppressive Agents In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Inhibitory Concentration 50 JC Virus Latent Virus Lead Literature Measures Mefloquine Metabolic Microdialysis Modification Multiple Sclerosis Neuraxis Neurons Oligodendroglia Outcome Patients Pattern Penetrance Penetration Personal Satisfaction Pharmaceutical Preparations Pharmacodynamics Phase Play Prevalence Progressive Multifocal Leukoencephalopathy Property Proteins Psoriasis Rare Diseases Recovery Rheumatoid Arthritis Risk Role Series Sirtuins Small Business Innovation Research Grant Staging Structure Survivors Symptoms Syndrome Testing Therapeutic Therapeutic immunosuppression Translations Validation Viral Virus Virus Diseases adalimumab base cell type clinically relevant cytotoxicity drug candidate effective therapy gene function immune function immunosuppressed improved in vitro testing in vivo indexing infliximab innovative technologies lead series lytic replication meetings natalizumab novel novel strategies nucleoside analog patient population pre-clinical preclinical efficacy preclinical safety promoter public health relevance receptor reconstitution restoration scaffold seropositive single molecule small molecule transcription factor viral DNA

Acquired Immunodeficiency Syndrome Address Adult Agonist Animal Model Anti-Inflammatory Agents Anti-Retroviral Agents Anti-inflammatory Antimalarials Antiviral Agents Area Astrocytes Autoimmune Diseases Autoimmune Process Biochemical Biodistribution Biological Assay Biological Markers Biological Sciences Blood - brain barrier anatomy Brain Brain Injuries Cell Culture Techniques Cells Central Nervous System Infections Cessation of life Cidofovir Clinic Clinical Crohn&apos s disease Cytarabine DNA-Directed DNA Polymerase Demyelinations Development Disabled Persons Disease Disease Progression Drug Kinetics Drug Targeting Enzymes Etanercept Excision Exhibits Functional disorder Genes Genetic Transcription Goals Growth Highly Active Antiretroviral Therapy Human Immune Immune system Immunocompromised Host Immunosuppression Immunosuppressive Agents In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Inhibitory Concentration 50 JC Virus Latent Virus Lead Literature Measures Mefloquine Metabolic Microdialysis Modification Multiple Sclerosis Neuraxis Neurons Oligodendroglia Outcome Patients Pattern Penetrance Penetration Personal Satisfaction Pharmaceutical Preparations Pharmacodynamics Phase Play Prevalence Progressive Multifocal Leukoencephalopathy Property Proteins Psoriasis Rare Diseases Recovery Rheumatoid Arthritis Risk Role Series Sirtuins Small Business Innovation Research Grant Staging Structure Survivors Symptoms Syndrome Testing Therapeutic Therapeutic immunosuppression Translations Validation Viral Virus Virus Diseases adalimumab base cell type clinically relevant cytotoxicity drug candidate effective therapy gene function immune function immunosuppressed improved in vitro testing in vivo indexing infliximab innovative technologies lead series lytic replication meetings natalizumab novel novel strategies nucleoside analog patient population pre-clinical preclinical efficacy preclinical safety promoter public health relevance receptor reconstitution restoration scaffold seropositive single molecule small molecule transcription factor viral DNA

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项目摘要

DESCRIPTION (provided by applicant): Reactivation of polyomavirus JCV in the brains of immunosuppressed individuals causes a devastating disease called progressive multifocal leukoencephalopathy (PML). There are no effective therapies available for PML. Although rare, the disease carries a >20% fatality rate and patients who survive are severely disabled due to brain damage caused by JCV infection and inflammation. Over a million individuals in the U.S. with acquired immune deficiency syndrome and individuals using immunosuppressive therapies are at risk for PML; depending on the underlying immunosuppressed condition, up to 3-5% will develop the disease. In particular, risk of PML limits the use of certain effective immunosuppressive drugs, e.g. natalizumab, adalimumab, etanercept, and infliximab for treatment of multiple sclerosis (MS), psoriasis, rheumatoid arthritis, and Crohn's disease, respectively. These drugs are counter-indicated for patients who are seropositive for JCV (up to 80% of healthy adults, and 30% of MS patients, as example). Previous strategies to develop a therapy for PML primarily focused on inhibiting JCV replication. Nucleoside analogues such as cytosine arabinoside, cidofovir and the anti-malarial drug mefloquine are effective in blocking JCV replication in culture, but they failed to demonstrate efficacy against PML in the clinic. The only treatment option for PML is to restore and allow the immune system to clear the viral infection; however, this often leads to immune-reconstitution inflammatory syndrome (IRIS) in which increased immune system activity actually increases the damage caused by the infection. The present project proposes to validate a novel mechanism of action, the activation of a host- encoded sirtuin protein by a single molecule that will simultaneously target different cellular sequelae of PML including JCV reactivation and IRIS. Sirtuins are NAD+-dependent deacetylases known for their role in regulating metabolic gene function and the inflammatory response. In addition, recent studies described herein point to a new role for Sirtuins as broad-spectrum viral restriction factors. A small molecule screen for sirtuin modulators identified broad-spectrum antivirals with nanomolar potency in inhibiting JCV growth in culture. The literature predicts the identified sirtuin modulators will also reduce inflammation, and importantl, one identified scaffold exhibited achievable biodistribution to the brain. Brain-penetrance minimizes the risk of poor drug availability to the viral and anti-inflammatory drug-targets of PML. The proposed SBIR phase 1 goal is to advance this hit to a lead while validating the hypothesis-driven antiviral and anti-inflammatory mechanisms of action. Confounding past attempts to develop an efficacious PML therapy, animal models do not exist for JCV that manifest the infection nor the symptoms of PML in the brain. The herein described mechanistic approach (as opposed to an antiviral-phenotypic approach) predicts pharmacodynamic markers to aid in determining a therapeutic window between tolerability and sufficient drug target-engagement. Such biomarkers will be measured in SBIR phase 2 and downstream to enable successful preclinical and clinical translation. In summary, a brain-penetrant lead that can simultaneously addresses viral infection and inflammatory components of PML, represents proof-of-principle for an innovative technology that addresses the devastating societal need for an effective PML therapeutic.

描述（由适用提供）：免疫抑制个体大脑中多瘤病毒JCV的重新激活会导致一种毁灭性疾病，称为进行性多灶性白细胞造成性脑病（PML）。 PML没有有效的疗法。尽管很少见，但由于JCV感染和感染引起的脑损伤，这种疾病的死亡率> 20％，而存活的患者严重残疾。在美国，有超过一百万的人患有获得免疫抑制综合症，使用免疫抑制疗法的人有PML的风险；根据潜在的免疫抑制条件，高达3-5％的疾病将发展。特别是，PML的风险限制了使用某些有效的免疫抑制药物的使用，例如Natalizumab，Adalimumab，Etanercept和英夫利昔单抗分别用于治疗多发性硬化症（MS），牛皮癣，类风湿关节炎和克罗恩病。这些药物针对JCV血清阳性的患者进行了反指明（最多80％的健康成年人和30％的MS患者）。先前开发用于PML的疗法的策略主要集中在抑制JCV复制上。核苷的类比，例如阿拉伯糖苷，cidofovir和抗疟疾药物甲氟喹有效阻止培养中的JCV复制，但它们未能在诊所证明对PML的有效性。 PML的唯一治疗选择是恢复并允许免疫系统清除病毒感染。但是，这通常会导致免疫恢复炎症综合征（IRIS），其中增加的免疫系统活性实际上会增加感染造成的损害。本项目的提案旨在验证一种新型的作用机理，即通过单个分子对宿主编码的Sirtuin蛋白的激活，该分子将仅针对PML的不同细胞后遗症，包括JCV重新激活和虹膜。 Sirtuins是NAD+依赖性脱乙酰基酶，以其在控制代谢基因功能和炎症反应中的作用而闻名。此外，最近的研究描述了Sirtuins作为广谱病毒限制因素的新作用。 SIRTUIN调节剂的小分子筛选鉴定出具有纳摩尔效力的广谱抗病毒药，可抑制JCV培养物的生长。文献预测，已鉴定的Sirtuin调节剂还将减少感染，并且重要的是，鉴定出的脚手架暴露于大脑的生物分布。脑渗透率可最大程度地减少PML病毒和抗炎药物目标的药物供应不良的风险。拟议的SBIR第1阶段目标是在验证假设驱动的抗病毒和抗炎作用机制的同时，将这一打击提高到领先地位。过去试图开发有效的PML疗法的尝试，对于表现出感染或大脑中PML症状的JCV而言，动物模型并不存在。本文描述的机械方法（与抗病毒 - 表型方法相反）预测了药效标记，以帮助确定耐受性和足够的药物靶向参与之间的治疗窗口。此类生物标志物将在SBIR第2阶段和下游测量，以实现成功的临床前和临床翻译。总而言之，可以轻松解决PML病毒感染和炎症成分的脑渗透铅代表了一种创新技术的原理证明，该技术解决了有效PML治疗的毁灭性社会需求。