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

• 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
• 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' 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

 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（由申请人提供）：免疫抑制个体大脑中多瘤病毒 JCV 的重新激活会导致一种称为进行性多灶性白质脑病 (PML) 的破坏性疾病。 PML 尚无有效疗法。尽管罕见，但这种疾病的死亡率高达 20% 以上，幸存的患者会因 JCV 感染和炎症引起的脑损伤而严重致残。在美国，超过 100 万患有获得性免疫缺陷综合症的人和使用免疫抑制疗法的人有患 PML 的风险；根据潜在的免疫抑制状况，高达 3-5% 的人会患上这种疾病。特别是，PML 的风险限制了某些有效免疫抑制药物的使用，例如：那他珠单抗、阿达木单抗、依那西普和英夫利昔单抗分别用于治疗多发性硬化症 (MS)、牛皮癣、类风湿性关节炎和克罗恩病。这些药物不适用于 JCV 血清反应呈阳性的患者（例如，高达 80% 的健康成年人和 30% 的多发性硬化症患者）。先前开发 PML 疗法的策略主要集中于抑制 JCV 复制。核苷类似物如阿拉伯胞嘧啶、西多福韦和抗疟疾药物甲氟喹可有效阻断 JCV 在培养物中的复制，但它们未能在临床中证明对 PML 的疗效。 PML 的唯一治疗选择是恢复并让免疫系统清除病毒感染；然而，这通常会导致免疫重建炎症综合征（IRIS），其中免疫系统活动的增加实际上会增加感染造成的损害。本项目拟验证一种新的作用机制，即通过单分子激活宿主编码的沉默调节蛋白，该分子将同时针对 PML 的不同细胞后遗症，包括 JCV 重新激活和 IRIS。 Sirtuins 是 NAD+ 依赖性脱乙酰酶，因其在调节代谢基因功能和炎症反应中的作用而闻名。此外，本文描述的最近研究指出了 Sirtuins 作为广谱病毒限制因子的新作用。对 Sirtuin 调节剂的小分子筛选鉴定出具有纳摩尔级效力的广谱抗病毒药物，可抑制 JCV 在培养物中的生长。文献预测，已鉴定的去乙酰化酶调节剂也将减少炎症，而且重要的是，一种已鉴定的支架表现出可实现的大脑生物分布。脑渗透率可最大限度地降低 PML 病毒和抗炎药物靶点药物可用性差的风险。拟议的 SBIR 第一阶段目标是将这一成果推向领先地位，同时验证假设驱动的抗病毒和抗炎作用机制。与过去开发有效的 PML 疗法的尝试相混淆的是，不存在表现出感染或大脑中 PML 症状的 JCV 动物模型。本文描述的机械方法（与抗病毒表型方法相反）预测药效标记物，以帮助确定耐受性和充分的药物靶点接合之间的治疗窗口。此类生物标志物将在 SBIR 第 2 期及下游进行测量，以实现成功的临床前和临床转化。总之，一种可以同时解决 PML 的病毒感染和炎症成分的脑部渗透性导线，代表了一种创新技术的原理验证，该技术可满足对有效 PML 治疗的毁灭性社会需求。