An Antiviral to Treat Progressive Multifocal Leukoencephalopathy_(PML)

 描述(由申请人提供)：免疫抑制患者大脑中多瘤病毒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。对于PML，目前还没有有效的治疗方法。虽然罕见，但这种疾病具有20%的病死率，幸存下来的患者由于JCV感染和炎症导致的脑损伤而严重残疾。在美国，100多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情况，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的免疫抑制药物的使用，例如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的Natalizumab、adalimumab、etanercept和infliximab。对于JCV血清阳性的患者(例如，高达80%的健康成年人和30%的多发性硬化症患者)，这些药物是相反的。之前开发PML治疗方法的策略主要集中在抑制JCV复制上。核苷类似物如阿糖胞苷、西多福韦和抗疟疾药物甲氟喹在培养上能有效地阻断JCV的复制，但在临床上未能证明它们对PML有效。PML的唯一治疗选择是恢复并允许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)，在这种情况下，免疫系统活动的增加实际上会增加感染造成的损害。本项目建议验证一种新的作用机制，即由单个分子激活宿主编码的sirtuin蛋白，该分子将同时靶向PML的不同细胞后遗症，包括JCV重新激活和IRIS。Sirtuins是一种依赖NAD+的脱乙酰酶，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，本文描述的最新研究指出sirtuins作为广谱病毒限制因子的新作用。Sirtuin调节剂的小分子筛选确定了在培养中抑制JCV生长的具有纳摩尔效力的广谱抗病毒药物。文献预测，已识别的sirtuin调节剂也将减少炎症，重要的是，已识别的支架之一显示出可实现的生物分布到大脑。脑外显性将PML的病毒和抗炎药物靶点的药物可获得性差的风险降至最低。建议的SBIR阶段1的目标是在验证假说驱动的抗病毒和抗炎作用机制的同时，将这一打击推向领先。与过去开发有效的PML治疗方法的尝试相混淆，JCV不存在在大脑中表现感染或PML症状的动物模型。这里描述的机械性方法(与抗病毒-表型方法相反)预测药效学标志物，以帮助确定耐受性和充分的药物靶向参与之间的治疗窗口。这些生物标志物将在SBIR第二阶段和下游进行测量，以实现成功的临床前和临床转换。总而言之，一种可以同时解决病毒感染和PML炎症成分的脑穿透性铅代表了一种创新技术的原则证明，该技术满足了对有效PML治疗的毁灭性社会需求。

 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.