An Antiviral to Treat Progressive Multifocal Leukoencephalopathy_(PML)

 描述（由申请方提供）：免疫抑制个体脑中多瘤病毒JCV的再活化导致一种称为进行性多灶性白质脑病（PML）的破坏性疾病。PML尚无有效的治疗方法。虽然罕见，但这种疾病的死亡率超过20%，存活的患者由于JCV感染和炎症引起的脑损伤而严重残疾。在美国，超过100万患有获得性免疫缺陷综合征的个体和使用免疫抑制疗法的个体有患PML的风险;根据潜在的免疫抑制状况，高达3-5%的人会发展成这种疾病。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）、银屑病、类风湿性关节炎和克罗恩病。这些药物对JCV血清反应阳性的患者（例如，高达80%的健康成人和30%的MS患者）具有反适应症。以前开发PML治疗的策略主要集中在抑制JCV复制。核苷类似物如阿糖胞苷、西多福韦和抗疟疾药物甲氟喹在阻断培养物中JCV复制方面是有效的，但它们未能在临床上证明对PML的疗效。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），其中增加的免疫系统活性实际上增加了感染引起的损害。本项目拟验证一种新的作用机制，即通过单一分子激活宿主编码的沉默调节蛋白，该分子将同时靶向PML的不同细胞后遗症，包括JCV再激活和IRIS。Sirtuins是NAD+依赖性脱乙酰酶，已知其在调节代谢基因功能和炎症反应中的作用。此外，本文描述的最近的研究指出了Sirtuins作为广谱病毒限制因子的新作用。对沉默调节蛋白调节剂的小分子筛选鉴定了在抑制培养物中JCV生长方面具有纳摩尔效力的广谱抗病毒药物。文献预测鉴定的沉默调节蛋白调节剂也将减少炎症，并且重要的是，一种鉴定的支架表现出可实现的脑生物分布。脑转移可最大限度地降低PML的病毒和抗炎药物靶点的药物可用性差的风险。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，将这一打击推向领先地位。混淆过去开发有效PML治疗的尝试，JCV的动物模型不存在，表现出感染或脑中PML症状。本文所述的机制方法（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标接合之间的治疗窗口。这些生物标志物将在SBIR 2期和下游进行测量，以实现成功的临床前和临床转化。总之，可以同时解决病毒感染和PML炎症成分的脑渗透电极导线代表了一种创新技术的原理证明，该技术可以解决对有效PML治疗的破坏性社会需求。

 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.