Development of a host-targeted antiviral as a chronic hepatitis B therapeutic with potential to achieve a functional cure

快速通道阶段I和II摘要 如果不治疗，慢性B型肝炎病毒（HBV）感染可导致肝硬化、肝细胞性肝硬化、肝细胞性肝细胞性肝硬化、肝细胞性肝细胞性肝硬化、肝细胞性肝细胞性肝硬化、肝细胞性肝 癌症或肝功能衰竭。目前的治疗方法有效地控制了这种疾病，但很少治愈。的目标 该建议是开发一种提供慢性HBV感染的“功能性治愈”的治疗剂，即，治疗 在血清中产生持续的、不可检测的HBV表面抗原（HBsAg）和rcDNA（病毒体的量度）。一 功能性治疗将使全世界约2.57亿人受益，其中包括约140万人。 美国慢性HBV感染者。申请人Evrys Bio最近描述了一种宿主- 针对病毒的脆弱性-去酰化酶的sirtuin家族，或SIRTs。SIRT调节剂具有广泛的- 对多种不同病毒（包括HBV）具有广谱抗病毒活性。与这项提议直接相关的是， Evrys已经在培养的原代人中鉴定出具有有效抗HBV活性的SIRT 2抑制剂系列。 肝细胞，阻断细胞外HBV rcDNA，HBsAg和HBeAg的积累以及细胞内 cccDNA -抗病毒作用表明SIRT 2抑制剂有可能有助于功能性治愈。相 本提案的I部分将证明Evrys SIRT 2抑制剂治疗HBV的可行性：具体目标1将 验证感染肝细胞中cccDNA的减少。这一目标将扩展HBV基因型D的结果 纳入HBV基因型A，概括HBV被SIRT 2抑制剂抑制的结论;这将证实 基于qPCR的结论是，通过测量 Southern印迹分析;它将描述体外阻断对蓄积的相对贡献， 通过SIRT 2抑制，cccDNA水平的降低与去稳定化有关。具体目标2将确定剂量 在FRG KO huHep小鼠中Evrys SIRT 2抑制剂示例的策略，确定了 可以达到预期的抗HBV EC 95。具体目标3将证明使用样本治疗的可行性 HBV感染的FRG KO huHep小鼠。第二阶段将开发一个原型：具体目标4将确定一个发展 候选人加上至少一个IND支持研究的备份，这些研究来自现有的近600个Evrys SIRT 2系列- 抑制剂的具体目标5将探索开发候选药物阻断HBV的机制 在人肝细胞中复制以促进临床翻译。

FAST-TRACK PHASE I and II ABSTRACT Without treatment, chronic hepatitis B virus (HBV) infection can lead to cirrhosis of the liver, hepatocellular carcinoma or liver failure. Current therapies effectively control the disease, but are rarely curative. The goal of this proposal is to develop a therapeutic providing a “functional cure” for chronic HBV infection, i.e., a therapy producing sustained, undetectable HBV surface antigen (HBsAg) and rcDNA (a measure of virions) in serum. A functional cure will potentially benefit about 257 million people worldwide, including approximately 1.4 million individuals with chronic HBV infection in the USA. The applicant, Evrys Bio, has recently described a host- targeted vulnerability of viruses – the sirtuin family of deacylases, or SIRTs. SIRT modulators have broad- spectrum antiviral activity against multiple, diverse viruses including HBV. Of direct relevance to this proposal, Evrys has identified a SIRT2-inhibitor series with potent anti-HBV activity in cultured primary human hepatocytes, blocking the accumulation of extracellular HBV rcDNA, HBsAg and HBeAg as well as intracellular cccDNA – antiviral effects that suggest SIRT2 inhibitors have potential to contribute to a functional cure. Phase I of this proposal will demonstrate the feasibility of Evrys SIRT2-inhibitors to treat HBV: Specific Aim 1 will validate the reduction of cccDNA in infected hepatocytes. This aim will extend the results with HBV genotype D to include HBV genotype A, generalizing the conclusion that HBV is inhibited by SIRT2 inhibitors; it will confirm the qPCR-based conclusion that cccDNA levels are reduced by SIRT2 inhibitors by measuring cccDNA in Southern blot analysis; and it will delineate the relative contributions of the in vitro block to accumulation versus destabilization to the reduction of cccDNA levels by SIRT2 inhibition. Specific Aim 2 will determine a dosing strategy for an exemplar of Evrys SIRT2-inhibitors in FRG KO huHep mice, identifying a well-tolerated dose that can achieve the desired anti-HBV EC95. Specific Aim 3 will demonstrate feasibility using the exemplar to treat HBV-infected FRG KO huHep mice. Phase II will develop a prototype: Specific Aim 4 will identify a development candidate plus at least one backup for IND enabling studies from an existing series of nearly 600 Evrys SIRT2- inhibitors. Specific Aim 5 will probe the mechanisms by which the development candidate blocks HBV replication in human hepatocytes to facilitate clinical translation.