A Novel Small Molecule Therapeutic for Acute Graft Versus Host Disease

摘要 异基因造血细胞移植(allo-HSCT)是治疗多种恶性肿瘤的有效方法。 非恶性血液和代谢性疾病，但其适用性受到移植物抗宿主病的限制 (GVHD)。移植物抗宿主病占造血干细胞移植后死亡的15%-30%，是发病的主要原因 在高达50%的接受者中。目前GvHD的预防和治疗仍然不太理想，主要依赖于 皮质类固醇和T细胞的广泛抑制。这种严重的免疫抑制会导致肿瘤。 复发和感染性并发症导致这些患者的生活质量较差和死亡率较高。 越来越多的证据表明，患者的肠道微生物区系在糖尿病的发生发展中起着重要作用。 急性GvHD。粪肠球菌和粪肠球菌在肠道微生物区系中占主导地位。 部分allo-HSCT患者在移植后，这种异常扩张可能先于血流感染。 这项建议的目的是评估CRS3123对急性移植物抗宿主病的防治效果 在allo-HSCT中。CRS3123是由Crestone，Inc.开发的高效窄谱抗菌剂， 具有选择性靶向细菌甲硫酰-tRNA合成酶(MetRS)的新作用机制 抑制蛋白质合成和细菌生长。CRS3123对粪肠球菌和 粪肠球菌，包括万古霉素耐药菌株。口服后大部分仍留在肠道内 这确保了较高的肠道浓度，并限制了全身暴露。重要的是，CRS3123显示最小 破坏了大多数细菌门，并在很大程度上保留了有益的肠道微生物群。我们假设有选择性的 CRS3123抑制致病肠球菌在肠道过度生长可减少移植物抗宿主病的发生 以及在不影响健康肠道微生物群的情况下进行allo-HSCT后的相关结果。为了检验这一假设， 我们将评估CRS3123对肠球菌的体外和体内抗菌活性，并确定 CRS3123在GvHD小鼠模型中的特定目的疗效2。这些拟议的研究将形成以下基础 未来针对肠球菌控制肠道微生物区系以预防或治疗急性呼吸道感染的临床试验 移植物抗宿主病和移植相关死亡率。

ABSTRACT Allogeneic hematopoietic cell transplantation (allo-HSCT) is an effective therapy for a number of malignant and non- malignant blood and metabolic diseases, but its applicability has been limited by graft-versus-host disease (GvHD). GvHD is responsible for 15-30% of deaths that occur following HSCT and is the main cause of morbidity in up to 50% of recipients. Current prevention and treatment of GvHD remains suboptimal and relies mainly on corticosteroids and the broad suppression of T cells. This profound immunosuppression can lead to tumor relapse and infectious complications contributing to a poor quality of life and high mortality in these patients. Increasing evidence suggests that the patients gut microbiota plays an important role in the development of acute GvHD. Enterococcus faecalis and Enterococcus faecium dominate the gut microflora of a substantial portion of allo-HSCT patients after transplant, and this abnormal expansion can precede bloodstream infections. The goal of this proposal is to evaluate the effect of CRS3123 on the prevention and treatment of acute GvHD in allo-HSCT. CRS3123 is a highly effective narrow spectrum antibacterial agent, developed by Crestone, Inc, with a novel mechanism of action that selectively targets bacterial methionyl-tRNA synthetase (MetRS) thereby inhibiting protein synthesis and bacterial growth. CRS3123 potently inhibits Enterococcus faecalis and Enterococcus faecium, including vancomycin-resistant strains. It remains largely in the gut after oral dosing which ensures high intestinal concentrations and limits systemic exposure. Importantly, CRS3123 shows minimal disruption of most bacterial phyla and largely spares the beneficial gut microbiota. We hypothesize that selective suppression of pathogenic enterococci overgrowth in the gut by CRS3123 would reduce the occurrence of GvHD and related outcomes following allo-HSCT without affecting the healthy gut microbiome. To test this hypothesis, we will evaluate the in vitro and in vivo activity of CRS3123 against enterococci in Specific Aim 1 and determine CRS3123 efficacy in a murine model of GvHD in Specific Aim 2. These proposed studies will form the basis for future clinical trials targeting the enterococci domination of the intestinal microbiota to prevent or treat acute GvHD and transplant-related mortality.