A Novel Small Molecule Therapeutic for Acute Graft Versus Host Disease

一种治疗急性移植物抗宿主病的新型小分子疗法

• 批准号: 10759657
• 负责人: CLIFFORD W MASON
• 金额: $ 29.58万
• 依托单位: CRESTONE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-02 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10759657
• 关键词: Acute Graft Versus Host Disease; Adrenal Cortex Hormones; Affect; Allogenic; Anaerobic Bacteria; Animal Disease Models; Animal Model; Animals; Anti-Bacterial Agents; Antibiotics; Bacteremia; Biological; Biological Availability; Body Weight decreased; C57BL/6 Mouse; Cessation of life; Clinical; Clinical Treatment; Clinical Trials; Clostridium difficile; Development; Disease; Dose; Effectiveness; Engraftment; Ensure; Enterococcus; Enterococcus faecalis; Enterococcus faecium; Evaluation; Exhibits; Feces; Female; Flow Cytometry; Frequencies; Future; Gastrointestinal tract structure; Goals; Growth; HLA Antigens; Hematologic Neoplasms; Hematological Disease; Hematopoietic Stem Cell Transplantation; Homologous Transplantation; Human; Immune system; Immunosuppression; In Vitro; Inbred BALB C Mice; Infection; Intestines; Leukocytes; Life; Link; Malignant - descriptor; Malignant Neoplasms; Metabolic Diseases; Methionine-tRNA Ligase; Methods; Modeling; Monitor; Morbidity - disease rate; Mus; Non-Malignant; Oral; Outcome; Pathogenicity; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phenotype; Play; Prevention; Production; Protein Synthesis Inhibition; Quality of life; Radiation; Relapse; Risk; Risk Reduction; Role; Safety; Sampling; Sepsis; Serial Passage; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Toxin; Translating; Transplant Recipients; Transplantation; Vancomycin Resistance; Vancomycin resistant enterococcus; allogeneic disease; chemotherapy; conditioning; effective therapy; gastrointestinal; gastrointestinal infection; graft vs host disease; gut microbes; gut microbiome; gut microbiota; hematopoietic cell transplantation; immunoprophylaxis; in vitro activity; in vivo; microbiome; microbiota; microbiota profiles; mortality; mouse model; mutant; novel; novel therapeutics; opportunistic pathogen; organ injury; prevent; prophylactic; prospective; resistant strain; small molecule therapeutics; tumor

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.

摘要 异基因造血干细胞移植（allo-HSCT）是治疗多种恶性肿瘤的有效方法， 非恶性血液和代谢疾病，但其适用性受到移植物抗宿主病的限制 （GvHD）。GvHD是HSCT后发生的死亡的15-30%的原因，并且是发病的主要原因 高达50%的接受者。目前GvHD的预防和治疗仍然不理想，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 复发和感染并发症导致这些患者的生活质量差和死亡率高。 越来越多的证据表明，患者的肠道微生物群在疾病的发展中起着重要作用。 急性GvHD。粪肠球菌和屎肠球菌占肠道微生物群落的大量 部分allo-HSCT患者在移植后出现异常扩张，这种异常扩张可能先于血流感染。 本提案的目的是评价CRS 3123对急性GvHD的预防和治疗作用 在allo-HSCT中。CRS 3123是一种高效的窄谱抗菌剂，由克雷斯通公司开发， 具有选择性靶向细菌甲硫氨酰-tRNA合成酶（MetRS）的新作用机制， 抑制蛋白质合成和细菌生长。CRS 3123有效抑制粪肠球菌， 屎肠球菌，包括万古霉素耐药菌株。口服给药后，它主要留在肠道中 其确保高肠浓度并限制全身暴露。重要的是，CRS 3123显示出最小的 破坏大多数细菌门，并在很大程度上保留有益的肠道微生物群。我们假设选择性的 通过CRS 3123抑制肠道中致病性肠球菌的过度生长将减少GvHD的发生 以及allo-HSCT后的相关结果，而不影响健康的肠道微生物组。为了验证这个假设， 我们将评估CRS 3123在体外和体内对肠球菌的活性，并确定 CRS 3123在GvHD鼠模型中的疗效，具体目标2。这些拟议的研究将构成以下方面的基础： 未来的临床试验针对肠球菌占主导地位的肠道微生物群，以预防或治疗急性 GvHD和移植相关死亡率。