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