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.
Public Health Relevance Statement: NARRATIVE Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used to treat cancer and other life-threatening diseases but is often complicated by graft-versus-host disease (GvHD) that can lead to organ injury, poor quality of life, and even death. There is increasing evidence that gut microbes, specifically enterococcal domination, play an important role in the development of GvHD. The goal of this project is to advance an important new therapeutic option for the prevention and treatment of GvHD following allo-HSCT by targeting gastrointestinal enterococci with a narrow-spectrum antibacterial drug.
Project Terms: Hematopoietic Stem Cell Transplant; Hematopoietic Stem Cell Transplantation; Antibacterial Agents; anti-bacterial; antibacterial; Anti-Bacterial Agents; Phase 2 Clinical Trials; phase II protocol; Phase II Clinical Trials; Engraftment; Therapeutic; Transplant Recipients; transplant patient; Hematologic Neoplasms; Hematologic Cancer; Hematologic Malignancies; Hematological Malignancies; Hematological Neoplasms; Hematological Tumor; Hematopoietic Cancer; Malignant Hematologic Neoplasm; Life; Frequencies; Oral; prophylactic; gastrointestinal; mutant; Animal Model; Animal Models and Related Studies; model of animal; novel; gastrointestinal infection; Prevention; Vancomycin Resistance; resistance to vancomycin; resistant to vancomycin; vancomycin resistant; Radiation; Acute Graft Versus Host Disease; Acute GVHD; acute graft vs host disease; acute graft vs. host disease; Modeling; Sampling; Pathogenicity; reduce risk; reduce risks; reduce that risk; reduce the risk; reduce these risks; reduces risk; reduces the risk; reducing risk; reducing the risk; risk-reducing; Risk Reduction; Vancomycin-resistant enterococci; Vancomycin resistant enterococcus; Effectiveness; preventing; prevent; Dose; Protein Synthesis Inhibition; in vivo; Allogenic; Clinical Treatment; trial regimen; trial treatment; Non-Malignant; nonmalignant; Monitor; C57BL/6 Mouse; Development; developmental; microbiome; immunoprophylaxis; blood infection; bloodstream infection; Sepsis; conditioning; Outcome; prospective; chemotherapy; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; tumor; effective treatment; effective therapy; resistance strain; resistant strain; in vitro activity; GI microbiota; Gastrointestinal microbiota; enteric microbial community; enteric microbiota; gastrointestinal microbial flora; gut commensal; gut community; gut flora; gut microbe community; gut microbial community; gut microbial composition; gut microbial consortia; gut microbiotic; gut microflora; intestinal flora; intestinal microbes; intestinal microbiota; intestinal microflora; intestinal tract microflora; gut microbiota; hematopoietic cellular transplantation; hematopoietic cell transplantation; GI microbiome; digestive tract microbiome; enteric microbiome; gastrointestinal microbiome; gut-associated microbiome; intestinal biome; intestinal microbiome; gut microbiome; small molecule therapeutics; microbial consortia; microbial flora; microflora; multispecies consortia; microbiota; microbiota patterns; microbiota signature; microbiota profiles; gut microbial species; gut microbes; injury to organs; organ injury; opportunistic pathogen; Corticoids; Corticosteroids; Adrenal Cortex Hormones; Affect; allogeneic disease; Animals; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Antibiotics; Bacteremia; bacteraemia; bacterial sepsis; Anaerobic Bacteria; anaerobe; Biological Availability; Bioavailability; Physiologic Availability; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Clinical Trials; Cessation of life; Death; Disease; Disorder; Animal Disease Models; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Exhibits; Feces; stool; Female; Flow Cytometry; Flow Cytofluorometries; Flow Cytofluorometry; Flow Microfluorimetry; Flow Microfluorometry; flow cytophotometry; Future; Gastrointestinal tract structure; Alimentary Canal; Digestive Tract; GI Tract; Gastrointestinal Tract; alimentary tract; digestive canal; Goals; graft vs host disease; GvHD; Homologous Wasting Disease; Runt Disease; graft versus host disease; graft vs. host disease; Growth; Generalized Growth; Tissue Growth; ontogeny; Hematological Disease; Blood Diseases; Hematologic Diseases; Hematological Disorder; blood disorder; HLA Antigens; HL-A Antigens; Human Leukocyte Antigens; Leukocyte Antigens; Human; Modern Man; Immune system; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; immune suppressive activity; immune suppressive function; immunosuppressive activity; immunosuppressive function; immunosuppressive response; In Vitro; Infection; Intestines; Intestinal; bowel; Leukocytes; Blood leukocyte; Leukocytes Reticuloendothelial System; Marrow leukocyte; White Blood Cells; White Cell; white blood cell; white blood corpuscle; Metabolic Diseases; Metabolic Disorder; Thesaurismosis; metabolism disorder; Methionine-tRNA Ligase; Met-tRNA Ligase; Methionyl T RNA Synthetase; Methionyl-tRNA Synthetase; Methods; Inbred BALB C Mice; BALB C Mouse; BALB/c; Morbidity - disease rate; Morbidity; mortality; Mus; Mice; Mice Mammals; Murine; Patients; Phenotype; Play; Production; Quality of life; QOL; Relapse; Risk; Role; social role; Safety; Serial Passage; Enterococcus faecalis; E faecalis; E. faecalis; S faecalis; S. faecalis; Streptococcus Group D; Streptococcus faecalis; T-Lymphocyte; T-Cells; thymus derived lymphocyte; Testing; Time; Tissues; Body Tissues; Toxin; Translating; Transplantation; transplant; Homologous Transplantation; Allogeneic Transplantation; Body Weight decreased; Weight Loss; Weight Reduction; body weight loss; wt-loss; Clostridium difficile; C diff; C difficile; C. diff; C. difficile; Clostridioides difficile; Streptococcus enterococcus group; Enterococcus; E faecium; E. faecium; S faceium; S faecium; S. faceium; S. faecium; Streptococcus faceium; Streptococcus faecium; Enterococcus faecium; Clinical; Malignant; Malignant - descriptor; biologic; Biological; Link; Ensure; Evaluation; HSC transplantation
