- Hon Wai Koon, PhD
Three key research interests
Intestinal fibrosis or stricture
Crohn’s disease (CD) currently affects around 1.6 million Americans (Crohn’s and Colitis Foundation). Approximately 30-50% of CD patients develop intestinal strictures, which is fibrosis of the intestine. Intestinal stricture often leads to costly hospitalization and surgery. There is no practical way of preventing or treating intestinal fibrosis. Some factors are associated with the development of intestinal fibrosis.
Dr. Koon discovered two novel diagnostic biomarkers and developed three therapeutic agents for stricturing CD (CDS) patients since 2010. He demonstrated the correlation between serum levels of antimicrobial peptides (cathelicidin and elafin) and the risk of intestinal strictures in CD patients. He established a machine-learning algorithm using multiple easy-to-obtain clinical parameters to improve the accuracy of indicating intestinal stricture risk among CD patients. Using RNA-sequencing and proteomics, Dr. Koon discovered multiple stricture-specific targets in the intestine of stricturing CD patients and utilized advanced pharmaceutical technologies to develop orally active drugs for ameliorating intestinal fibrosis. His innovations and inventions were patented and published in peer-reviewed journals.
C. difficile infection
Clostridioides difficile infection (CDI) is a growing threat to the healthcare system and its patients. CDI causes severe diarrhea and colitis in patients. According to the Centers for Disease Control and Prevention (CDC), there are almost half a million infections in the United States annually. Old age, hospitalization, immunocompromised status, and previous C. difficile exposure are risk factors for CDI. Postmenopausal women are also associated with an increased trend of CDI-related hospitalization, suggesting hormonal influence. Some studies suggest gender differences in CDI disease outcomes. Additionally, about 1/6 of CDI cases will recur in 2-8 weeks. The use of standard antibiotics is associated with a high relapse rate. Fecal microbiota transplantation (FMT) has a 90% success rate, but cases with severe adverse effects were reported. As current therapeutic options are not ideal, optimization is necessary.
Therefore, Dr. Koon utilized high-throughput screening (HTS) to discover cell signaling pathways and metabolomics to discover metabolites that influence the pathological effects of C. difficile toxins. He identified several novel orally active drugs and metabolites that modulate gut microbiota, immune responses, and intestinal epithelial cell survival in infected animals. These reagents can be safely and effectively used alone or with existing therapeutic regimens to inhibit primary infection and prevent recurrence. Dr. Koon also assisted multiple drug companies in elucidating the mechanisms of action of therapeutic drugs.
Obesity and diabetes
The Centers for Disease Control and Prevention (CDC) reported that 8.6% of U.S. adults are diagnosed with type 2 diabetes mellitus (T2DM). T2DM is characterized by hyperglycemia with a combination of insulin resistance and relative insulin deficiency. Globally, more men are diagnosed with T2DM than women. The development of T2DM involves many factors and is a topic of intense research.
Dr. Koon discovered the roles of antimicrobial peptides (cathelicidin and elafin) in the development of T2DM. Serum levels of elafin are correlated with fasting blood glucose levels and hemoglobin A1c levels in men with T2DM but not in women with T2DM. Elafin modulates systemic inflammation and serum exosomal miRNA levels. These factors influence leptin secretion, sensitivity, and food intake, reversing obesity and hyperglycemia. His discovery is crucial to understand the gender difference of T2DM and the miRNA-cytokine-hormone axis in the development of obesity and T2DM.
Currently funded research projects
- NIH R01 grant: Orally elafin therapy for intestinal fibrosis (PI: Koon)
- CCF Senior Research Award: Oral metabolite therapy for intestinal fibrosis (PI: Koon)
- Artugen Therapeutics grant: Effects of therapeutic bacterial agents for C. difficile infection (PI: Koon)
- NIH R44: Novel oral yeast immunotherapies for ulcerative colitis (Co-investigator: Koon)
- Private donation: Innovative research for IBD (PI: Koon)
- UCLA I3T Core Technology Award (PI: Koon)
- CCF student research fellowship award (PI: Koon)
In the news
- Prof. Koon is a recipient of the 2021 Undergraduate Research Week Faculty Mentor Award
- UCLA Research Alerts: Metabolite therapy proves effective in treating C. difficile in mice
Prof. Koon has 47+ peer-reviewed publications, reviews, and book chapters. Complete list of published work in My Bibliography
About Prof. Koon
Prof. Koon is a professor in UCLA’s Vatche and Tamar Manoukian Division of Digestive Diseases. He received a master’s degree in pharmacology and a Ph.D. in molecular biology at the University of Hong Kong. He then completed his postdoctoral training in gastroenterology at the Beth Israel Deaconess Medical Center of Harvard Medical School in Boston.
Prof. Koon focuses on basic, clinical, and translational research on inflammatory bowel disease (IBD), C. difficile infection, and metabolic diseases. Over the last decade, Prof. Koon discovered antimicrobial peptides cathelicidin and elafin as serum biomarkers for indicating the presence of intestinal strictures in Crohn’s disease (CD) patients and predicting the future clinical activity in IBD patients. Prof. Koon developed a convenient machine-learning algorithm to indicate intestinal strictures in CD patients accurately. Some of his inventions were patented and licensed to a diagnostic company for commercial development.
In recent years, Prof. Koon has established a biobank comprising blood, serum exosomes, mesenteric and skin adipose tissues, and intestinal tissues from healthy subjects and IBD patients. By utilizing next-generation transcriptome analysis, including spatial RNA sequencing, whole-transcriptome RNA sequencing, and single-cell RNA profiling, he identified multiple biomarkers and molecular targets that might be relevant to intestinal fibrosis. He also discovered the chemical communication between fat and intestine and identified an immune cell-derived cytokine during intestinal fibrosis development.
Prof. Koon is actively involved in developing new therapeutic approaches for gastrointestinal diseases. He utilized orally active modified cathelicidin mimic CSA13-Eudragit and elafin-Eudragit formulations for reversing colitis-associated intestinal fibrosis and C. difficile infection (CDI) in mice. Oral administration of CSA13-Eudragit ameliorates intestinal inflammation via modulation of the intestinal microbiome environment. He identified several orally active therapeutic metabolites effective against intestinal fibrosis and CDI through untargeted metabolomics studies. On the other hand, Prof. Koon identified the sex difference in CDI disease development. The estrogen in females is protective against CDI. He found oral estrogen-like soy isoflavone genistein treatment can inhibit C. difficile toxin-mediated cell death and inflammatory responses. Oral genistein treatment ameliorated intestinal injury in CDI.
Prof. Koon was the first to discover the role of antimicrobial peptides (cathelicidin and elafin) in obesity and prediabetes, and type II diabetes. He observed abnormal levels of serum cathelicidin and elafin in patients with prediabetes and type II diabetes. Cathelicidin regulates obesity and non-alcoholic fatty liver disease (NAFLD) in high-fat diet-treated mice by reducing CD36 expression. Recently, Prof. Koon generated an orally active modified elafin formulation for influencing miRNA load in serum exosomes. As a result, the serum exosomes carry miRNAs that improve leptin sensitivity and increase leptin expression, leading to reduced food intake. As a result, the reduced food intake suppression subsequently ameliorates obesity, hyperglycemia, and liver steatosis in high-fat diet-treated mice.
His discoveries were published in Gastroenterology, Scientific Reports, Cellular and Molecular Gastroenterology and Hepatology, and the Journal of Infectious Diseases.
In recent years, Prof. Koon has been collaborating with multiple pharmaceutical companies in drug development. He utilized whole-transcriptome RNA sequencing and multiplex assays to discover molecular targets in C. difficile infection (CDI). For example, he identified that macrophage inflammatory protein-1 alpha (MIP-1a) is a common CDI mediator among humans and mice. Furthermore, MIP-1a specifically mediates inflammatory responses and diarrhea during CDI. Therefore, this immunological discovery helps evaluate disease activity in CDI and therapy development against CDI. He also characterized the protective effects of a live biotherapeutic ADS024 against C. difficile toxins in human colonic epithelial cells. Prof. Koon has been utilizing high-throughput drug screening to find actionable molecular pathways in intestinal fibrosis and C. difficile infection. The data will be used for developing next-generation therapeutics for these diseases.
Prof. Koon has published 47 peer-reviewed manuscripts. Prof. Koon’s projects have been funded by CCF, NIH, industrial funds, and philanthropic donors. His research team consists of a postdoctoral researcher and several undergraduate research students. His laboratory, at the MacDonald Research Laboratories building, is a hub of researcher interactions. Prof. Koon’s team has advanced research platforms such as a robotic liquid handling system, automated imaging system, flow cytometer, human 3D organoid and ex-vivo cultures, high-throughput screening, and immunological and microbiologically humanized animals. Prof. Koon’s research provides an integrated view of interactions between different systems. He welcomes research collaborations for discovering solutions for gastrointestinal and metabolic diseases.