Inhibiting cGAS-STING Pathway as a Therapeutic Target in Inflammatory Bowel Disease
Abstract
This proposal will address the Peer Reviewed Medical Research Program’s (PRMRP’s) Topic Area on Inflammatory Bowel Diseases (IBDs) and PRMRP’s strategic goal to Develop and test new treatments to minimize toxicity and mitigate the inflammatory disease state. Currently >3 million Americans are living with IBDs, a relapsing condition with no cure. Symptomatic patients have acute inflammation of the colon and rectum that gives rise to recurring diarrhea, severe stomachache, blood and mucus in stools, and extreme fatigue. Nearly 40% of patients develop resistance to current clinical therapies, and those with long-term symptoms develop other chronic conditions including cancer, arthritis, and liver disease. Many clinically approved drugs are also limited in their ability to target the site of inflammation resulting in severe off-target toxicities. Further, prolonged use of immunomodulators gives rise to side effects such as osteoporosis and increased risk of lymphoma. Therefore, an unmet clinical need exists for new therapeutic strategies that will specifically target the colon and rectum in IBDs, reduce inflammation with minimal toxicities, and improve the abundance of beneficial gut microorganisms to enable long-term protection against IBD flare-ups. Our objective is to address this clinical challenge with a new paradigm in treatment for IBDs where hyaluronic acid (HA)-based therapeutic micelles will be designed and loaded with a novel drug that inhibits the stimulator of interferon genes (STING) protein. Recent studies in mouse models and clinical studies in patients now strongly support that activation of the STING protein (through gut bacterial DNA) worsens IBD symptoms. Yet not a single drug inhibiting the STING protein is available to IBD patients. This is in part due to poor bioavailability of the drugs after oral delivery, resulting in rapid clearance before therapeutic benefit is achieved. These drugs also have poor targeting ability, often failing to reach the site of inflammation and instead accumulating in other organs that leads to severe toxicities. The innovation of this work lies in the smart design of the STING-inhibiting micelles (SIMs), which overcomes the current clinical challenges by encapsulating the STING inhibitor in the micelles such that the drug is retained in the body for hours. HA is a natural biopolymer already in human use, and micelles are drug carriers currently in clinical trials (trial # NCT03168061, etc.). The micelles also reach the site of inflammation as HA naturally targets CD44 receptors expressed in the inflammatory colon. Further, our micelles also include a biocompatible linker that is designed to trigger drug release primarily at the site of inflammation substantially minimizing off-target toxicities, and drug encapsulation in micelles also ensures dose-controlled delivery in patients, saving high costs of treatment. As IBD is contributed to by multiple risk factors in a genetically predisposed patient, in Aim 1, we will model environmental risk factor in a dextran sulfate sodium (DSS)-induced colitis mouse model, and in Aim 2, we will model microbial risk factor in a bacterial-induced colitis model. Here we will develop therapeutic SIMs and both benchmark against current clinical drugs 5-ASA, prednisone, and VSL#3, as well as study combination of SIMs with these drugs. By integrating robust mouse models and multiple preclinical analysis, we will understand the therapeutic impact of SIMs providing the missing causal link between patient’s immune response and gut microorganisms. The near-term impact of our project will allow a safe micellar formulation of a potent drug for immediate reduction in IBDs symptoms with low doses and minimal side effects and enable a healthy gut environment. Our hypothesis is that by combining SIMs with current clinical drugs, we will enable a potential cure for patients that will improve the diversity and stability of beneficial gut microbiota
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310071
Entities
People
- Rizia Bardhan
Organizations
- Iowa State University
- United States Army