Engineered Microbes for the Oral Treatment of Rheumatoid Arthritis Without Immunosuppression
Abstract
Rheumatoid arthritis (RA) is a disease best known for its painful and disabling effects on joints but it also affects other organs, such as the heart and lungs, and reduces life expectancy of the patients. During RA, both cells that form the joint and cells of the immune system change their behavior, become aggressive, and damage the cartilage and bone in the joints. Drugs currently available to treat RA mainly focus on the immune system. However, because the role of the immune system is to protect from cancer and infections, these drugs cause immunosuppression and increase the risk of severe infections and some cancers. In addition, these drugs need to be injected repeatedly throughout the lifetime of the patient. The mode of action of these drugs and the requirement for their injection reduce both their efficacy and the ability of patients to reliably take their treatment as prescribed by their physician. We currently do not have any drugs that specifically target aggressive joint cells during RA. Novel drugs that target joint cells but not immune cells, and that do not require injection, are needed to improve the quality of life and the life expectancy of patients with RA. The joint cells we want to target for the treatment of RA are called fibroblast-like synoviocytes (FLS). FLS are present in all joints, but during RA they become aggressive and play a major role in disease progression. As they become aggressive during RA, FLS have more of a protein called KCa1.1 at their surface. The role of KCa1.1 is to let potassium ions in and out of the cells and more KCa1.1 allows more potassium movement and increases the ability of the cells to divide, move, and produce proteins that increase inflammation. Using IbTX, a single compound originally isolated from the venom of a scorpion that selectively targets KCa1.1, one can stop the aggressive behavior or FLS from patients with RA in test tubes. The injection of IbTX also reduces arthritis severity in rats with diseases that mimic RA. However, IbTX needs to be injected every day or every other day. A new method to give IbTX to patients with RA without injections would make this an even more attractive drug. We propose to modify a probiotic bacterium to produce IbTX in the gut of rats with arthritis. Probiotics are known as good bacteria found in yogurts and other fermented foods that have multiple health benefits and are safe to eat. We have selected a specific probiotic called Lactobacillus reuteri that is commercially available and can easily be genetically modified. We will modify L. reuteri to produce either IbTX or an IbTX mutant that cannot affect KCa1.1 as a control. We will then measure how much IbTX L. reuteri can produce and release in test tubes and in the intestines of rats, how much of this IbTX can get into the bloodstream of the rats, and how efficacious feeding L. reuteri producing IbTX to rats is in reducing arthritis. Probiotics have been modified to produce desirable proteins and venom components are already used in the clinic to treat various diseases, for example, Exenatide, used to treat type 2 diabetes, is a protein found in the saliva of the Gila monster. Here, we propose the first probiotic engineered to produce a venom component to treat RA. This approach could be used to engineer L. reuteri or other probiotics to deliver many different biologic therapeutics, including Exenatide, orally for the treatment of a wide range of diseases. Our approach could revolutionize drug delivery.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210036
Entities
People
- Christine Beeton
Organizations
- Baylor College of Medicine
- United States Army