Intra-Articular Immunoregulatory Microparticles to Induce Systemic Remission in Rheumatoid Arthritis
Abstract
In this project we wish to focus on developing a therapeutic agent for a novel treatment of rheumatoid arthritis (RA), one of the most frequent rheumatologic diseases, using sustained-release drug delivery, which are the Fiscal Year 2022 Peer Reviewed Medical Research Program Topic Areas. Despite the availability of several therapies for RA that suppress the immune system, a large number of RA patients unfortunately fail to achieve disease remission and keep experiencing joint pain, swelling, and functional limitation. Further suppressing the immune system in these patients is not a viable option as it could cause infections. Even in patients in whom RA therapies work well, reducing the dose or, ideally, ending immunosuppressive treatment is preferred. However, RA relapses in many patients when the dose is reduced. Our solution to this problem is to boost joint defenses against inflammation that are otherwise insufficient to block progression of RA. The goal is to develop a treatment that would treat RA without suppressing protective immune functions, so that they could be combined with current autoimmune targeted treatments for RA without increasing the risk of serious infections and cancer. The project is based on the observation that inflammation in one joint can affect inflammation in other joints in RA patients. Studies have shown that the effect can be carried out by cells that are able to move from the joints around the body and into other joints. By treating joint-resident cells using direct joint (also called intra- articular) injections with the agent developed in this project, it could be possible to cause them to produce anti-inflammatory signals to block autoimmune attacks against joint tissues. As these cells are mobile, the method will help reduce joint inflammation throughout the body but will not induce or enhance generalized immune suppression because they act only in response to signals in the RA-affected joint. We have strong evidence that our agent is effective: Injection in an inflamed joint of a mouse model of RA leads to persistent reduced inflammation not only in the injected joints but also in all other joints, and protected joints from damage without immunosuppressive effects. Intra-articular injections have a long history of safe use in RA patients and our agent consists of materials that are already used in medications for other diseases and have a long history of safety in humans. Thus, our agent has the profile to resolve the unmet medical need for more effective combination therapies which would not increase the risk of infections. Additional work to demonstrate that our agent will improve disease control needs to be conducted before it can be tested in humans. This project is focused on conducting important research in widely used and previously established animal models of RA to show that our agent is safe and effective. Optimizing the agent to further prolong its persistence in the joints, show that the disease-controlling effect is safe and lasting, and identify signals that could be used to confirm that the agent is working appropriately. Measuring the effectiveness of controlling disease by combining the agent with two key RA medications to which some patients show a partial response, an effect that can also be seen in the animal model. The research will also focus on testing whether there is additional suppression of immune function. Performing safety studies and measuring the duration over which our agent is cleared in primates, which are commonly used to evaluate the safety of new RA therapeutics and have joints that mimic the size of humans. Package the collected data on safety and effectiveness of our agent and request a meeting with the U.S. Food and Drug Administration for feedback and an assessment of the readiness of the technology for clinical trials in humans. Our proposal addresses a critical problem in combating RA -- nearly one-third of RA
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310970
Entities
People
- Nisarg Shah
Organizations
- United States Army