Targeting PTPRS for Therapy of Rheumatoid Arthritis
Abstract
In the proposed project we will develop a therapeutic agent for the treatment of rheumatoid arthritis (RA), one of the most frequent rheumatologic diseases and one of the key Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Areas. Despite the availability of several therapies for RA that target the immune system, a large number of RA patients fails to achieve disease remission and keep experiencing joint pain, swelling, and functional limitation. A proposed solution to this problem would be the development of therapies that specifically target joint-lining cells, called synoviocytes, which become activated during RA and contribute to joint inflammation and destruction of cartilage and bone. We found that a protein called PTPRS, belonging to a family of proteins that is currently unexploited as drug targets, is present at high levels on the surface of synoviocytes in the joints of RA patients. In synoviocytes, PTPRS is able to inhibit intracellular biochemical signals that promote joint inflammation and destruction. We found a way to activate PTPRS using a portion of the PTPRS protein (called PTPRS Ig1&2) that acts as a decoy molecule. PTPRS Ig1&2 treatment decreases activation of synoviocytes, reducing their movement and their ability to destroy cartilage. Importantly, we have also shown that treatment of arthritic mice with PTPRS Ig1&2 decreases disease severity. Treatment with PTPRS Ig1&2 is not expected to suppress immune functions and could be combined with immune targeted treatments for RA without increasing the risk of infections. Our goal is to validate PTPRS Ig1&2 as a therapeutic agent for RA. Our objectives in this proposal are to: (1) Scale-up production of the PTPRS Ig1&2 protein. We are currently able to produce protein on a small to medium scale. In order to produce sufficient protein for further animal studies as well as safety and regulatory studies, we will work with a private contractor to optimize large-scale production. (2) Further validate PTPRS Ig1&2 as a therapeutic agent for RA. We have abundant data showing that PTPRS Ig1&2 decreases aggressiveness of synoviocytes from RA patients and treats RA in mice. We will perform additional studies to show that PTPRS Ig1&2 treats RA in the collagen-induced arthritis mouse model, "the gold standard" for anti-RA therapy validation, and demonstrate that PTPRS Ig1&2 can be used in combination with current immune-targeted RA therapies to provide improved treatment of RA in mice. (3) Confirm the safety of PTPRS Ig1&2. We will work with a private contractor to characterize the effects of the administration of PTPRS Ig1&2 in monkeys in order to determine the safe doses of PTPRS Ig1&2 that can be used. Our proposal addresses a critical problem in combating RA, that existing RA therapies that target the immune system do not result in disease remission in a large portion of patients. By targeting PTPRS in synoviocytes, which are not immune cells, we propose that we can decrease synoviocyte-mediated joint damage in a way that can be combined with current RA therapies. This project will allow us to develop our candidate therapeutic agent, PTPRS Ig1&2, toward the goal of testing it in humans. In the short term, publication of the data produced within this proposal will stimulate RA-relevant research by pointing the attention of the scientific community to synoviocytes and PTPRS as possible targets for useful therapies. In the long term, we hope that our work will lead to a novel type of therapy that can be combined with currently available options to alleviate the suffering of patients affected by RA. This project has military relevance because RA affects approximately 1 in 100 people; however, military personnel have increased rates and severity of disease. Thus, in addition to the general population, improved RA treatments stand to improve the quality of life and careers of active military members, as well as of Veterans,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610751
Entities
People
- Nunzio Bottini
Organizations
- United States Army
- University of California, San Diego