Targeting PTPRS for Therapy of Rheumatoid Arthritis
Abstract
In this proposal we wish to expand our current award that is focused on developing a therapeutic agent for a novel combination treatment of rheumatoid arthritis (RA), one of the most frequent rheumatologic diseases and a key Fiscal Year 2019 Peer Reviewed Medical Research Program Topic Area. Despite the availability of several therapies for RA that target the immune system, a large number of RA patients fail 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. The goal is to develop treatments that would inhibit the action of synoviocytes without suppressing immune functions, so that these agents could be combined with current immune targeted treatments for RA without increasing the risk of infections. Our current project is focused on early development of a therapeutic agent that targets a protein called PTPRS. PTPRS belongs to a family of proteins that is currently unexploited as drug targets and 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 Ig1&2) that acts as a decoy molecule. Ig1&2 treatment decreases activation of synoviocytes, reducing their ability to move and destroy cartilage. Within the current project, we have developed a more potent variant of Ig1&2, achieved production of large amounts of highly pure Ig1&2, and shown that treatment with Ig1&2 reduces disease severity in multiple mouse models of RA without suppressing immune functions. In addition, we have demonstrated that the Ig1&2 potentiates the therapeutic effect of one of the immune-targeted medications utilized for RA when the combination of the two agents are used in arthritic mice. The discoveries we made within the current award suggest that Ig1&2 has the ideal profile to resolve the unmet medical need for more effective combination therapies, which would not increase the risk of infections. However, in order to convince an industrial partner to begin commercialization of Ig1&2 and walk the path toward clinical trials in humans, we realized that we need some additional work in order to increase value of our technology and de-risk it. This expansion award is focused on overcoming three important hurdles to the transfer of our technology to an industrial partner: (1) Showing that Ig1&2 works well in combination with two additional immune-targeting RA medications that we suspect enhance the anti-arthritic activity of Ig1&2 when administered in combination protocols. These experiments will be carried out in our laboratory utilizing a well-established mouse model of RA. (2) Performing toxicity studies in mice and primates. We will focus on confirming that Ig1&2 does not suppress immune functions and making sure that mice treated with Ig1&2 for nine months don’t display organ damages. In primates treated with Ig1&2 for 3 months, we will also assess organ damage. With the help of a specialized firm, we will package all these safety data and request a preliminary meeting with the Food and Drug Administration for an assessment of the readiness of the technology for trials in humans. (3) Finding a marker of efficacy of Ig1&2 in human synoviocytes using isolated human synoviocytes and whole joint biopsies from RA patients. Such a marker will be important to help understand whether the drug reaches synoviocytes during clinical trials. Our proposal addresses a critical problem in combating RA, that existing RA therapies have limited efficacy while suppressing immune functions. By targeting PTPRS in synoviocyt
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010733
Entities
People
- Nunzio Bottini
Organizations
- United States Army
- University of California, San Diego