Targeting SMS2-Regulated Germinal Center B-Cell Tolerance for Lupus Treatment
Abstract
Antimalarial agents, such as hydroxychloroquine, have been prescribed over the past 60 years for patients with lupus because of their ability to impede early disease progression in most patients, oral availability, and good safety profile. However, high levels of antimalarial agents in the body can result in abdominal symptoms that affect quality of life and contribute to lack of adherence in many lupus patients, as well as rare but severe eye and heart problems. In this proposal, we aim to enhance the beneficial effects of antimalarial agents with lower effective doses, doing so by using them in combination with another safe and orally available agent of a different type, 2OHOA. In our studies of lupus disease in preclinical mouse models, we found that 2OHOA activated a novel protective pathway to selectively eliminate the self-reactive B cells, which otherwise would produce toxic anti-DNA antibodies to drive lupus disease. In addition, although the way antimalarial agents work to mitigate lupus disease is poorly understood, studies by other scientists provide compelling evidence to suggest that they may act at a different point on the same pathway we found and thus, may synergize with 2OHOA to more potently block the development of lupus B cells. We therefore propose to study the combined beneficial effects of hydroxychloroquine and 2OHOA in animal models of lupus, and characterize the underlying mechanisms that lead to improved efficacy. If the proposed studies do show the predicted synergy, we would gain deeper insight into the causes of lupus disease and would have developed an innovative approach that selectively targets the underlying defect in lupus with higher efficacy, fewer side effects, with two drugs that are orally available, and that are suitable for almost every lupus patient. We also project that our proposed work could lead to a Food and Drug Administration-approved treatment for lupus disease in a relatively short period, since 2OHOA has already been proven safe in a clinical trial of certain tumors in Europe, and this could help justify and move it more quickly to a clinical trial. Thus, funding of this proposal could help to address the unmet need in lupus treatment by significantly advancing our understanding of lupus as well as by seriously improving the treatment of this disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010651
Entities
People
- Chongmin Huan
Organizations
- SUNY Downstate Health Sciences University
- United States Army