Targeting interferon-stimulated transcription as a novel lupus therapy

Type I interferons are produced by the body in order to fight off viral infections. However, patients with lupus produce type I interferons even in the absence of infection, resulting in long-lasting inflammation, which can damage many different organs in the body. Our project will explore a novel strategy to reduce this chronic inflammation while sparing the normal responses to infection, which other lupus treatments under development to inhibit type I interferons may disrupt. Type I interferons work by stimulating other proteins that switch on certain genes, and we will test combinations of drugs that may block these genes from turning on in human cells. Our results could identify a set of drug combinations that reduce inflammation with the least impact on normal antiviral defenses. Because the research will focus on drugs that have already been approved for other conditions or are being tested in other diseases, we anticipate that this research could progress to clinical trials within three years.

What this study means for people with lupus

“We are investigating a strategy for treating lupus that may be just as effective as other drugs under development for the disease but with less suppression of the immune system.  We are focusing on drugs that are already approved or being tested for other diseases, which should speed the start of clinical trials for any of the drugs we find are promising.”

Lupus is a chronic autoinflammatory disease. The current understanding of lupus suggests a genetic predisposition conferring increased risk of disease, coupled with an as yet unidentified environmental or infectious trigger. A common aspect of lupus is an interferon (IFN)-stimulated gene (ISG) signature, and there is growing evidence that IFN and ISGs contribute to, and may cause, pathologic symptoms. In particular, some rare monogenic forms of lupus involve mutations in genes that directly impact the type I IFN pathway. Therefore, targeting the IFN pathway is an attractive therapeutic approach, and therapies directed at neutralizing circulating type I IFN or its receptor have shown efficacy in both animal and human trials. A significant limitation of this approach, however, is increased risk of infection, due to the critical role the IFN pathway plays in antiviral responses. We will test an alternative therapeutic approach that modulates the IFN signaling pathway downstream of receptor activation or limits expression of ISG proteins that contribute to pathogenesis. Hypothesis: We hypothesize that inflammatory aspects of lupus can be modulated pharmacologically by a combination of inhibitors targeting select aspects of IFN-dependent signaling and transcription. We further hypothesize that a combinatorial drug approach can achieve therapeutic efficacy at reduced drug concentrations relative to monotherapy while simultaneously reducing side effects and preserving a degree of innate immune responsiveness. Aims: 1. Characterize human lymphocyte cell lines bearing defined genetic lesions that cause chronic ISG-dependent inflammation. 2. Define drug combinations that modulate the availability and function of BRD4 during chronic IFN signaling and characterize the impact on inflammatory gene signatures. 3. Determine the differential action of JAK1 and TYK2 kinases in autoinflammation and target them to resolve inflammatory gene expression. Impact: Our approach could have a number of advantages: use of small molecule inhibitors rather than biologics; targeting discrete subsets of IFN action to inhibit selective pathogenic effects; and modulating the degree of pathway inhibition to impede chronic activation while preserving acute responses necessary for antiviral function. Use of clinically approved drugs or compounds undergoing active clinical development will accelerate translation into patient care. Approach: We will employ human fibroblasts and lymphocytes bearing mutations in the IFN pathway that are linked to autoinflammatory diseases and lupus. We will determine drug combinations capable of modulating chronic inflammatory signaling while preserving acute antiviral responses and limiting off-target effects. The goal is to provide predictions of viable therapeutic drug combinations, and to predict biomarkers to monitor efficacy and patient stratification.