The cyclic GAMP pathway in SLE

Drugs like hydroxychloroquine (HCQ) are used in 70-80 percent of patients with lupus to help provide relief of joint pain and skin rashes. HCQ is known to reduce cells’ production of type I interferons, immune system molecules that drive chronic inflammation and other symptoms of the disease. Our research recently uncovered an additional mechanism for how these drugs work in lupus. We have designed a new drug, X6, that we expect to be more effective and less toxic than current anti-malarial therapies. Our previous studies found that X6 reduced levels of type I interferons in mice. We now plan to rigorously test the drug to determine whether it is safe in human cells. We will also perform further studies of X6 in mice to determine how it circulates through the body and whether it is superior to HCQ. Positive results from these studies would allow us to perform further studies that could lead to a phase I clinical trial.

What this study means for people with lupus

“Current anti-malarial therapies like hydroxychloroquine are often used to treat lupus. We have developed a new drug that is similar to these anti-malarials, X6, that we believe is more effective and less toxic than current medications. With our Target Identification in Lupus grant, we are performing further tests of the drug’s safety and effects in human cells and in mice. If these tests are successful, we will move toward clinical trials of the drug in patients with lupus.”

Current therapy for SLE is inadequate and most drugs have unacceptable side effects. The only drug, (Benlysta, GSK), approved for the treatment of lupus in the last 50 years has only modest effects compared to placebo. The interferon (IFN) Receptor blocker currently in Phase III studies carries the risk of virus infection. There is, therefore a significant unmet need for lupus treatment, especially for drugs that work upstream of Interferon (IFN) induction. IFN-I is strongly implicated in the pathogenesis of SLE as well as monogenic ‘interferonopathies’ such as Aicardi-Goutieres Syndrome (AGS) caused by mutations in the DNA exonuclease, TREX1. A recently described DNA-activated IFN-I pathway, cyclic GMP-AMP (cGAMP) synthase (cGAS), was linked to subsets of AGS and SLE. Our published data showed increased cGAS mRNA expression in 1/3 of SLE patients and cGAMP was detected in ~15% SLE patients. Supported by a previous ALR grant, we performed in silico screening for cGAS inhibitors and synthesized a novel drug named X6, that belongs to the antimalarial drug (AMD) class of aminoacridines that have a remarkable safety record in over 70 years of human use. Our preliminary data showed that, X6, blocked cGAS in vitro as well as in a proof of principle in vivo experiment. X6 significantly reduced the interferon stimulated gene (ISG) expression, cGAMP production and heart inflammation in the Trex1-/- mouse model of AGS. To further the preclinical development of X6 by better understanding its mechanisms of action, pharmacology, and ADME (absorption, distribution, metabolism, and excretion) properties, we propose to: Aim 1) Define the mechanism of action and toxicological targets of X6 in vitro; and Aim 2) Determine the ADME profiles of X6 in mice. Since we have only shown proof of principle and target engagement of X6 in a mouse model of AGS (Trex1 knockout), we propose to test X6 in a lupus mouse model known to depend on the cGAS-STING pathway: Aim 3) Compare the efficacy of drug X6 versus HCQ in Trex1D18N/D18N (Trex1 D18N mutant) mice. Our hypothesis in Aims 1 and 2 are that we will be able to better define drug: target interactions and pharmacologic properties of the drug. In Aim 3, we hypothesize that X6 will be effective in prevention and treatment of lupus in the Trex1 D18N mutant mouse. If X6 shows a statistically significant improvement in most parameters studied, especially kidney disease, in Trex1 mutant mice compared to HCQ, this will add strong support to move the drug to commercialization, which is our long-term goal. Since it has now been shown that, in TREX1 deficiency or mutation, DNA stimulates IFN through the cGAS pathway and cGAMP has been detected in SLE patients, our follow on study of a therapeutic to attenuate cGAS function is highly relevant to the purpose and goals of the Target Identification in Lupus (TIL) program and the mission of the Lupus Research Alliance (LRA). We believe that completion of these studies will be IND enabling