A drug that blocks a DNA-cutting enzyme, called irinotecan, should be considered as a treatment option for people with systemic lupus erythematosus researchers argued, after confirming the compound’s benefit in yet another lupus mouse model.
The research team believes that clinical trials are now needed to explore the treatment in lupus patients, but underscored that preclinical studies should continue in parallel to obtain a deeper understanding of the mechanisms behind the drug’s actions.
The study, “Suppression of lupus nephritis and skin lesions in MRL/lpr mice by administration of the topoisomerase I inhibitor irinotecan,” was recently published in the journal Arthritis Research & Therapy.
While working on earlier experiments that focused on cancer, researchers at University Hospital Bern, in Switzerland, stumbled onto the finding that a drug blocking the enzyme topoisomerase I suppressed lupus nephritis in a lupus mouse model.
Topoisomerase I is an enzyme that cuts one of the DNA strands to allow the DNA spiral to unwind into a more relaxed state. Once the spiral has loosened its coil, the enzyme, often referred to as just topo I, glues cut strands back together.
Blocking the enzyme has different effects in dividing and non-dividing cells. If topo I is prevented from working in dividing cells, DNA-copying mechanisms introduce so much damage that the cells often die. Irinotecan, and other topo I blockers, are often used as anticancer drugs for this reason, because cancer cells are highly active dividing cells. In non-dividing cells, the treatment can prevent DNA copying, but it does not kill the cells.
The Bern research team first experimented with high doses of irinotecan, similar to what is used for chemotherapy in humans. But as they didn’t intend to develop another chemotherapeutic agent, they soon lowered the dose.
These earlier experiments revealed that doses, 50 times lower than those used as chemotherapy, could still treat lupus nephritis in mice. Researchers also discovered that the mechanisms had nothing to do with immunosuppression. Rather, topo I increased the binding of antibodies to double-stranded DNA in the lupus mice. Blocking topo I prevented this autoimmune reaction, suggesting that relaxation of DNA in itself contributes to lupus autoimmunity.
Because evidence from one mouse model is not enough to bring a treatment to clinical trials, the team decided to explore the treatment in another, genetically different lupus model, called MRL/lpr mice.
They found that treating lupus mice with both high and low doses of irinotecan prevented several lupus-like symptoms, such as proteins in the urine (signaling kidney disease) and skin lesions. Early on, both doses were equally effective, but after 18–20 weeks of treatment, the lower dose did not suppress skin lesions to a large degree.
Further analyses showed that DNA relaxation, through the actions of topo I, increased the binding of antibodies of IgG type against double-stranded DNA anti-dsDNA. The treatment did not affect antibodies of IgM type — a finding that researchers believe may be beneficial, as earlier data suggests that IgM type antibodies may be protective in lupus.
Although the low dose was not as effective in managing skin lesions in this mouse model, the research team argued that an intermediate dose — still much lower than that used for chemotherapy — may be effective.
“Although the mechanism is not fully understood yet, it seems that topo I inhibition represents a specific and targeted therapy for SLE beyond immunosuppression,” they concluded. “Therefore, first clinical trials applying low-dose irinotecan to human SLE patients are urgently required.”