Autoimmune lymphoproliferative syndrome (ALPS) is an inborn error of immunity characterized by lymphadenopathy, splenomegaly, autoimmune cytopenias, and an increased number of double-negative T cells (DNTs). ALPS is most often caused by pathogenic variants in FAS (ALPS-FAS). ALPS-FAS is linked to enhanced PI3Kδ/mTOR signaling. Leniolisib is a selective oral PI3Kδ inhibitor approved for treatment of activated PI3Kδ syndrome (APDS). We hypothesized that leniolisib could be effective in ALPS and tested this in a murine model.
Six-week-old female MRL/MpJ-Faslpr/J (MRL/lpr-/-) mice were daily dosed by oral gavage for 7 weeks at 40 or 80 mg/kg leniolisib or vehicle (8 mice per group). Body weight was monitored daily, and urine for protein analysis was collected pre-study and at weeks 3 and 7. After 7 weeks, mice were sacrificed to quantify spleen and lymph node weights; blood counts and lymphocyte subsets in blood, bone marrow, spleen, and lymph nodes.
No changes in body weight were observed, but leniolisib caused a significant decrease in urinary protein at 3 weeks. A significant decrease in weights of spleen (40 and 80 mg/kg) and lymph nodes (80 mg/kg) was seen after leniolisib treatment. Leniolisib did not induce changes in any cell type in bone marrow. In blood, white blood cells, lymphocytes, and monocytes decreased in the 80 mg/kg leniolisib group. A slight increase in hemoglobin, hematocrit, and red blood cell distribution width was seen in both leniolisib groups. No effect was seen on cell count of neutrophils, eosinophils, basophils, red blood cells, or platelet numbers. At 80 mg/kg, leniolisib significantly decreased cell counts of CD4-/CD8- DNTs and CD3+ T cells in blood, spleen, and lymph nodes. In spleen, cell counts of CD19+ B cells and CD4+ T cells decreased.
It is concluded that leniolisib is an effective treatment in a murine ALPS model, which has potential as a treatment for ALPS patients with significant lymphoproliferation.
