Blocking Inflammation-linked PI3K-Delta Molecule Could Lead to EBA Therapy, Mouse Study Suggests
Treatment targeting a specific molecule involved in inflammation — called PI3K-delta — eased skin lesions and prevented blistering in mouse models of epidermolysis bullosa acquisita (EBA), according to a new study.
The research, “Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita,” was published in the journal Frontiers in Immunology.
Studies in animal models have elucidated the precise mechanisms underlying EBA’s induction and effector phases. In the induction phase, these mechanisms involve the production of autoantibodies against the skin protein type VII collagen (COL7). In the effector phase, they are characterized by the binding of these autoantibodies to their targets at the junction between the dermis and epidermis. The complement system — part of the immune system that helps the functioning of antibodies —also is activated, among other mechanisms.
One of the cell signaling pathways activated in animal models of EBA includes a protein called PI3K-beta, which leads to the release of inflammatory molecules, reactive oxygen species (ROS), and enzymes that collectively contribute to the formation of lesions.
Another component of the PI3K family — PI3K-delta — is involved in the response of white blood cells to diverse stimuli. Pharmacological inhibition and genetic inactivation of PI3K-delta-dependent pathways showed efficacy in preclinical models of inflammation and in lymphoma patients.
Specifically, studies with PI3K-delta inhibitors demonstrated that both antibody responses and the generation of autoantibodies in some models require PI3K-delta. Distinct functions of neutrophils, a type of immune cell, both in vitro and in vivo are also PI3K-delta dependent.
These data suggest that pharmacological targeting of the PI3K-delta pathway could block two key pathways in EBA, the team hypothesized, namely autoantibody production and activation of myeloid cells, which include neutrophils, macrophages, and other immune cells.
Researchers thereby tested the effects of a new, oral, selective PI3K-delta inhibitor called LAS191954 in two mouse models of EBA. The compound was given once daily at 1 or 3 mg/kg of body weight.
In the first “immunization” model, treatments were conducted for a period of six weeks. The percentage of affected body surface area was assessed weekly. Determination of plasma levels of LAS191954, as well as other biochemical measurements, were also performed. The team also assessed the skin infiltration of white blood cells in the animals’ ears.
In the second model, which induced EBA by anti-COL7 antibody transfer, treatments were started one day before the first antibody injection and maintained throughout a 12-day period. Mice were assessed every fourth day.
Results showed that chronic administration of LAS191954 led to a dose-dependent amelioration and even normalization of widespread skin lesions in mice with immunization-induced EBA. The findings also revealed that treatment with LAS191954 was superior to treatment with corticosteroids.
Of note, levels of circulating autoantibodies were similar in all groups, which, according to the team, suggests a mode of action of the inhibitor independent of B-cells, a type of white blood cell associated with antibody production.
LAS191954 also prevented blistering in the antibody transfer model of EBA, where disease develops independently of B-cells.
In vitro data (in cells) also showed that LAS191954 impaired the activation of human myeloid cells by EBA stimuli. In particular, the release of harmful ROS was inhibited in a PI3K-delta-dependent mechanism. This finding was confirmed when using a different PI3K-delta inhibitor, IC87114.
LAS191954 also regulated the EBA-characteristic dermal-epidermal separation in vitro, “thus pointing to an important role of [PI3K-delta] in EBA effector functions,” the scientists wrote.
“Taken together, our results provide new evidence that targeting the [PI3K-delta] pathway may be a suitable approach for the treatment of EBA,” they added.
Of note, five of the study’s authors are employees of the pharmaceutical company Almirall, a global pharmaceutical company focused on skin health and based in Barcelona, Spain.