Therapeutic Effect of a Novel Phosphatidylinositol-3-Kinase δ Inhibitor in Experimental Epidermolysis Bullosa Acquisita

Abstract

Epidermolysis bullosa acquisita (EBA) is a rare, but prototypical, organ-specific autoimmune disease, characterized and caused by autoantibodies against type VII collagen (COL7). Mucocutaneous inflammation, blistering, and scarring are the clinical hallmarks of the disease. Treatment of EBA is difficult and mainly relies on general immunosuppression. Hence, novel treatment options are urgently needed. The phosphatidylinositol-3-kinase (PI3K) pathway is a putative target for the treatment of inflammatory diseases, including EBA. We recently discovered LAS191954, an orally available, selective PI3Kδ inhibitor. PI3Kδ has been shown to be involved in B cell and neutrophil cellular functions. Both cell types critically contribute to EBA pathogenesis, rendering LAS191954 a potential drug candidate for EBA treatment. We, here, demonstrate that LAS191954, when administered chronically, dose-dependently improved the clinical phenotype of mice harboring widespread skin lesions secondary to immunization-induced EBA. Direct comparison with high-dose corticosteroid treatment indicated superiority of LAS191954. Interestingly, levels of circulating autoantibodies were unaltered in all groups, indicating a mode of action independent of the inhibition of B cell function. In line with this, LAS191954 also hindered disease progression in antibody transfer-induced EBA, where disease develops dependent on myeloid, but independent of B cells. We further show that, in vitro, LAS191954 dose-dependently impaired activation of human myeloid cells by relevant disease stimuli. Specifically, immune complex-mediated and C5a-mediated ROS release were inhibited in a PI3Kδ-dependent manner. Accordingly, LAS191954 also modulated the dermal–epidermal separation induced in vitro by co-incubation of immune complexes with polymorph nuclear cells, thus pointing to an important role of PI3Kδ in EBA effector functions. Altogether, these results suggest a new potential mechanism for the treatment of EBA and potentially also other autoimmune bullous diseases.

Visualization of autoantibodies and neutrophils in vivo identifies novel checkpoints in autoantibody-induced tissue injury

“…In experimental EBA, myeloid effector cells bind to the immune complexes in a specific Fc gamma receptor-dependent manner in both mice and humans 54,55 . This binding leads to a yet-to-be-defined signaling cascade within the myeloid cells that involves PI3K beta and delta, as well as, AKT, p38 MAPK, AKT, Src family kinases, SYK, and RORα [56][57][58][59][60][61][62][63] . Ultimately, myeloid cells release proteases 64 and ROS 35 , which, in turn, cause subepidermal blistering and may further enhance the influx of myeloid cells into the skin 65 .…”

From bench to bedside: evolving therapeutic targets in autoimmune blistering disease

“…The PI3K/Akt/mTOR pathway is constitutively activated in B‐cell malignancies leading to derangements in growth and survival . The δ isoform is primarily expressed on leucocytes and is critical for antigen‐induced BCR signalling. Inactivation of PI3Kδ suppresses T‐regulatory cell function and impedes their ability to restrict CD4+ and CD8+ effector T‐cell function .…”

“…LAS191954, a selective PI3Kδ inhibitor, has been found to induce a dose‐dependent improvement of clinical phenotype in immunization‐induced EBA mice with superiority to high dose corticosteroids (Table ) …”

“…LAS191954, a selective PI3Kd inhibitor, has been found to induce a dose-dependent improvement of clinical phenotype in immunization-induced EBA mice with superiority to high dose corticosteroids ( Table 3). 109 Idelalisib is a PI3Kd inhibitor which is FDA approved for use in CLL, follicular lymphoma and small lymphocytic lymphoma. 111 However, immune dysregulation has led to high rates of infection and autoimmune toxicities, including hepatitis and pneumonitis, which has limited its use.…”

Perspective From the 5th International Pemphigus and Pemphigoid Foundation Scientific Conference

“…This trial was based on findings in preclinical animal models of epidermolysis bullosa acquisita (EBA) ( 10 ), where DMF reduced clinical disease severity in mice with already clinically manifest skin lesions. In addition to DMF, preclinical EBA models ( 11 ) have defined several new therapeutic targets, i.e., SYK ( 12 , 13 ) and novel compounds ( 14 ).…”