Modulating the PI3K Signalling Pathway in Activated PI3K Delta Syndrome: a Clinical Perspective

Activated phosphoinositide-3-kinase (PI3K) delta syndrome (APDS) is an inborn error of immunity characterised by immune dysregulation. Since the discovery of genetic mutations resulting in PI3K delta overactivation, treatment of APDS patients has begun to focus on modulation of the PI3K pathway in addition to supportive therapies. The mTOR inhibitor sirolimus has been used effectively for some clinical manifestations of this condition, however the arrival of specific PI3K delta inhibitor leniolisib has shown promising early results and may provide a more targeted approach. This review summarizes key aspects of PI3K pathway biology and discusses potential options for nuanced modulation of the PI3K pathway in APDS from a clinical perspective, highlighting differences from PI3K inhibition in haematological malignancies.