The activity of a peptide derived from the enzyme phosphatidylinositol 3-kinase gamma (PI3Kγ) on the functionality of the membrane protein CFTR was evaluated. In particular, its modulating action of chlorine transport and its ability to regulate the localization of CFTR in the membrane have been studied.
The tests were conducted using bronchial epithelial cells and intestinal organoids derived from both healthy individuals and patients with F508del/F508del mutation. The peptide induced an increase in the amount of F508del-CFTR on the plasma membrane, but it did not function as a corrector of the CFTR, in fact, it did not modulate the transport of chlorine. Instead, it showed an amplifying effect on the action of Orkambi and Trikafta when administered with these drugs. The peptide can therefore enhance the effectiveness of approved combinations of CFTR channel modulators for patients carrying the F508del-CFTR allele opening new therapeutic avenues.

Pubblications

• Sala V, Murabito A, Ghigo A, Inhaled Biologicals for the Treatment of Cystic Fibrosis, Recent Pat Inflamm Allergy Drug Discov 2019;13(1):19-26.

Congress abstracts

• Ghigo A, Sala V, Murabito A et al. A PI3Kγ mimetic peptide enhances the therapeutic effects of CFTR correctors and potentiators via coordinated activation of luminal CFTR and basolateral CA2+- activated K+ channels, North American Cystic Fibrosis Conference (NACF), 21-23 October 2020, virtual conference.
• Murabito A, Li M, Raimondi A et al. Characterisation of the molecular mechanisms underlying PI3Kγ-dependent stabilisation of CFTR at the plasma membrane, 43rd European Cystic Fibrosis Conference – 2020 (ECFC), virtual conference.
• Sala V, Murabito A, Butnarasu CS, Drug-like properties of an inhaled peptide-based therapy for Cystic Fibrosis, ECFS Hands-On Workshop on Epithelial Systems: Physiology and Pathophysiology, Lisbon, Portugal, 22-26 July 2019.