Paroxysmal nocturnal hemoglobinuria (PNH) is a stem cell disorder caused by a mutation in a gene called phosphatidylinositol glycan anchor biosynthesis class A gene (PIGA). PIGA produces a protein important in the formation of a group of proteins called glycophosphatidylinositol anchored proteins (GPI-AP). GPI-AP are attached to the cell membrane via a small anchor. Among them CD59 and CD55 are major targets for therapy.
Due to PIGA mutation, PNH cells fail to synthesize a correct anchor and thereby lack of proper GPI-AP. To date, the drug developments for PNH have focused on supportive therapies to improve hemoglobin levels due to hemolysis or prevent thrombotic complications. Most successful to date were complement blockers designed for alleviation of hemolysis due to deficiency in complement. These therapies work by deactivating GPI-AP (CD55 and CD59). Our proposal focuses on the possibility to test agents selectively reducing the fraction of GPI-AP deficient cells and consequently improving the growth of GPI-AP normal cells.
We identified an agent (CGS-15943) selectively arresting the growth of GPI-AP deficient cells. CGS-15943 has a potential for translation into PNH precision medicine and might represent an alternative curative strategy for PNH.