Protein inhibitor-1 (gene therapy)

Class

Constitutively-active protein inhibitor-1 (I-1c) AAV gene therapy

Protein phosphatase inhibitor-1 (I-1) is a regulatory protein that controls how heart muscle cells handle calcium, the ion that triggers each heartbeat's contraction and relaxation. Normally, I-1 becomes active only when phosphorylated by protein kinase A, part of the adrenaline-responsive signaling cascade. Once active, I-1 blocks a phosphatase enzyme called PP1, which otherwise removes an inhibitory phosphate mark from phospholamban, a protein that restrains the calcium pump SERCA2a in the sarcoplasmic reticulum, the cell's internal calcium store. By suppressing PP1, active I-1 keeps phospholamban phosphorylated and SERCA2a unrestrained, improving the speed and completeness of calcium reuptake between heartbeats and strengthening subsequent contractions. In failing hearts, calcium handling is impaired and SERCA2a activity is often reduced, contributing to weak contraction and poor relaxation. The gene therapy approach delivers, via an adeno-associated virus (AAV) vector, a constitutively active version of I-1 that suppresses PP1 without requiring ongoing adrenergic stimulation. This is intended to durably enhance calcium cycling and contractile performance in heart failure, offering a molecular route to inotropic support that does not depend on chronically stimulating the beta-adrenergic system, a strategy long associated with toxicity when maintained pharmacologically.