Development of an Agent-Based Model to Investigate Durability of Factor IX Activity in Hemophilia B Patients Treated With Etranacogene Dezaparvovec

Abstract

Many currently approved gene therapies use adeno-associated virus (AAV) to deliver DNA sequences encoding protein(s)-of-interest into cells. The AAV viral genome forms stable, circular DNA structures called episomes after entering the nuclei. Therapeutic proteins are then generated in vivo from transcription and translation of these episomes, and long-term durability thus depends on episome stability. Prior modeling work has utilized differential equation-based models to characterize AAV uptake and subsequent protein production. However, episome loss associated with target cell turnover is poorly described with these models. Here, an agent-based model (ABM) to overcome this shortcoming is developed. The liver was used as the example organ as it is known to be self-renewing and has been a common target for gene therapies. In this model, each hepatocyte is an agent, capable of division and death. When transduced, these agents acquire and carry episomes. During cell division, episomes are passed from mother to daughter cells. All episomes are presumed lost when transduced cells die. The ABM was applied to etranacogene dezaparvovec (formerly AMT-061 or CSL222), a liver-targeting gene therapy for hemophilia B consisting of AAV serotype 5 particles encoding a transgene for the Padua variant (R338L) of coagulation factor IX (FIX). ABM-simulated FIX activity in patients receiving this therapy was consistent with clinical observations over more than 2 years following treatment. This ABM was then used to generate 20-year predictions and explore biological mechanisms underlying long-term durability. The ABM framework and approach should be applicable to investigating durability of other AAV-based gene therapies.