Gene Therapy Bio-factory: Mathematical Modeling of the Human Eye Pharmacokinetics

Neovascular age-related macular degeneration (nAMD) is one of the leading causes of irreversible blindness in the industrialized world. In nAMD, abnormal blood vessel growth occurs under the macula, leading to exudation and scarring, distorting central vision. Current nAMD standard of care involves repeated intraocular injections of drugs that target the vascular endothelial growth factor (VEGF) signaling pathway (anti-VEGF drugs). These treatments have a high burden on patients, caregivers and physicians. Gene therapy based long-lasting production of anti-VEGF proteins in the eye (bio-factory approach) may address some of the limitations of current therapies. We adapt a previously developed three-compartment (retina, vitreous humor, aqueous humor) pharmacokinetic model in rabbits to simulate the pharmacokinetics of anti-VEGF proteins in the human eye delivered by intravitreal injection or produced via the gene therapy bio-factory approach. The model is used to estimate the protein levels in the vitreous humor and retina, and the retina anti-VEGF production rate starting from clinically measured anti-VEGF protein levels in the aqueous, using gene therapy.