Faculty Collaboration Database

Development of an inducible anti-VEGF rAAV gene therapy strategy for the treatment of wet AMD. Sci Rep 2018 Aug 06;8(1):11763

Date

08/08/2018

Pubmed ID

30082848

Pubmed Central ID

PMC6079038

DOI

10.1038/s41598-018-29726-7

Scopus ID

2-s2.0-85051247613 (requires institutional sign-in at Scopus site)   45 Citations

Abstract

Vascular endothelial growth factor (VEGF) is a key mediator in the development and progression of choroidal neovascularization (CNV) in patients with wet age-related macular degeneration (AMD). As a consequence, current treatment strategies typically focus on the administration of anti-VEGF agents, such as Aflibercept (Eylea), that inhibit VEGF function. While this approach is largely successful at counteracting CNV progression, the treatment can require repetitive (i.e. monthly) intravitreal injections of the anti-VEGF agent throughout the patient's lifetime, imposing a substantial financial and medical burden on the patient. Moreover, repetitive injection of anti-VEGF agents over a period of years may encourage progression of retinal and choroidal atrophy in patients with AMD, leading to a decrease in visual acuity. Herein, we have developed a single-injection recombinant adeno-associated virus (rAAV)-based gene therapy treatment for wet AMD that prevents CNV formation through inducible over-expression of Eylea. First, we demonstrate that by incorporating riboswitch elements into the rAAV expression cassette allows protein expression levels to be modulated in vivo through oral supplementation on an activating ligand (e.g. tetracycline). We subsequently utilized this technology to modulate the intraocular concentration of Eylea following rAAV delivery, leading to nearly complete (p = 0.0008) inhibition of clinically significant CNV lesions in an established mouse model of wet AMD. The results shown in this study pave the way for the development of a personalized gene therapy strategy for the treatment of wet AMD that is substantially less invasive and more clinically adaptable than the current treatment paradigm of repetitive bolus injections of anti-VEGF agents.

Author List

Reid CA, Nettesheim ER, Connor TB, Lipinski DM

Authors

Thomas B. Connor MD Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin
Daniel M. Lipinski PhD Associate Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Choroidal Neovascularization
Dependovirus
Enzyme-Linked Immunosorbent Assay
Female
Genetic Therapy
HEK293 Cells
Humans
Mice
Mice, Inbred C57BL
Microscopy, Confocal
Riboswitch
Software
Vascular Endothelial Growth Factor A
Wet Macular Degeneration