Systemic Delivery of Genes to Retina Using Adeno-Associated Viruses

Mutations in more than 80 genes lead to photoreceptor degeneration. Although subretinal delivery of genes to photoreceptor neurons using AAV vectors has proven itself as an efficient therapeutic and investigative tool in various mouse models, the surgical procedure itself could lead to loss of retinal function even in healthy animals, complicating the interpretation of experimental studies and requiring thoroughly designed controls. A noninvasive approach, such as a systemic delivery of genes with AAV through the bloodstream, may serve as a promising direction in tool development. Previous studies have established that AAV9 is capable of crossing the blood-brain and blood-retina barrier and even has a limited capacity to transduce photoreceptors. AAV-PHP.eB is a novel AAV9-based mutant capsid that crosses the blood-brain barrier and efficiently transduces central nervous system in the adult mice. Here, we investigated its ability to cross the blood-retina barrier and transduce retinal neurons. Control experiments demonstrated virtually nonexisting ability of this capsid to transduce retinal cells via intravitreal administration but high efficiency to transduce photoreceptors via subretinal route. Systemic delivery of AAV-PHP.eB in adult mice robustly transduced horizontal cells throughout the entire retina, but not photoreceptors. Our study suggests that AAV-PHP.eB crosses the intra-retinal blood-retinal barrier (IR-BRB), efficiently transduces horizontal cells located adjacent to IR-BRB, but has very limited ability to further penetrate retina and reach photoreceptors.