Adeno Associated Virus (AAV) as a Tool for Clinical and Experimental Delivery of Target Genes into the Mammalian Retina

Abstract

With an increasing number of identified causative genes, the widespread use of gene therapy is quickly becoming feasible. Once a target gene is selected, it is important to have a cell delivery method that is both specific and efficient. Cell type specificity and high efficiency is particularly important for the treatment of retinal degeneration, since viruses are efficient gene delivery vehicles for the nervous system, but often bring with them non-specific infections. In this review, we focus on adeno-associated virus (AAV). Over the last few decades, AAV has become a leading choice for safe gene delivery, in part due to its replication deficiency in cells without a helper virus. Here, we summarize the tropism of recombinant AAV (rAAV) for various types of mammalian retinal neurons in relation to capsid serotype and administration method. We also include our recent findings on an AAV serotype that AAV was specifically infected mouse cone photoreceptors when delivered by subretinal administration.

Cyclin-Dependent Kinase Inhibitor 2b Mediates Excitotoxicity-Induced Death of Retinal Ganglion Cells

“…Intravitreal AAV2 injection induced transgene expression under control of the CMV promoter in RGCs as well as in other retinal cells. [38][39][40] We believe that the phenotypic changes observed in AAV2-infected retinas could be attributed primarily to altered expression of Cdkn2a or Cdkn2b in RGCs, as shown by the following results. First, a higher infection efficiency was found in RGCs than in other cell types in AAV2-infected retinas ( Supplementary Fig.…”

“…Previous studies have reported that retinal cells, such as amacrine, bipolar, and horizontal cells, as well as RGCs express NMDA receptor subunits, and are potentially sensitive to NMDA. [38][39][40] Thus, NMDA-mediated loss of the retinal cells, other than RGCs, could induce RGC death as its secondary effect. However, intravitreal NMDA injection increased the number of TUNEL þ cells in the GCL earlier than in the INL and outer nuclear layer (ONL; Supplementary Fig.…”

VEGFD Protects Retinal Ganglion Cells and, consequently, Capillaries against Excitotoxic Injury

“…We intravitreally injected adult wild-type mice with recombinant adeno-associated viruses (rAAVs) containing neuron-specific expression cassettes for VEGFD (rAAV-VEGFD) 43,50 or as control, LacZ (rAAV-LacZ), with additional hemagglutinin (HA; for rAAV-VEGFD) or Flag (for rAAV-LacZ) tags to facilitate their detection. Intravitreal injection of rAAVs is a robust method used successfully to achieve long-lasting, stable gene delivery 52 and is under consideration in clinical trials. 53 rAAV-VEGFD has been previously used effectively to boost neuronal expression of VEGFD 43,50 and does not infect cells of the microvasculature ( Figure S1A).…”

RAD52: Viral Friend or Foe?

“…As a gene delivery tool, however, AAV continues to be exceptionally popular with genome engineers. This popularity stems from many factors including ease of use, but is highlighted by its inability to spread to other non-target tissues without a helper virus and by a large number of serotypes that permit the design of AAV-based gene delivery vectors to many mammalian organs with good degrees of specificity (see, for example: [49,50]).…”