Vectors and Gene Delivery to the Retina

Abstract

One of the great advantages of the retina as a target tissue for gene delivery is the wide array of genetic tools that have been developed in the past decade. This includes a variety of vectors for therapeutic gene delivery to most types of retinal neurons and glia, as well as cell type-specific promoters for restricted gene expression in distinct neuronal subtypes. Within the scope of neuroscience applications and for gene therapy, it is now routine to express reporter genes, replacement genes, neuronal activity indicators, and microbial opsins in specific neuronal types in the mouse retina. However, there are considerable anatomical, physiological, immunological, and behavioral differences between the mouse and the human that limit the usefulness of these tools in humans and nonhuman primates. Several advances are now being made toward the goal of applying viral targeting tools to understand the primate retina. Here, we describe these advances, consider their potential to advance our understanding of the primate retina, and describe what will be needed to move forward.

AAV-Mediated Gene Delivery to 3D Retinal Organoids Derived from Human Induced Pluripotent Stem Cells

“…Most inherited retinal diseases affect the outer retina and to correct the disease phenotype, the delivery of therapeutic genes to hiPSCs-derived PRs and RPE cells constitutes an important step. Recombinant AAVs (rAAVs) are the first choice for gene delivery to retinal cells for 2 of 16 gene therapy [8]. They are non-pathogenic, non-integrative, and highly efficient as they can infect post-mitotic cells and provide long-term expression of a given transgene [9].…”

“…Because of the localization of these receptors on target cells, the entry of certain rAAVs is facilitated over others. In the retina, the cell-type specificity also depends on the injection route with intravitreal injections, bringing the rAAVs in contact with inner retinal cells and subretinal injections and facilitating vector access to the outer retinal cells [8,11]. In our hiPSC-derived organoids [12,13], laminated neural retina obtained after several weeks of differentiation displays photoreceptor precursors on the outside and ganglion cell precursors in the center of the structures.…”

Trans-ocular Electric Current In Vivo Enhances AAV-Mediated Retinal Gene Transduction after Intravitreal Vector Administration

“…The route of gene administration affects the efficacy of retinal AAV-mediated gene therapy. Commonly used AAV serotypes 1, 2, 5, 8, and 9 efficiently transduce the RPE and/or photoreceptors in the wild-type (WT) adult rodent retina only when given by subretinal injection 11, 12, 13, 14, 15, 16, 17, 18. Unfortunately, this limits vector distribution primarily to the region surrounding the site of subretinal administration 19, 20.…”

Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions

“…It allows the targeting of specific cell types by delivering the vector as close as possible to the desired tissue. 43 Figure 2 offers a schematic view of the three principal modes of delivery: subretinal, intravitreal and suprachoroidal.…”