Abstract
Transduction of retinal pigment epithelial cells with an adeno-associated viral vector (AAV) based on serotype 2 has partially corrected retinal blindness in Leber congenital amaurosis type 2. However, many applications of gene therapy for retinal blindness rely on the efficient transduction of rod and cone photoreceptor which is difficult to achieve with first generation vector technology. To address this translational need, we evaluated rod and cone photoreceptor targeting of 4 novel AAV capsids (AAV7, AAV9, rh.64R1 and rh.8R) versus AAV2 and AAV8 in a foveated retina. Eyes of 20 nonhuman primates were injected subretinally in the proximity of the fovea. While numerous vectors efficiently transduced rods, only AAV9 targeted cones both centrally and peripherally efficiently at low doses, likely due to the abundance of galactosylated glycans, the primary receptor for AAV9, on cone photoreceptors. We conclude AAV9 is an ideal candidate for strategies that require restoration of cone photoreceptor function.
Highlights
The normal human retina contains two main classes of lightsensing neurons: rod photoreceptors (PR), which are sensitive to dim light, and cone PR, which respond to bright light stimuli.Gene mutations hinder the function of either or both of these sets of cells, and lead to their degeneration and subsequent loss of vision
Cynomolgus macaques, 2–3 years of age, were injected subretinally with 109 or 1010 GC of associated viral vector (AAV).cytomegalovirus promoter (CMV).eGFP packaged with the respective capsids
We show that AAV9 uniquely targets cone PRs at high efficiency
Summary
The normal human retina contains two main classes of lightsensing neurons: rod photoreceptors (PR), which are sensitive to dim light, and cone PR, which respond to bright light stimuli.Gene mutations hinder the function of either or both of these sets of cells, and lead to their degeneration and subsequent loss of vision. PR transduction is feasible with high-dose AAV2 vectors in canine, feline and primate animal models where it targets rods more efficiently than cones [6,11,12]. Six promising capsids representing different clades were selected for evaluation in NHP including AAV2, AAV7, AAV8, AAV9, rh.8R and rh.64R1 in order to quantitatively assess RPE, rod and cone transduction.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
