TY - JOUR
T1 - Proteosomal degradation impairs transcytosis of AAV vectors from suprachoroidal space to retina
AU - Ding, Kun
AU - Shen, Jikui
AU - Hackett, Sean
AU - Khan, Mahmood
AU - Campochiaro, Peter A.
N1 - Funding Information:
Funding Supported by EY031097 from the National Eye Institute and an unrestricted grant from Research to Prevent Blindness, New York, NY.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.
PY - 2021/12
Y1 - 2021/12
N2 - Suprachoroidal injection provides a new route of delivery for AAV vectors to retinal pigmented epithelial cells and photoreceptors that can be done in an outpatient setting and is less invasive and potentially safer than subretinal injection, the most common route of delivery for ocular gene therapy. After suprachoroidal injection of AAV8 or AAV9 vectors, there is strong transduction of photoreceptors, but it is unclear how vector traverses the retinal pigmented epithelium. In this study, we found that transduction of photoreceptors was significantly increased after suprachoroidal injection of AAV2tYF-CBA-GFP versus AAV2-CBA-GFP vector. Compared with AAV2, AAV2tYF is more resistant to proteosomal degradation. Treatment with protease inhibitors significantly increased photoreceptor transduction after suprachoroidal injection of AAV5-GRK1-GFP. These data suggest that after suprachoroidal injection, AAV vectors access photoreceptors by transcytosis through retinal pigmented epithelial cells during which they are subject to proteosomal degradation, which if suppressed can enhance transduction of photoreceptors.
AB - Suprachoroidal injection provides a new route of delivery for AAV vectors to retinal pigmented epithelial cells and photoreceptors that can be done in an outpatient setting and is less invasive and potentially safer than subretinal injection, the most common route of delivery for ocular gene therapy. After suprachoroidal injection of AAV8 or AAV9 vectors, there is strong transduction of photoreceptors, but it is unclear how vector traverses the retinal pigmented epithelium. In this study, we found that transduction of photoreceptors was significantly increased after suprachoroidal injection of AAV2tYF-CBA-GFP versus AAV2-CBA-GFP vector. Compared with AAV2, AAV2tYF is more resistant to proteosomal degradation. Treatment with protease inhibitors significantly increased photoreceptor transduction after suprachoroidal injection of AAV5-GRK1-GFP. These data suggest that after suprachoroidal injection, AAV vectors access photoreceptors by transcytosis through retinal pigmented epithelial cells during which they are subject to proteosomal degradation, which if suppressed can enhance transduction of photoreceptors.
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U2 - 10.1038/s41434-021-00233-1
DO - 10.1038/s41434-021-00233-1
M3 - Article
C2 - 33542456
AN - SCOPUS:85100491814
SN - 0969-7128
VL - 28
SP - 740
EP - 747
JO - Gene Therapy
JF - Gene Therapy
IS - 12
ER -