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Effects of Stuffer DNA on the Suppression of Choroidal Neovascularization by a rAAV Expressing a mTOR-Inhibiting shRNAopen access

Authors
Lee, Steven Hyun SeungChang, HeeSoonKim, Hee JongChoi, Jun-SubKim, JinKim, Ji HyunWoo, Ha-NaNah, Seung KwanJung, Sang JoonLee, Joo YongPark, KeerangPark, Tae KwannLee, Heuiran
Issue Date
13-Sep-2019
Publisher
Nature Publishing Group
Keywords
GFP; RNAi; choroidal neovascularization; mammalian target of rapamycin; recombinant adeno-associated virus; stuffer DNA; wet age-related macular degeneration
Citation
Molecular Therapy - Methods and Clinical Development, v.14, pp 171 - 179
Pages
9
Journal Title
Molecular Therapy - Methods and Clinical Development
Volume
14
Start Page
171
End Page
179
URI
https://scholarworks.bwise.kr/sch/handle/2021.sw.sch/4209
DOI
10.1016/j.omtm.2019.06.004
ISSN
2329-0501
Abstract
Choroidal neovascularization (CNV) is the defining characteristic of the wet subtype of age-related macular degeneration (AMD), which is a rapidly growing global health problem. Previously, we had demonstrated the therapeutic potential of gene therapy against CNV using short hairpin RNA (shRNA) delivered via recombinant adeno-associated virus (rAAV), which abrogates mammalian-to-mechanistic (mTOR) activity in a novel manner by simultaneously inhibiting both mTOR complexes. Both the target and use of gene therapy represent a novel treatment modality against AMD. Here, the xenogeneic GFP gene used as a reporter in previous studies was removed from the virus vector to further develop the therapeutic for clinical trials. Instead, a stuffer DNA derived from the 3' UTR of the human UBE3A gene was used to ensure optimal viral genome size for efficient rAAV assembly. The virus vector containing the stuffer DNA, rAAV2-shmTOR-SD, positively compares to one encoding the shRNA and a GFP expression cassette in terms of reducing CNV in a laser-induced mouse model, as determined by fundus fluorescein angiography. These results were confirmed via immunohistochemistry using anti-CD31, while a TUNEL assay showed that rAAV2-shmTOR-SD possesses anti-apoptotic properties as well. The qualities exhibited by rAAV2-shmTOR-SD demonstrate its potential as a human gene therapeutic for the treatment of wet AMD.
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