PMID- 32106292
OWN - NLM
STAT- MEDLINE
DCOM- 20200415
LR  - 20211204
IS  - 1552-5783 (Electronic)
IS  - 0146-0404 (Print)
IS  - 0146-0404 (Linking)
VI  - 61
IP  - 2
DP  - 2020 Feb 7
TI  - Inhibition of mTOR via an AAV-Delivered shRNA Tested in a Rat OIR Model as a 
      Potential Antiangiogenic Gene Therapy.
PG  - 45
LID - 10.1167/iovs.61.2.45 [doi]
LID - 45
AB  - PURPOSE: Recent studies have shown that inhibitors of the mechanistic target of 
      rapamycin (mTOR) play important roles in proliferating endothelial cells within 
      the retinal vasculature. Here we explore the effects of inhibiting mTOR as a 
      potential gene therapeutic against pathological retinal angiogenesis in a rat 
      model of oxygen-induced retinopathy (OIR). METHODS: Sprague-Dawley pups were used 
      to generate the OIR model, with a recombinant adeno-associated virus expressing 
      an shRNA (rAAV2-shmTOR-GFP) being administered via intravitreal injection on 
      returning the rats to normoxia, with appropriate controls. Immunohistochemistry 
      and TUNEL assays, as well as fluorescein angiography, were performed on 
      transverse retinal sections and flat mounts, respectively, to determine the in 
      vivo effects of mTOR inhibition. RESULTS: Compared with normal control rats, as 
      well as OIR model animals that were either untreated (20.95 +/- 6.85), mock-treated 
      (14.50 +/- 2.47), or injected with a control short hairpin RNA (shRNA)-containing 
      virus vector (16.64 +/- 4.92), rAAV2-shmTOR-GFP (4.28 +/- 2.86, P = 0.00103) 
      treatment resulted in dramatically reduced neovascularization as a percentage of 
      total retinal area. These results mirrored quantifications of retinal avascular 
      area and vessel tortuosity, with rAAV2-shmTOR-GFP exhibiting significantly 
      greater therapeutic efficacy than the other treatments. The virus vector was 
      additionally shown to reduce inflammatory cell infiltration into retinal tissue 
      and possess antiapoptotic properties, both these processes having been implicated 
      in the pathophysiology of angiogenic retinal disorders. CONCLUSIONS: Taken 
      together, these results demonstrate the strong promise of rAAV2-shmTOR-GFP as an 
      effective and convenient gene therapy for the treatment of neovascular retinal 
      diseases.
FAU - Lee, Steven Hyun Seung
AU  - Lee SHS
AD  - .
AD  - .
FAU - Chang, HeeSoon
AU  - Chang H
AD  - .
FAU - Kim, Ji Hyun
AU  - Kim JH
AD  - .
AD  - .
FAU - Kim, Hee Jong
AU  - Kim HJ
AD  - .
FAU - Choi, Jun-Sub
AU  - Choi JS
AD  - .
FAU - Chung, Sunho
AU  - Chung S
AD  - ,.
FAU - Woo, Ha-Na
AU  - Woo HN
AD  - .
AD  - .
FAU - Lee, Kyoung Jin
AU  - Lee KJ
AD  - .
AD  - .
FAU - Park, Keerang
AU  - Park K
AD  - .
FAU - Lee, Joo Yong
AU  - Lee JY
AD  - .
AD  - ,.
FAU - Lee, Heuiran
AU  - Lee H
AD  - .
AD  - .
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Invest Ophthalmol Vis Sci
JT  - Investigative ophthalmology & visual science
JID - 7703701
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Dependovirus/*genetics
MH  - Disease Models, Animal
MH  - Gene Knockdown Techniques/*methods
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors
MH  - Humans
MH  - RNA Interference
MH  - RNA, Small Interfering
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Retinal Neovascularization/*therapy
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
PMC - PMC7329967
COIS- Disclosure: S.H.S. Lee, None; H. Chang, None; J.H. Kim, None; H.J. Kim, None; 
      J.S. Choi, None; S. Chung, None; H.N. Woo, None; K.J. Lee, None; K. Park, None; 
      J.Y. Lee, None; H. Lee, None
EDAT- 2020/02/28 06:00
MHDA- 2020/04/16 06:00
PMCR- 2020/02/01
CRDT- 2020/02/28 06:00
PHST- 2020/02/28 06:00 [entrez]
PHST- 2020/02/28 06:00 [pubmed]
PHST- 2020/04/16 06:00 [medline]
PHST- 2020/02/01 00:00 [pmc-release]
AID - 2762337 [pii]
AID - IOVS-19-27903 [pii]
AID - 10.1167/iovs.61.2.45 [doi]
PST - ppublish
SO  - Invest Ophthalmol Vis Sci. 2020 Feb 7;61(2):45. doi: 10.1167/iovs.61.2.45.