PMID- 31043342
OWN - NLM
STAT- MEDLINE
DCOM- 20200226
LR  - 20220716
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 27
IP  - 7
DP  - 2019 Jul 3
TI  - AKT3 Gene Transfer Promotes Anabolic Reprogramming and Photoreceptor 
      Neuroprotection in a Pre-clinical Model of Retinitis Pigmentosa.
PG  - 1313-1326
LID - S1525-0016(19)30175-3 [pii]
LID - 10.1016/j.ymthe.2019.04.009 [doi]
AB  - Mutations within over 250 known genes are associated with inherited retinal 
      degeneration. Clinical success following gene-replacement therapy for congenital 
      blindness due to RPE65 mutations establishes a platform for the development of 
      downstream treatments targeting other forms of inherited ocular disease. 
      Unfortunately, several challenges relevant to complex disease pathology and 
      limitations of current gene-transfer technologies impede the development of 
      related strategies for each specific form of inherited retinal degeneration. 
      Here, we describe a gene-augmentation strategy that delays retinal degeneration 
      by stimulating features of anabolic metabolism necessary for survival and 
      structural maintenance of photoreceptors. We targeted two critical points of 
      regulation in the canonical insulin/AKT/mammalian target of rapamycin (mTOR) 
      pathway with AAV-mediated gene augmentation in a mouse model of retinitis 
      pigmentosa. AAV vectors expressing the serine/threonine kinase, AKT3, promote 
      dramatic preservation of photoreceptor numbers, structure, and partial visual 
      function. This protective effect was associated with successful reprogramming of 
      photoreceptor metabolism toward pathways associated with cell growth and 
      survival. Collectively, these findings underscore the importance of AKT activity 
      and downstream pathways associated with anabolic metabolism in photoreceptor 
      survival and maintenance.
CI  - Copyright (c) 2019 The American Society of Gene and Cell Therapy. Published by 
      Elsevier Inc. All rights reserved.
FAU - McDougald, Devin S
AU  - McDougald DS
AD  - Center for Advanced Retinal and Ocular Therapeutics, F.M. Kirby Center for 
      Molecular Ophthalmology, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA 19104, USA.
FAU - Papp, Tyler E
AU  - Papp TE
AD  - Center for Advanced Retinal and Ocular Therapeutics, F.M. Kirby Center for 
      Molecular Ophthalmology, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA 19104, USA.
FAU - Zezulin, Alexandra U
AU  - Zezulin AU
AD  - Center for Advanced Retinal and Ocular Therapeutics, F.M. Kirby Center for 
      Molecular Ophthalmology, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA 19104, USA.
FAU - Zhou, Shangzhen
AU  - Zhou S
AD  - Center for Advanced Retinal and Ocular Therapeutics, F.M. Kirby Center for 
      Molecular Ophthalmology, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA 19104, USA.
FAU - Bennett, Jean
AU  - Bennett J
AD  - Center for Advanced Retinal and Ocular Therapeutics, F.M. Kirby Center for 
      Molecular Ophthalmology, Perelman School of Medicine, University of Pennsylvania, 
      Philadelphia, PA 19104, USA. Electronic address: jebennet@pennmedicine.upenn.edu.
LA  - eng
GR  - P30 EY001583/EY/NEI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190414
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (AKT3 protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 6)
RN  - EC 3.1.4.35 (Pde6b protein, mouse)
SB  - IM
MH  - Animals
MH  - Cell Survival/genetics
MH  - Cells, Cultured
MH  - Cyclic Nucleotide Phosphodiesterases, Type 6/genetics
MH  - Disease Models, Animal
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors
MH  - Gliosis/genetics/therapy
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Mutant Strains
MH  - Neuroprotection/*genetics
MH  - Photoreceptor Cells, Vertebrate/*metabolism
MH  - Point Mutation
MH  - Proto-Oncogene Proteins c-akt/*genetics
MH  - Retinal Degeneration/therapy
MH  - Retinitis Pigmentosa/genetics/*therapy
MH  - Signal Transduction/*genetics
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - *Transduction, Genetic
MH  - Visual Acuity/genetics
PMC - PMC6612630
OTO - NOTNLM
OT  - AAV
OT  - AKT
OT  - gene therapy
OT  - neuroprotection
OT  - photoreceptor
OT  - retinitis pigmentosa
OT  - rheb
EDAT- 2019/05/03 06:00
MHDA- 2020/02/27 06:00
PMCR- 2020/07/03
CRDT- 2019/05/03 06:00
PHST- 2018/10/24 00:00 [received]
PHST- 2019/04/04 00:00 [revised]
PHST- 2019/04/08 00:00 [accepted]
PHST- 2019/05/03 06:00 [pubmed]
PHST- 2020/02/27 06:00 [medline]
PHST- 2019/05/03 06:00 [entrez]
PHST- 2020/07/03 00:00 [pmc-release]
AID - S1525-0016(19)30175-3 [pii]
AID - 10.1016/j.ymthe.2019.04.009 [doi]
PST - ppublish
SO  - Mol Ther. 2019 Jul 3;27(7):1313-1326. doi: 10.1016/j.ymthe.2019.04.009. Epub 2019 
      Apr 14.