PMID- 37449272
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230922
IS  - 1662-4548 (Print)
IS  - 1662-453X (Electronic)
IS  - 1662-453X (Linking)
VI  - 17
DP  - 2023
TI  - Caspase-9 inhibition confers stronger neuronal and vascular protection compared 
      to VEGF neutralization in a mouse model of retinal vein occlusion.
PG  - 1209527
LID - 10.3389/fnins.2023.1209527 [doi]
LID - 1209527
AB  - PURPOSE: Retinal vein occlusion (RVO) is a sight-threatening condition typically 
      treated with intravitreal injection of vascular endothelial growth factor (VEGF) 
      antagonists. Treatment response to anti-VEGF therapies is highly variable, with 
      poor visual outcomes and treatment response in patients with significant retinal 
      nonperfusion following RVO. Recently, caspase-9 has been identified as a potent 
      regulator of edema, gliosis, and neuronal dysfunction during acute retinal 
      hypoxia. The purpose of this study was to compare the therapeutic effect of 
      caspase-9 inhibition against VEGF-neutralization in an established mouse model of 
      RVO. METHODS: Adult male C57Bl/6 J mice were randomized to induction of RVO and 
      treatment with either vehicle, intravitreal injection of anti-VEGF antibody, 
      topical administration of a selective caspase-9 inhibitor (Pen1-XBir3), or a 
      combination therapy. Animals were followed on days 1, 2, and 8 after RVO with 
      fundus retinal imaging, and with optical coherence tomography (OCT) to capture 
      retinal swelling, capillary nonperfusion (measured by disorganization of retinal 
      inner layers, DRIL), hyperreflective foci (HRF), and retinal atrophy. Focal 
      electroretinography (ERG) measurements were performed on day 7. Histology was 
      performed on retinal sections from day 8. RESULTS: Both VEGF neutralization and 
      caspase-9 inhibition showed significant retinal protection from RVO compared to 
      vehicle treatment arm. Retinal reperfusion of occluded veins was accelerated in 
      eyes receiving caspase-9 inhibitor, but not significantly different from vehicle 
      in the anti-VEGF group. Retinal edema was suppressed in all treatment groups, 
      with approximately 2-fold greater edema reduction with caspase-9 inhibition 
      compared to VEGF neutralization. HRF were reduced similarly across all treatment 
      groups compared to vehicle. Retinal detachment was reduced only in eyes treated 
      with caspase-9 inhibitor monotherapy. Caspase-9 inhibition reduced retinal 
      atrophy and preserved ERG response; VEGF neutralization did not prevent 
      neurodegeneration following RVO. CONCLUSION: Caspase-9 inhibition confers 
      stronger neuronal and vascular protection compared to VEGF neutralization in the 
      mouse laser-induced model of RVO.
CI  - Copyright (c) 2023 Avrutsky, Chen, Lawson, Snipas, Salvesen and Troy.
FAU - Avrutsky, Maria I
AU  - Avrutsky MI
AD  - Department of Pathology and Cell Biology, Vagelos College of Physicians and 
      Surgeons, Columbia University, New York, NY, United States.
FAU - Chen, Claire W
AU  - Chen CW
AD  - Department of Pathology and Cell Biology, Vagelos College of Physicians and 
      Surgeons, Columbia University, New York, NY, United States.
FAU - Lawson, Jacqueline M
AU  - Lawson JM
AD  - Department of Pathology and Cell Biology, Vagelos College of Physicians and 
      Surgeons, Columbia University, New York, NY, United States.
FAU - Snipas, Scott J
AU  - Snipas SJ
AD  - NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 
      La Jolla, CA, United States.
FAU - Salvesen, Guy S
AU  - Salvesen GS
AD  - NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 
      La Jolla, CA, United States.
FAU - Troy, Carol M
AU  - Troy CM
AD  - Department of Pathology and Cell Biology, Vagelos College of Physicians and 
      Surgeons, Columbia University, New York, NY, United States.
AD  - Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia 
      University, New York, NY, United States.
AD  - The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, 
      Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 
      United States.
LA  - eng
GR  - R01 NS081333/NS/NINDS NIH HHS/United States
GR  - T32 EY013933/EY/NEI NIH HHS/United States
PT  - Journal Article
DEP - 20230628
PL  - Switzerland
TA  - Front Neurosci
JT  - Frontiers in neuroscience
JID - 101478481
PMC - PMC10336837
OTO - NOTNLM
OT  - VEGF
OT  - caspase-9
OT  - cell penetrating peptide
OT  - edema
OT  - ischemia
OT  - neurodegeneration
OT  - neurovascular
OT  - retinal vein occlusion
COIS- CT and MA are listed as inventors on patent applications filed by the Trustees of 
      Columbia University in the City of New York related to the therapeutic use of 
      caspase-9 inhibitors. MA received consulting income from Opera Therapeutics. The 
      remaining authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/07/14 13:07
MHDA- 2023/07/14 13:08
PMCR- 2023/01/01
CRDT- 2023/07/14 04:00
PHST- 2023/04/20 00:00 [received]
PHST- 2023/06/05 00:00 [accepted]
PHST- 2023/07/14 13:08 [medline]
PHST- 2023/07/14 13:07 [pubmed]
PHST- 2023/07/14 04:00 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.3389/fnins.2023.1209527 [doi]
PST - epublish
SO  - Front Neurosci. 2023 Jun 28;17:1209527. doi: 10.3389/fnins.2023.1209527. 
      eCollection 2023.