June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Pegylated Arginase 1 as a Treatment for Acute Central Nervous System (CNS) Injury
Author Affiliations & Notes
  • Abdelrahman Fouda
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
    James and Jean Culver Vision Discovery Institute, Augusta, Georgia, United States
  • Wael Eldahshan
    Pharmacology, Augusta University, Augusta, Georgia, United States
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
  • Zhimin Xu
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
    James and Jean Culver Vision Discovery Institute, Augusta, Georgia, United States
  • Tahira Lemtalsi
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
    James and Jean Culver Vision Discovery Institute, Augusta, Georgia, United States
  • Esraa Shosha
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
    James and Jean Culver Vision Discovery Institute, Augusta, Georgia, United States
  • Paul Ning-Man Cheng
    Bio-cancer Treatment International, Hong Kong
  • S. Priya Narayanan
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
    James and Jean Culver Vision Discovery Institute, Augusta, Georgia, United States
  • Robert W Caldwell
    Pharmacology, Augusta University, Augusta, Georgia, United States
    James and Jean Culver Vision Discovery Institute, Augusta, Georgia, United States
  • Ruth B Caldwell
    Vascular Biology Center, Augusta University, Augusta, Georgia, United States
    James and Jean Culver Vision Discovery Institute, Augusta, Georgia, United States
  • Footnotes
    Commercial Relationships   Abdelrahman Fouda, Augusta University (P); Wael Eldahshan, None; Zhimin Xu, None; Tahira Lemtalsi, None; Esraa Shosha, None; Paul Cheng, Biocancer Treatment International (E); S. Priya Narayanan, None; Robert Caldwell, Augusta University (P); Ruth Caldwell, Augusta University (P)
  • Footnotes
    Support  National Institute of Health (NIH grant R01-EY11766 to RBC, RWC), the Department of Veterans Affairs, Office of Research and Development (BX001233 to RBC), K99 award (1K99EY029373-01A1 to AF) and the NIH core grant number P30EY031631 to the Culver Vision Discovery Institute at Augusta University.
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 2999. doi:
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    • Get Citation

      Abdelrahman Fouda, Wael Eldahshan, Zhimin Xu, Tahira Lemtalsi, Esraa Shosha, Paul Ning-Man Cheng, S. Priya Narayanan, Robert W Caldwell, Ruth B Caldwell; Pegylated Arginase 1 as a Treatment for Acute Central Nervous System (CNS) Injury. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2999.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Arginase 1 (A1) is the enzyme that hydrolyzes the semi-essential amino acid, arginine, to ornithine and urea. We have previously shown that A1 deletion worsens retinal ischemic injury while intravitreal treatment with a pegylated form of the enzyme (PEG-A1: recombinant human arginase covalently attached to methoxy polyethylene glycol ) is protective. In this translational study, we aimed to study the utility of systemic PEG-A1 treatment in mouse models of acute retinal and brain injury.

Methods : Cohorts of WT mice were subjected to retinal ischemia-reperfusion (IR) injury, traumatic optic neuropathy (TON), or brain stroke via middle cerebral artery occlusion (MCAO) and treated with intraperitoneal injections of PEG-A1 or vehicle (PEG only). Drug penetration into the CNS tissues was measured by western blotting for PEG. Neuroprotection was measured in a blinded fashion using NeuN (neuronal marker) immuno-labeling of retina flat-mounts and quantification of brain infarct area using triphenyl tetrazolium chloride (TTC) staining. Furthermore, ex vivo retina explants and in vitro retina neuron cultures were subjected to oxygen-glucose deprivation (OGD) followed by reoxygenation (R) and treatment with PEG-A1.

Results : PEG-A1 given systemically did not cross the intact blood-retina or blood-brain barriers in sham controls but reached the retina and brain tissues after the breakdown of the permeability barriers in all tested models of acute CNS injury. Systemic delivery of PEG-A1 provided statistically significant (p<0.05) neuroprotection after retinal IR injury (increasing neuronal survival to 62% vs 40% in the vehicle group), TON (increasing neuronal survival to 78% vs 62% in the vehicle group), and stroke (reducing infarct size to 34% vs 41% in the vehicle group). PEG-A1 treatment was also neuroprotective in retina explants subjected to OGD/R (73% neuronal survival as compared to 55% in untreated or 48% in PEG only treated explants). PEG-A1 treatment was not effective in promoting survival in retinal neuronal cultures exposed to OGD/R.

Conclusions : Systemic PEG-A1 administration is neuroprotective and provides an excellent route to deliver the drug to the retina and the brain after acute CNS injury.

This is a 2021 ARVO Annual Meeting abstract.

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