Neuroserpin Gene Therapy Inhibits Retinal Ganglion Cell Apoptosis and Promotes Functional Preservation in Glaucoma
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Neuroserpin Gene Therapy Inhibits Retinal Ganglion Cell Apoptosis and Promotes Functional Preservation in Glaucoma. / Chitranshi, Nitin; Rajput, Rashi; Godinez, Angela; Pushpitha, Kanishka; Mirzaei, Mehdi; Basavarajappa, Devaraj; Gupta, Veer; Sharma, Samridhi; You, Yuyi; Galliciotti, Giovanna; Salekdeh, Ghasem H; Baker, Mark; Graham, Stuart L; Gupta, Vivek K.
in: MOL THER, Jahrgang 31, Nr. 7, 05.07.2023, S. 2056-2076.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Neuroserpin Gene Therapy Inhibits Retinal Ganglion Cell Apoptosis and Promotes Functional Preservation in Glaucoma
AU - Chitranshi, Nitin
AU - Rajput, Rashi
AU - Godinez, Angela
AU - Pushpitha, Kanishka
AU - Mirzaei, Mehdi
AU - Basavarajappa, Devaraj
AU - Gupta, Veer
AU - Sharma, Samridhi
AU - You, Yuyi
AU - Galliciotti, Giovanna
AU - Salekdeh, Ghasem H
AU - Baker, Mark
AU - Graham, Stuart L
AU - Gupta, Vivek K
N1 - Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
PY - 2023/7/5
Y1 - 2023/7/5
N2 - Our research has proven that the inhibitory activity of the serine protease inhibitor neuroserpin (NS) is impaired because of its oxidation deactivation in glaucoma. Using genetic NS knockout (NS-/-) and NS overexpression (NS+/+ Tg) animal models and antibody-based neutralization approaches, we demonstrate that NS loss is detrimental to retinal structure and function. NS ablation was associated with perturbations in autophagy and microglial and synaptic markers, leading to significantly enhanced IBA1, PSD95, beclin-1, and LC3-II/LC3-I ratio and reduced phosphorylated neurofilament heavy chain (pNFH) levels. On the other hand, NS upregulation promoted retinal ganglion cell (RGC) survival in wild-type and NS-/- glaucomatous mice and increased pNFH expression. NS+/+Tg mice demonstrated decreased PSD95, beclin-1, LC3-II/LC3-I ratio, and IBA1 following glaucoma induction, highlighting its protective role. We generated a novel reactive site NS variant (M363R-NS) resistant to oxidative deactivation. Intravitreal administration of M363R-NS was observed to rescue the RGC degenerative phenotype in NS-/- mice. These findings demonstrate that NS dysfunction plays a key role in the glaucoma inner retinal degenerative phenotype and that modulating NS imparts significant protection to the retina. NS upregulation protected RGC function and restored biochemical networks associated with autophagy and microglial and synaptic function in glaucoma.
AB - Our research has proven that the inhibitory activity of the serine protease inhibitor neuroserpin (NS) is impaired because of its oxidation deactivation in glaucoma. Using genetic NS knockout (NS-/-) and NS overexpression (NS+/+ Tg) animal models and antibody-based neutralization approaches, we demonstrate that NS loss is detrimental to retinal structure and function. NS ablation was associated with perturbations in autophagy and microglial and synaptic markers, leading to significantly enhanced IBA1, PSD95, beclin-1, and LC3-II/LC3-I ratio and reduced phosphorylated neurofilament heavy chain (pNFH) levels. On the other hand, NS upregulation promoted retinal ganglion cell (RGC) survival in wild-type and NS-/- glaucomatous mice and increased pNFH expression. NS+/+Tg mice demonstrated decreased PSD95, beclin-1, LC3-II/LC3-I ratio, and IBA1 following glaucoma induction, highlighting its protective role. We generated a novel reactive site NS variant (M363R-NS) resistant to oxidative deactivation. Intravitreal administration of M363R-NS was observed to rescue the RGC degenerative phenotype in NS-/- mice. These findings demonstrate that NS dysfunction plays a key role in the glaucoma inner retinal degenerative phenotype and that modulating NS imparts significant protection to the retina. NS upregulation protected RGC function and restored biochemical networks associated with autophagy and microglial and synaptic function in glaucoma.
U2 - 10.1016/j.ymthe.2023.03.008
DO - 10.1016/j.ymthe.2023.03.008
M3 - SCORING: Journal article
C2 - 36905120
VL - 31
SP - 2056
EP - 2076
JO - MOL THER
JF - MOL THER
SN - 1525-0016
IS - 7
ER -