The Mechanisms of Neuroprotection by Topical Rho Kinase Inhibition in Experimental Mouse Glaucoma and Optic Neuropathy DOI Creative Commons
Sarah Quillen, Elizabeth Kimball,

Kelsey A. Ritter-Gordy

et al.

Investigative Ophthalmology & Visual Science, Journal Year: 2024, Volume and Issue: 65(13), P. 43 - 43

Published: Nov. 20, 2024

Purpose: The purpose of this study was to delineate the neuroprotective mechanisms topical 2% ripasudil (Rip), a Rho kinase (ROCK) inhibitor. Methods: In 340 mice, scheduled Rip or balanced salt solution (BSS) saline drops were intermittently, unilaterally delivered. Intracameral microbead glaucoma (GL) injection increased intraocular pressure (IOP) from 1 day 6 weeks (6W), whereas other mice underwent optic nerve (ON) crush. Retinal ganglion cell (RGC) loss assessed using retinal wholemount anti-RNA Binding Protein with Multiple Splicing (RBPMS) labeling and ON axon counts. Axonal transport quantified β-amyloid precursor protein (APP) immunolocalization. Micro-Western (Wes) analysis expression. Immunofluorescent expression ROCK pathway molecules, quantitative astrocyte structural changes, biomechanical strains (explanted eyes) evaluated. activity assays conducted in separate regions. Results: At 6W GL, mean RGC 6.6 ± 13.3% 36.3 30.9% BSS (P = 0.04, n 10/group). soma after crush lower (68.6 8.2%) than (80.5 5.7%, P 0.006, After (34 5.0%) (51 8.1%, 0.03, APP within unmyelinated (UON) unaffected by Rip. Maximum principal mechanical similarly BSS-treated mice. 2 reduced GL eyes. pROCK2/ROCK2 ratio rose retina eyes, but not Conclusions: Topical crush, suppression signaling ON. neuroprotection appear involve effects on both responses IOP elevation.

Language: Английский

RGC-specific ATF4 and/or CHOP deletion rescues glaucomatous neurodegeneration and visual function DOI Creative Commons
Fang Fang, Pingting Liu, Haoliang Huang

et al.

Molecular Therapy — Nucleic Acids, Journal Year: 2023, Volume and Issue: 33, P. 286 - 295

Published: July 15, 2023

Endoplasmic reticulum (ER) stress has been linked with various acute and chronic neurodegenerative diseases. We previously found that optic nerve (ON) injury diseases induce neuronal ER in retinal ganglion cells (RGCs). further demonstrated germline deletion of CHOP preserves the structure function both RGC somata axons mouse glaucoma models. Here we report RGC-specific and/or its upstream regulator ATF4 synergistically promotes ON survival visual crush silicone oil-induced ocular hypertension (SOHU) Consistently, topical application ATF4/CHOP chemical inhibitor ISRIB or CRISPR-mediated knockdown downstream effector Gadd45a also delivers significant neuroprotection SOHU model. These studies suggest blocking intrinsic axis is a promising strategy for neurodegeneration.

Language: Английский

Citations

14
Clinical Approaches for Mitochondrial Diseases DOI Creative Commons
Seongho Hong, Sanghun Kim, Kyoungmi Kim

et al.

Cells, Journal Year: 2023, Volume and Issue: 12(20), P. 2494 - 2494

Published: Oct. 20, 2023

Mitochondria are subcontractors dedicated to energy production within cells. In human mitochondria, almost all mitochondrial proteins originate from the nucleus, except for 13 subunit that make up crucial system required perform 'oxidative phosphorylation (OX PHOS)', which expressed by mitochondria's self-contained DNA. Mitochondrial DNA (mtDNA) also encodes 2 rRNA and 22 tRNA species. replicates autonomously, independent of its heredity follows a non-Mendelian pattern, exclusively passing mother children. Numerous studies have identified mtDNA mutation-related genetic diseases. The consequences various types mutations, including insertions, deletions, single base-pair studied reveal their relationship Most diseases exhibit fatal symptoms, leading ongoing therapeutic research with diverse approaches such as stimulating defective OXPHOS system, replacement, allotropic expression enzymes. This review provides detailed information on two topics: (1) caused (2) mechanisms current treatments clinical trials.

Language: Английский

Citations

10
Bilateral astrocyte reaction to unilateral insult in the optic projection to the brain DOI Creative Commons
Joseph M. Holden, David J. Calkins

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(14)

Published: March 31, 2025

Emotions coordinate our behavior and physiological states during survival-salient events pleasurable interactions. Even though we are often consciously aware of current emotional state, such as anger or happiness, the mechanisms giving ...Emotions felt in body, somatosensory feedback has been proposed to trigger conscious experiences. Here reveal maps bodily sensations associated with different emotions using a unique topographical self-report method. In ...

Language: Английский

Citations

0
Retinal damage promotes mitochondrial transfer in the visual system of a mouse model of Leber hereditary optic neuropathy DOI Creative Commons

Pascal Ezan,

Eléonore Hardy, Alexis‐Pierre Bemelmans

et al.

Neurobiology of Disease, Journal Year: 2024, Volume and Issue: 201, P. 106681 - 106681

Published: Sept. 25, 2024

Language: Английский

Citations

1
Five-Year Outcomes of Lenadogene Nolparvovec Gene Therapy in Leber Hereditary Optic Neuropathy DOI Creative Commons
Patrick Yu‐Wai‐Man, Nancy J. Newman, Valérie Biousse

et al.

JAMA Ophthalmology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 19, 2024

Importance Limited studies have assessed the long-term benefit/risk of gene therapy for Leber hereditary optic neuropathy (LHON). Objective To determine safety and efficacy lenadogene nolparvovec in patients with LHON due to MT-ND4 variant up 5 years after administration. Design, Setting, Participants The RESCUE REVERSE Long-Term Follow-up Study (RESTORE), conducted from 2018 2022, is 5-year follow-up study 2 phase 3 clinical (Efficacy Lenadogene Nolparvovec Treatment Vision Loss Up 6 Months From Onset Due Mutation) 7 1 Year Mutation). At end each study, ie, administration, were offered enrollment RESTORE trial, a multinational, multicenter, prospective an additional follow-up. Patients received eye sham injection other eye. Intervention was administered as single intravitreal RESCUE/REVERSE studies. Main Outcomes Measures included best-corrected visual acuity (BCVA), quality life using National Eye Institute functioning questionnaire 25 (NEI VFQ-25), adverse events. Results Among 76 who (n = 39) 37) studies, 72 (94.7%) completed these studies; 62 (81.6%) participated 55 (72.4%) mostly male (49 [79.0%]) mean (SD) age 35.9 (15.3) at treatment. baseline, BCVA 1.5 (0.5) logMAR (20/600 Snellen) eyes be treated 1.4 (20/500) eyes. trials, treatment, reached value (0.6) (20/500). change baseline year −0.05 (+1 line) 0.01 (−0 therapy–treated eyes, respectively (difference, −0.03; 95% CI, −0.16 0.09; P .60). Five bilateral improvement nadir similar that observed years, −0.4 (more than +4 lines) (0.4) (+4 −0.05; −0.15 0.04; .27). An least −0.3 (+3 66.1% participants (41 62). Between intraocular inflammation noted 4 8 events event sham. Conclusions Relevance In this analysis unilaterally demonstrated sustained good profile This evidence persistent benefit over time promising use patients. Trial Registration ClinicalTrials.gov Identifier: NCT03406104

Language: Английский

Citations

1
Current Status of Clinical Trials Design and Outcomes in Retinal Gene Therapy DOI
Boris Rosin, Eyal Banin, José‐Alain Sahel

et al.

Cold Spring Harbor Perspectives in Medicine, Journal Year: 2023, Volume and Issue: 14(7), P. a041301 - a041301

Published: Sept. 11, 2023

Boris Rosin1, Eyal Banin2 and Jose-Alain Sahel1,2,3 1The UPMC Vision Institute, University of Pittsburgh, Pennsylvania 15219, USA 2Division Ophthalmology, Hadassah-Hebrew Medical Center, Jerusalem 91120, Israel 3Institut Hospitalo-Universitaire FOReSIGHT, Paris 75012, France Correspondence: brosin{at}pitt.edu

Language: Английский

Citations

3
Meet the Editorial Board Member DOI
David J. Calkins

Current Neuropharmacology, Journal Year: 2024, Volume and Issue: 22(14), P. 2271 - 2271

Published: July 15, 2024

Language: Английский

Citations

0
The Mechanisms of Neuroprotection by Topical Rho Kinase Inhibition in Experimental Mouse Glaucoma and Optic Neuropathy DOI Creative Commons
Sarah Quillen, Elizabeth Kimball,

Kelsey A. Ritter-Gordy

et al.

Investigative Ophthalmology & Visual Science, Journal Year: 2024, Volume and Issue: 65(13), P. 43 - 43

Published: Nov. 20, 2024

Purpose: The purpose of this study was to delineate the neuroprotective mechanisms topical 2% ripasudil (Rip), a Rho kinase (ROCK) inhibitor. Methods: In 340 mice, scheduled Rip or balanced salt solution (BSS) saline drops were intermittently, unilaterally delivered. Intracameral microbead glaucoma (GL) injection increased intraocular pressure (IOP) from 1 day 6 weeks (6W), whereas other mice underwent optic nerve (ON) crush. Retinal ganglion cell (RGC) loss assessed using retinal wholemount anti-RNA Binding Protein with Multiple Splicing (RBPMS) labeling and ON axon counts. Axonal transport quantified β-amyloid precursor protein (APP) immunolocalization. Micro-Western (Wes) analysis expression. Immunofluorescent expression ROCK pathway molecules, quantitative astrocyte structural changes, biomechanical strains (explanted eyes) evaluated. activity assays conducted in separate regions. Results: At 6W GL, mean RGC 6.6 ± 13.3% 36.3 30.9% BSS (P = 0.04, n 10/group). soma after crush lower (68.6 8.2%) than (80.5 5.7%, P 0.006, After (34 5.0%) (51 8.1%, 0.03, APP within unmyelinated (UON) unaffected by Rip. Maximum principal mechanical similarly BSS-treated mice. 2 reduced GL eyes. pROCK2/ROCK2 ratio rose retina eyes, but not Conclusions: Topical crush, suppression signaling ON. neuroprotection appear involve effects on both responses IOP elevation.

Language: Английский

Citations

0