Visual Field Mean Deviation Slopes: A Potential Primary Endpoint for Clinical Trials in Glaucoma Neuroprotection DOI Creative Commons

Carlos Gustavo De Moraes,

Keith J. Lane,

Xiao Wang

et al.

Research Square (Research Square), Journal Year: 2022, Volume and Issue: unknown

Published: Nov. 11, 2022

Abstract The purpose of this retrospective, longitudinal study is to evaluate the relationship between MD slope from visual field tests collected over a short period time (2 years) and current United States’ Food Drug Administration (FDA) recommended endpoints for outcomes. If correlation strong highly predictive, clinical trials employing slopes as primary could be employed in neuroprotection with shorter duration help expedite development novel IOP-independent therapies. Visual patients or suspected glaucoma were selected an academic institution evaluated based on two functional progression endpoints: 1) five more locations worsening by at least 7 dB, 2) 5 test upon GCP algorithm. A total 467 (76.6%) 472 (77.4%) eyes reached Endpoints B, respectively, any point time. 359 (58.8%) progressed faster than 0 dB/year, 278 (45.5%) -0.5 200 (32.7%) -1.0 dB/year. It was found that experiencing rapid 24-2 2-year likely reach one FDA accepted during soon after period.

Language: Английский

Novel frontiers in neuroprotective therapies in glaucoma: Molecular and clinical aspects DOI
Alessandra Boccaccini,

Dario Cavaterra,

Carmela Carnevale

et al.

Molecular Aspects of Medicine, Journal Year: 2023, Volume and Issue: 94, P. 101225 - 101225

Published: Nov. 24, 2023

Language: Английский

Citations

9
Comparison of SNCG and NEFH Promoter–Driven Expression of Human SIRT1 Expression in a Mouse Model of Glaucoma DOI Creative Commons

Nuala O’Neill,

Miranda Meng,

Brahim Chaqour

et al.

Translational Vision Science & Technology, Journal Year: 2024, Volume and Issue: 13(8), P. 37 - 37

Published: Aug. 23, 2024

Purpose: Adeno-associated virus (AAV) demonstrates promise in delivering therapeutic genes to retinal ganglion cells (RGCs). Delivery of neuroprotective is constrained by packaging size and/or cell selectivity. This study compares the ability RGC-selective gamma-synuclein (SNCG) promoter and smaller neurofilament heavy chain (NEFH) promoter, as well portions atonal bHLH transcription factor 7 (ATOH7) enhancer, drive gene expression RGCs. Methods: AAV2 constructs with green fluorescent protein (GFP) or human sirtuin 1 (hSIRT1) driven cytomegalovirus (CMV) enhancer NEFH (AAV2–eCMV–NEFH) distal active sequences ATOH7 (DiATOH7) SNCG (AAV2–DiATOH7–SNCG) were intravitreally injected into C57BL/6J mice. RGCs immunolabeled Brn3a antibodies counted. AAV utmost transduction efficiency used test efficacy hSIRT1 12-week-old mice subjected microbead (MB)-induced intraocular pressure (IOP) elevation. Visual function was measured using optokinetic responses (OKRs). Results: The eGFP AAV2–eCMV–NEFH similar that AAV2–eCMV–SNCG AAV2–DiATOH7–SNCG. When combined a larger less efficient than shorter DiATOH7 enhancer. Similarly, AAV2–eCMV–SNCG. latter two vectors equally increasing RGC survival improving visual mouse model MB-induced IOP Conclusions: promoters represent comparable selective sequences; however, offers size. Translational Relevance: Smaller enhancer–promoter combinations can be deliver for treatment optic neuropathies including glaucoma.

Language: Английский

Citations

2
Endoplasmic reticulum stress-related deficits in calcium clearance promote neuronal dysfunction that is prevented by SERCA2 gene augmentation DOI Creative Commons
Yukihiro Shiga,

Aline Giselle Rangel Olguin,

Sana El Hajji

et al.

Cell Reports Medicine, Journal Year: 2024, Volume and Issue: unknown, P. 101839 - 101839

Published: Nov. 1, 2024

Language: Английский

Citations

2
Elevated Intraocular Pressure and Glaucomatous Optic Neuropathy: Genes to Disease Mechanisms, Therapeutic Drugs, and Gene Therapies DOI Creative Commons
Najam A. Sharif

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(6), P. 870 - 870

Published: June 12, 2023

This review article focuses on the pathogenesis of and genetic defects linked with chronic ocular hypertension (cOHT) glaucoma. The latter disease constitutes a group degenerative diseases whose hallmark features are damage to optic nerve, apoptotic demise retinal ganglion cells, disturbances within brain regions involved in visual perception considerable impairment that can lead blindness. Even though number pharmaceuticals, surgical device-based treatments already exist addressing cOHT associated most prevalent glaucoma types, primary open-angle (POAG), they be improved upon terms superior efficacy reduced side-effects longer duration activity. linkage pathology certain genes via genome-wide studies illuminating new approaches finding novel treatment options for aforementioned disorders. Gene replacement, gene editing CRISPR-Cas9, use optogenetic technologies may replace traditional drug-based therapies and/or augment existing therapeutics POAG future.

Language: Английский

Citations

6
Neuroprotection of Rodent and Human Retinal Ganglion Cells In Vitro/Ex Vivo by the Hybrid Small Molecule SA-2 DOI Creative Commons
Jennifer H. Pham, Gretchen A. Johnson, Rajiv Rangan

et al.

Cells, Journal Year: 2022, Volume and Issue: 11(23), P. 3741 - 3741

Published: Nov. 23, 2022

The mechanisms underlying the neuroprotective effects of hybrid antioxidant-nitric oxide donating compound SA-2 in retinal ganglion cell (RGC) degeneration models were evaluated. vitro trophic factor (TF) deprivation model primary rat RGCs and ex vivo human explants used to mimic glaucomatous neurodegeneration. Cell survival was assessed after treatment with vehicle or SA-2. In separate experiments, tert-Butyl hydroperoxide (TBHP) endothelin-3 (ET-3) RGCs, respectively, induce oxidative damage. Mitochondrial intracellular reactive oxygen species (ROS) following treatments. TF model, produced a significant decrease apoptotic dead counts increase RGC explants. stress-induced models, production ROS observed SA-2-treated group compared vehicle-treated group. Compound against various insults by reducing apoptosis decreasing levels. Amelioration mitochondrial cellular stress may be potential therapeutic strategy for preventing neurodegeneration RGCs.

Language: Английский

Citations

9
A potential primary endpoint for clinical trials in glaucoma neuroprotection DOI Creative Commons

Carlos Gustavo De Moraes,

Keith J. Lane,

Xiao Wang

et al.

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: May 2, 2023

The purpose of this retrospective, longitudinal study is to evaluate the relationship between MD slope from visual field tests collected over a short period time (2 years) and current United States' Food Drug Administration (FDA) recommended endpoints for outcomes. If correlation strong highly predictive, clinical trials employing slopes as primary could be employed in neuroprotection with shorter duration help expedite development novel IOP-independent therapies. Visual patients or suspected glaucoma were selected an academic institution evaluated based on two functional progression endpoints: (A) five more locations worsening by at least 7 dB, (B) test upon GCP algorithm. A total 271 (57.6%) 278 (59.1%) eyes reached Endpoints B, respectively during follow up period. median (IQR) reaching vs. not Endpoint B -1.19 (-2.00 -0.41) 0.36 (0.00 1.00) dB/year -1.16 (-1.98 -0.40) 0.41 (0.02 1.03) dB/year, (P < 0.001). It was found that experiencing rapid 24-2 2-year average tenfold likely reach one FDA accepted soon after

Language: Английский

Citations

5
Recently Approved Drugs for Lowering and Controlling Intraocular Pressure to Reduce Vision Loss in Ocular Hypertensive and Glaucoma Patients DOI Creative Commons
Najam A. Sharif

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(6), P. 791 - 791

Published: May 26, 2023

Serious vision loss occurs in patients affected by chronically raised intraocular pressure (IOP), a characteristic of many forms glaucoma where damage to the optic nerve components causes progressive degeneration retinal and brain neurons involved visual perception. While risk factors abound have been validated for this glaucomatous neuropathy (GON), major one is ocular hypertension (OHT), which results from accumulation excess aqueous humor (AQH) fluid anterior chamber eye. Millions around world suffer asymptomatic degenerative eye disease. Since clinical evidence has revealed strong correlation between reduction elevated IOP/OHT GON progression, drugs, devices, surgical techniques developed lower control IOP. The constant quest new pharmaceuticals other modalities with superior therapeutic indices recently yielded health authority-approved novel drugs unique pharmacological signatures mechanism(s) action AQH drainage microdevices effectively durably treating OHT. A nitric oxide-donating conjugate latanoprost, an FP-receptor prostaglandin (PG; latanoprostene bunod), rho kinase inhibitors (ripasudil; netarsudil), non-PG EP2-receptor-selective agonist (omidenepag isopropyl), form PG slow-release intracameral implant (Durysta) represent additions pharmaceutical toolchest mitigate ravages Despite these advances, early diagnosis OHT still lags behind would benefit further concerted effort attention.

Language: Английский

Citations

5
Synergistic neuroprotection by phytocompounds of Bacopa monnieri in scopolamine-induced Alzheimer’s disease mice model DOI

Shehla Shoukat,

Muhammad Amir Zia,

Muhammad Uzair

et al.

Molecular Biology Reports, Journal Year: 2023, Volume and Issue: 50(10), P. 7967 - 7979

Published: Aug. 3, 2023

Language: Английский

Citations

4
Dynamic functional and structural remodeling during retinal regeneration in zebrafish DOI Creative Commons

Lindsey M. Barrett,

Diana M. Mitchell,

Peter C. Meighan

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: Nov. 30, 2022

Zebrafish regenerate their retinas following damage, resulting in restoration of visual function. Here we evaluate recovery retinal function through qualitative and quantitative analysis the electroretinogram (ERG) over time correlation to histological features regenerated tissue.Retinas adult zebrafish were lesioned by intravitreal injection 10 μM (extensive lesion; destroys all neurons) or 2 (selective spares photoreceptors) ouabain. Unlesioned contralateral served as controls. Function circuitry was analyzed at selected timepoints using ERG recordings from live zebrafish, whole eyes processed for analyses immediately thereafter.Qualitative assessment waveforms during regeneration revealed dynamic changes that heterogeneous on an individual level within each sampling time, but still followed common waveform patterns a per-fish population-level basis. Early period (13-30 days post injury; DPI), both lesion types, b-waves essentially not detected, unmasked increased apparent amplitudes, implicit times, half-widths a-waves (vs. controls). In control recordings, d-waves obviously (OFF-bipolar responses) regenerating several fish became prominent 30DPI dominated post-photoreceptor response (PPR). Beyond 45DPI, detectable, ratio d- b-wave contributions progressively shifted with most, all, displaying PPR. At latest (extensive, 90DPI; selective, 80DPI), measurable approached normal (implicit times half-widths), amplitudes restored levels. Histological which ERGs recorded showed progressed, PKCa + ON-bipolar terminals parvalbumin amacrine cell processes more stereotypically positioned deep sublaminae INL after type, consistent shift PPR seen recordings.Taken together, these data suggest photoreceptor-OFF-bipolar component/connectivity may functionally recover mature earlier compared photoreceptor-ON-bipolar component, though timeframe such happens is Collectively our studies gradual functional regeneration.

Language: Английский

Citations

6
Transcriptomic profiling of retinal cells reveals a subpopulation of microglia/macrophages expressing Rbpms marker of retinal ganglion cells (RGCs) that confound identification of RGCs DOI Creative Commons
William C. Theune, Matthew P. Frost, Ephraim F. Trakhtenberg

et al.

Brain Research, Journal Year: 2023, Volume and Issue: 1811, P. 148377 - 148377

Published: April 28, 2023

Language: Английский

Citations

3