A molecular switch for neuroprotective astrocyte reactivity.

The intrinsic mechanisms that regulate neurotoxic versus neuroprotective astrocyte phenotypes and their effects on central nervous system degeneration and repair remain poorly understood. Here we show that injured white matter astrocytes differentiate into two distinct C3-positive and C3-negative reactive populations, previously simplified as neurotoxic (A1) and neuroprotective (A2)1,2, which can be further subdivided into unique subpopulations defined by proliferation and differential gene expression signatures. We find the balance of neurotoxic versus neuroprotective astrocytes is regulated by discrete pools of compartmented cyclic adenosine monophosphate derived from soluble adenylyl cyclase and show that proliferating neuroprotective astrocytes inhibit microglial activation and downstream neurotoxic astrocyte differentiation to promote retinal ganglion cell survival. Finally, we report a new, therapeutically tractable viral vector to specifically target optic nerve head astrocytes and show that raising nuclear or depleting cytoplasmic cyclic AMP in reactive astrocytes inhibits deleterious microglial or macrophage cell activation and promotes retinal ganglion cell survival after optic nerve injury. Thus, soluble adenylyl cyclase and compartmented, nuclear- and cytoplasmic-localized cyclic adenosine monophosphate in reactive astrocytes act as a molecular switch for neuroprotective astrocyte reactivity that can be targeted to inhibit microglial activation and neurotoxic astrocyte differentiation to therapeutic effect. These data expand on and define new reactive astrocyte subtypes and represent a step towards the development of gliotherapeutics for the treatment of glaucoma and other optic neuropathies.

Glaucoma: now and beyond.

The glaucomas are a group of conditions leading to irreversible sight loss and characterised by progressive loss of retinal ganglion cells. Although not always elevated, intraocular pressure is the only modifiable risk factor demonstrated by large clinical trials. It remains the leading cause of irreversible blindness, but timely treatment to lower intraocular pressure is effective at slowing the rate of vision loss from glaucoma. Methods for lowering intraocular pressure include laser treatments, topical medications, and surgery. Although modern surgical innovations aim to be less invasive, many have been introduced with little supporting evidence from randomised controlled trials. Many cases remain undiagnosed until the advanced stages of disease due to the limitations of screening and poor access to opportunistic case finding. Future research aims to generate evidence for intraocular pressure-independent neuroprotective treatments, personalised treatment through genetic risk profiling, and exploration of potential advanced cellular and gene therapies.

AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?

Glaucoma and uveitis are non-vascular ocular diseases which are among the leading causes of blindness and visual loss. These conditions have distinct characteristics and mechanisms but share a multifactorial and complex nature, making their management challenging and burdensome for patients and clinicians. Furthermore, the lack of symptoms in the early stages of glaucoma and the diverse aetiology of uveitis hinder timely and accurate diagnoses, which are a cause of poor visual outcomes under both conditions. Although current treatment is effective in most cases, it is often associated with low patient adherence and adverse events, which directly impact the overall therapeutic success. Therefore, long-lasting alternatives with improved safety and efficacy are needed. Gene therapy, particularly utilising adeno-associated virus (AAV) vectors, has emerged as a promising approach to address unmet needs in these diseases. Engineered capsids with enhanced tropism and lower immunogenicity have been proposed, along with constructs designed for targeted and controlled expression. Additionally, several pathways implicated in the pathogenesis of these conditions have been targeted with single or multigene expression cassettes, gene editing and silencing approaches. This review discusses strategies employed in AAV-based gene therapies for glaucoma and non-infectious uveitis and provides an overview of current progress and future directions.

Vision protection and robust axon regeneration in glaucoma models by membrane-associated Trk receptors.

Activation of neurotrophic factor signaling is a promising therapy for neurodegeneration. However, the transient nature of ligand-dependent activation limits its effectiveness. In this study, we solved this problem by inventing a system that forces membrane localization of the intracellular domain of tropomyosin receptor kinase B (iTrkB), which results in constitutive activation without ligands. Our system overcomes the small size limitation of the genome packaging in adeno-associated virus (AAV) and allows high expression of the transgene. Using AAV-mediated gene therapy in the eyes, we demonstrate that iTrkB expression enhances neuroprotection in mouse models of glaucoma and stimulates robust axon regeneration after optic nerve injury. In addition, iTrkB expression in the retina was also effective in an optic tract transection model, in which the injury site is near the superior colliculus. Regenerating axons successfully formed pathways to their brain targets, resulting in partial recovery of visual behavior. Our system may also be applicable to other trophic factor signaling pathways and lead to a significant advance in the field of gene therapy for neurotrauma and neurodegenerative disorders, including glaucoma.

Neuroserpin gene therapy inhibits retinal ganglion cell apoptosis and promotes functional preservation in glaucoma.

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.

Aqueous misdirection syndrome: clinical outcomes and risk factors for treatment failure.

PURPOSE: To evaluate the outcomes of postoperative aqueous misdirection and factors predicting failure of interventions. METHODS: This retrospective study included 49 eyes from 47 patients with aqueous misdirection following glaucoma or cataract surgery. Resolution of aqueous misdirection (AM) was deepening of the central anterior chamber (AC) and intraocular pressure (IOP) ≤ 21 mmHg. The Cox proportional hazards regression model was used to evaluate risk factors for failure of various treatments. RESULTS: 10/49 eyes (20%) resolved with conservative management, and 39/49 eyes (80%) needed multiple intervention, of which 95% (37/39) eyes achieved resolution of aqueous misdirection. Pseudophakia predicted the need for multiple interventions with a hazard ratio of 2.391 (1.158-4.935), p = 0.02). Among the risk factors assessed for resolution of AM, longer axial length (HR: 0.61 (0.414-0.891), p < 0.01) and eyes with prior glaucoma surgery predicted resolution (HR: 0.142 (0.027-0.741), p < 0.01) and delayed presentation predicted failure (HR: 1.002 (1.0002-1.0031), p < 0.02). CONCLUSION: Pseudophakic eyes were more refractory and predicted the need for multiple interventions. Eyes with prior glaucoma surgery and those with longer axial length had achieved resolution faster, and delayed presentation was a risk factor for failure to resolve.

Telemedicine for Screening and Follow-Up of Glaucoma: A Descriptive Study.

Introduction: Glaucoma is a leading cause of irreversible blindness. It is a prevalent disease worldwide, affecting ∼70 million people and expected to reach up to 112 million by 2040. Purpose: The aim of this study is to describe the implementation and initial experience of a telemedicine program to monitor glaucoma and glaucoma suspect patients in a large, integrated health care system during the COVID-19 pandemic. Methods: A retrospective chart review of established glaucoma or glaucoma suspect patients who participated in a telemedicine evaluation at the ophthalmic center of a large, Colombian health care system between June 2020 and April 2023 was conducted. Clinical and sociodemographic variables were analyzed. Generated clinical orders for additional testing, surgical procedures, follow-ups, and referrals, as well as changes in medical treatment, were evaluated. Results: A total of 11,034 telemedicine consults were included. The mean ± standard deviation age of this group was 63 ± 17.2 years and 67% were female. Of the patients who attended teleconsults, 49% were glaucoma suspects and 38.5% were followed with a diagnosis of open-angle glaucoma. After the consult, 25% of patients were referred to a glaucoma specialist, 40% had additional testing ordered, and 8% had a surgical procedure ordered, mainly laser iridotomy (409 cases). Almost a third of patients returned for subsequent telemedicine visits after the initial encounter. Despite some technical difficulties, 99.8% of patients attended and completed their scheduled telemedicine appointments. Conclusions: A telemedicine program aimed to monitor established glaucoma patients can be successfully implemented. Established patients within an integrated health care system have high adherence to the virtual model. Further research by health care institutions and government agencies will be key to expand coverage to additional populations. Clinical Trial Registration Number: CEIFUS 1026-24.

AAV-NDI1 Therapy Provides Significant Benefit to Murine and Cellular Models of Glaucoma.

Glaucoma, a leading cause of blindness, is a multifactorial condition that leads to progressive loss of retinal ganglion cells (RGCs) and vision. Therapeutic interventions based on reducing ocular hypertension are not always successful. Emerging features of glaucoma include mitochondrial dysfunction and oxidative stress. In the current study, NDI1-based gene therapy, which improves mitochondrial function and reduces reactive oxygen species, was delivered intraocularly via an adeno-associated viral vector (AAV). This AAV-NDI1 therapy protected RGCs from cell death in treated (1552.4 ± 994.0 RGCs/mm2) versus control eyes (1184.4 ± 978.4 RGCs/mm2, p < 0.05) in aged DBA/2J mice, a murine model of glaucoma. The photonegative responses (PhNRs) of RGCs were also improved in treated (6.4 ± 3.3 µV) versus control eyes (5.0 ± 3.1 µV, p < 0.05) in these mice. AAV-NDI1 also provided benefits in glaucomatous human lamina cribrosa (LC) cells by significantly increasing basal and maximal oxygen consumption rates and ATP production in these cells. Similarly, NDI1 therapy significantly protected H2O2-insulted primary porcine LC cells from oxidative stress. This study highlights the potential utility of NDI1 therapies and the benefits of improving mitochondrial function in the treatment of glaucoma.

[Glaucoma Patient with Suspected Flammer Syndrome: Diagnostic Procedures and Therapeutic Implications]. / Glaukompatient mit Verdacht auf Flammer-Syndrom: diagnostische Schritte und therapeutische Konsequenzen.

If glaucoma damage develops despite normal intraocular pressure or if the damage progresses despite well-controlled intraocular pressure, we usually find other risk factors. One important group are the vascular factors. We should focus not only on the classical risk factors of atherosclerosis, such as arterial hypertension or dyslipidaemia, but also on dysregulation of blood flow, especially on primary vascular dysregulation (PVD). Low blood pressure, either current or in adolescence, low body mass index or frequently cold hands and feet may provide important hints. Very often PVD is coupled with a number of other symptoms and signs, and we then speak of a Flammer Syndrome (FS). If there is any indication of FS, we take a targeted patient history, undertake 24 h blood pressure monitoring, measure retinal venous pressure, and perform a dynamic retinal vessel analysis or nail fold capillary microscopy. This is especially recommended if the patient is relatively young or the damage is progressing rapidly. If the suspicion is confirmed, we then try to reduce the drops in blood pressure, lower the retinal venous pressure, improve the regulation of blood flow and reduce the oxidative stress in the mitochondria.

The Effect of Yoga on Intraocular Pressure Using the "iCare HOME2" Tonometer.

BACKGROUND: Various yoga positions may have an unfavorable impact on intraocular pressure (IOP) and may therefore be seen as a potential risk factor for the progression of glaucoma. The new "iCare HOME2" is a handheld self-tonometer for IOP measurements outside clinical settings. This is the first study to evaluate the immediate effect of common yoga postures on the IOP of healthy and glaucomatous eyes using the "iCare HOME2" self-tonometer and to compare the time of IOP recovery in both groups. METHODS: This is a single-center, prospective, observational study including 25 healthy and 25 glaucoma patients performing the following yoga positions: "legs up" (Viparita Karani), "bend over" (Uttanasana), "plough pose" (Halasana), and the "down face dog" (Adho Mukha Svanasana) for 90 s each, with a 2-min break in between. IOP was measured with the "iCare HOME2" before, during, and after each position. RESULTS: IOP significantly increased in all eyes in all positions (p < 0.05), showing no statistically significant difference between healthy or glaucomatous eyes (p > 0.05). The mean rise in IOP in healthy subjects was 1.6 mmHg (SD 1.42; p = 0.037), 14.4 mmHg (SD 4.48; p < 0.001), 7.5 mmHg (SD 4.21; p < 0.001), and 16.5 mmHg (SD 3.71; p < 0.001), whereas in glaucoma patients, IOP rose by 2.8 mmHg (SD 2.8; p = 0.017), 11.6 mmHg (SD 3.86; p < 0.001), 6.0 mmHg (SD 2.24; p < 0.001), and 15.1 mmHg (SD 4.44; p < 0.001) during the above listed yoga positions, repsectively. The highest increase in IOP was seen in the down face position, reaching mean IOP values above 31 mmHg in both study groups. IOP elevation was observed immediately after assuming the yoga position, with no significant change during the following 90 s of holding each pose (p > 0.05). All IOP values returned to baseline level in all individuals, with no significant difference between healthy and glaucoma participants. CONCLUSION: Our data show that common yoga positions can lead to an acute IOP elevation of up to 31 mmHg in healthy as well as glaucoma eyes, with higher IOP values during head-down positions. Given that IOP peaks are a major risk factor for glaucomatous optic neuropathy, we generally advise glaucoma patients to carefully choose their yoga exercises. If and to what extent practicing yoga leads to glaucoma progression, however, remains unclear and warrants further research.