Beyond hypertrophy: Changing views of astrocytes in glaucoma.

Astrocytes serve multiple roles in helping to maintain homeostatic physiology of central nervous system tissue, ranging from metabolic support to coupling between vascular and neural elements. Astrocytes are especially critical in axonal tracts such as the optic nerve, where axons propagate energy-demanding action potentials great distances. In disease, astrocyte remodeling is a dynamic, multifaceted process that is often over-simplified between states of quiescence and reactivity. In glaucoma, axon degeneration in the optic nerve is characterized by progressive stages. So too is astrocyte remodeling. Here, using quantitative analysis of light and electron micrographs of myelinated optic nerve sections from the DBA/2J mouse model of glaucoma, we offer further insight into how astrocyte organization reflects stages of degeneration. This analysis indicates that even as axons degenerate, astrocyte gliosis in the nerve increases without abject proliferation, similar to results in the DBA/2J retina. Gliosis is accompanied by reorganization. As axons expand prior to frank degeneration, astrocyte processes retract from the extra-axonal space and reorient towards the nerve edge. After a critical threshold of expansion, axons drop out, and astrocyte processes distribute more evenly across the nerve reflecting gliosis. This multi-stage process likely reflects local rather than global cues from axons and the surrounding tissue that induce rapid reorganization to promote axon survival and extend functionality of the nerve.

Addressing neurodegeneration in glaucoma: Mechanisms, challenges, and treatments.

Glaucoma is the leading cause of irreversible blindness globally. The disease causes vision loss due to neurodegeneration of the retinal ganglion cell (RGC) projection to the brain through the optic nerve. Glaucoma is associated with sensitivity to intraocular pressure (IOP). Thus, mainstay treatments seek to manage IOP, though many patients continue to lose vision. To address neurodegeneration directly, numerous preclinical studies seek to develop protective or reparative therapies that act independently of IOP. These include growth factors, compounds targeting metabolism, anti-inflammatory and antioxidant agents, and neuromodulators. Despite success in experimental models, many of these approaches fail to translate into clinical benefits. Several factors contribute to this challenge. Firstly, the anatomic structure of the optic nerve head differs between rodents, nonhuman primates, and humans. Additionally, animal models do not replicate the complex glaucoma pathophysiology in humans. Therefore, to enhance the success of translating these findings, we propose two approaches. First, thorough evaluation of experimental targets in multiple animal models, including nonhuman primates, should precede clinical trials. Second, we advocate for combination therapy, which involves using multiple agents simultaneously, especially in the early and potentially reversible stages of the disease. These strategies aim to increase the chances of successful neuroprotective treatment for glaucoma.

A Phase 2 Trial to Test Safety and Efficacy of ST-100, a Unique Collagen Mimetic Peptide Ophthalmic Solution for Dry Eye Disease.

Objective: Dry eye disease (DED) is a worldwide source of ocular discomfort. This first-in-human phase 2 clinical study determined the efficacy of treating signs and symptoms of DED using an ophthalmic solution of synthesized mimetic of human collagen (ST-100). Design: This double-masked, randomized, study compared high (60 µg/mL) and low (22 µg/mL) dose ST-100 to vehicle utilizing the Ora, Inc. Controlled Adverse Environment (CAE) during a 28-day period. Participants: Participants included males and females ≥ 18 years of age with signs and symptoms of DED for ≥ 6 months that worsened during CAE exposure who were not taking any topical prescription therapeutic. Intervention: Participants applied ST-100 or vehicle placebo topically to both corneas (1 drop) twice daily via a blow-fill-sealed preservative-free container. Main Outcome Measures: The prespecified primary efficacy sign end point was mean change from baseline (CFB) in total corneal fluorescein staining, and the primary symptom end point was mean CFB in ocular discomfort. A secondary prespecified efficacy end point was CFB in unanesthetized Schirmer's test for tear film production. Results: Of 160 subjects in the intent-to-treat population (112 female, 48 male, median age 64), 146 completed the study. Total corneal fluorescein staining CFB improved for high-dose ST-100, with superiority over vehicle when both eyes were considered together (2-sample t test: P = 0.0394). High-dose ST-100 was superior to vehicle in Schirmer's CFB for the study eye (least squares mean difference [confidence interval] = 2.3 [0.6, 4.0], P = 0.0094). For study eyes, the proportion of Schirmer's test responders (CFB ≥ 10 mm, Schirmer's responder rate) was 12.2% for high-dose ST-100 versus 0.0% for vehicle (P = 0.0266). The CFB for ocular discomfort score improved in study eyes for high- and low-dose ST-100 (paired t test, P = 0.0133, P = 0.0151, respectively) but without superiority over vehicle (ANCOVA: P = 0.5696, P = 0.8968, respectively). ST-100 Schirmer's responders also demonstrated total elimination of worsening of corneal fluorescein stain during the stress of CAE sessions. Conclusions: ST-100 significantly improved tear production and related outcomes in DED and was well-tolerated in reducing symptoms. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Collagen in the central nervous system: contributions to neurodegeneration and promise as a therapeutic target.

The extracellular matrix is a richly bioactive composition of substrates that provides biophysical stability, facilitates intercellular signaling, and both reflects and governs the physiological status of the local microenvironment. The matrix in the central nervous system (CNS) is far from simply an inert scaffold for mechanical support, instead conducting an active role in homeostasis and providing broad capacity for adaptation and remodeling in response to stress that otherwise would challenge equilibrium between neuronal, glial, and vascular elements. A major constituent is collagen, whose characteristic triple helical structure renders mechanical and biochemical stability to enable bidirectional crosstalk between matrix and resident cells. Multiple members of the collagen superfamily are critical to neuronal maturation and circuit formation, axon guidance, and synaptogenesis in the brain. In mature tissue, collagen interacts with other fibrous proteins and glycoproteins to sustain a three-dimensional medium through which complex networks of cells can communicate. While critical for matrix scaffolding, collagen in the CNS is also highly dynamic, with multiple binding sites for partnering matrix proteins, cell-surface receptors, and other ligands. These interactions are emerging as critical mediators of CNS disease and injury, particularly regarding changes in matrix stiffness, astrocyte recruitment and reactivity, and pro-inflammatory signaling in local microenvironments. Changes in the structure and/or deposition of collagen impact cellular signaling and tissue biomechanics in the brain, which in turn can alter cellular responses including antigenicity, angiogenesis, gliosis, and recruitment of immune-related cells. These factors, each involving matrix collagen, contribute to the limited capacity for regeneration of CNS tissue. Emerging therapeutics that attempt to rebuild the matrix using peptide fragments, including collagen-enriched scaffolds and mimetics, hold great potential to promote neural repair and regeneration. Recent evidence from our group and others indicates that repairing protease-degraded collagen helices with mimetic peptides helps restore CNS tissue and promote neuronal survival in a broad spectrum of degenerative conditions. Restoration likely involves bolstering matrix stiffness to reduce the potential for astrocyte reactivity and local inflammation as well as repairing inhibitory binding sites for immune-signaling ligands. Facilitating repair rather than endogenous replacement of collagen degraded by disease or injury may represent the next frontier in developing therapies based on protection, repair, and regeneration of neurons in the central nervous system.