1. Early detection of retinal damage
1a. Early detection of retinal damage by non-invasive imaging techniques
Early detection of glaucoma is challenging because the disease often lacks obvious symptoms or pain, making it too late for intervention when there is already irreversible and massive RGC death. In glaucoma management, one of the main parameters is the thinning of the retinal nerve fiber layer (RNFL), which is formed by RGC axons. Current commercial OCT devices use a near-infrared (NIR) light source to monitor alterations in RNFL thickness in eye diseases. However, NIR-OCT often fails to detect subtle changes in the RNFL, and significant RNFL thinning usually correlates with late-stage RGC death. Therefore, our goal is to establish a new biomarker for neural damage in early glaucoma.
In the past nine years, I have developed an innovative imaging technique, the vis-OCT fibergram (vis-OCTF), in collaboration with Dr. Hao Zhang at Northwestern University, for visualization and quantification of RGC axon bundle patterning in wild-type mice and mice with retinal damage (Song et al., 2013; Chen et al., 2015; Yi et al., 2016; Grannonico et al., 2021; Miller et al., 2020; Grannonico et al., 2023). We were the first to show that RGC axon bundle damage documented by vis-OCTF is a more sensitive and accurate indicator of RGC damage than the widely used RNFL and ganglion cell inner plexiform layer (GCIPL) thicknesses in mouse models of glaucoma. This advancement not only enhances our understanding of disease progression at a finer anatomical level but also holds promise for the early detection of retinal damage in patients suspected of having glaucoma.
1b. Tree Shrew is a valuable bridge between mice and humans in glaucoma research
Mouse glaucoma models have been widely used to study RGC damage and its underlying mechanisms due to their well-established disease models and the availability of genetic tools. Indeed, we developed our vis-OCT system and its associated analytic tools using mouse models. However, as nocturnal animals, the total number of RGCs in a mouse retina is less than 10% of that in primate retinas, reflecting a primitive visual system. To enhance the translation of retina research from mouse models to humans, we have adopted the tree shrew (Tupaia belangeri) as a valuable intermediary. Tree shrews, being diurnal para-primates, have played a pivotal role in visual neuroscience over the past five decades. With superior color vision, a fovea-like structure (primitive visual streak), and well-developed visual pathways, tree shrews serve as an excellent model for understanding eye development, health, and disease. We are the first to examine the tree shrew retina in vivo by vis-OCT. Our recent findings showed that shrew retina features a dense RNFL and a thick GCL, making the inner retinal structure more akin to that of humans compared to mice. Therefore, we are working to develop tree shrew retina as a model system for glaucoma research. Leveraging tree shrew eyes for retinal imaging will provide valuable insights for developing novel biomarkers for RGC damage, surpassing the limitations posed by mouse models.
1c. Clinical application of vis-OCTF to monitor patients’ retinal damage
As vis-OCT offers significantly improved spatial resolution and sensitivity compared to commercially available NIR-OCT, we are testing this novel imaging system in patients with various eye diseases. The Institutional Review Boards (IRB) at UVA have approved two studies: 'Evaluation of Longitudinal Changes in Retinal Layer Structure in Acute, Subacute, and Chronic Optic Neuropathies Using Visible Light OCT' (HSR210376) and 'Evaluation of Longitudinal Changes of the Retinal Layer Structure in Young and Adult Aniridia' (HSR230455). In collaboration with glaucoma experts Dr. Peter Netland and Dr. Michael Krause at UVA Ophthalmology, we are applying this innovative vis-OCT technology to capture detailed retina images of patients' eyes, alongside age-matched healthy volunteers. Additionally, we are optimizing the vis-OCTF imaging system for more efficient clinical use. The detailed axon bundle structures captured by vis-OCT can be further analyzed for early signs of RGC damage.
As pioneers in the field, we are proud to be among the first groups implementing this novel imaging technology and its associated analytic tools. By doing so, we aim to establish comprehensive individual records that will provide doctors with invaluable insights into the dynamic changes occurring in the neural retina over time.
2. Understanding retinal development and degeneration
2a. Normal development and function of the retina and the visual system
Understanding the normal development of the RGC complex yet characteristic morphology will help in comprehending the misregulation of RGC development and synaptic function that results in devastating vision loss in eye diseases. For example, we developed a new analytic tool to examine the visual-response properties of RGCs using a multi-electrode array recording system (Cantrell et al., 2010; Chen et al., 2014). Using this system, we characterized the maturation of type-specific RGCs and showed that NT-3 modulates the maturation of RGC light-response properties (Cantrell et al., 2010). Moreover, I have had a long and successful collaboration with Jianhua Cang's laboratory to investigate the visual signal transformation from the retina to higher visual centers in the brain (e.g., Wang et al., 2009; Rangarajan, Lawhn-Heath et al., 2011; Zhao et al., 2013; Inayat et al., 2015; Shi et al., 2017). One recent achievement includes the establishment of the tree shrew eye model system. These collective efforts provide a foundational understanding of how disruptions in visual system function occur in glaucoma and offer insights into strategies for preserving vision in patients with eye diseases.
2b. ipRGC in Glaucoma
We previously established a mouse model of chronic intraocular pressure (IOP) elevation, mimicking human tension-related glaucoma (Feng et al., 2013a; Feng et al., 2013b; Chen et al., 2015). This model allowed us to investigate how different populations of RGCs respond to the disease insult and the underlying mechanisms involved (Puyang et al., 2016; Feng et al., 2017). Our work was among the first to show that RGC degeneration is type-dependent (Chen et al., 2015) and that BDNF can protect RGCs in a type-specific manner against both acute optic nerve injury (Feng et al., 2017) and chronic IOP elevation (Feng et al., 2016).
After I moved to UVA, Dr. Provencio and I established another successful collaboration to examine the differential survival of intrinsically photosensitive retinal ganglion cells (ipRGCs) and its functional consequences in animal models of glaucoma. Our studies demonstrate that ipRGCs, similar to other types of RGCs, degenerate and die in a type-dependent manner in glaucoma. We continue to characterize how glaucoma affects ipRGC circuitry, particularly how light information impacts sleep-wake rhythmicity and anxiety. Given the high prevalence of sleep and mood disorders among patients with glaucoma, our study provides valuable insights into ipRGC-mediated circuitry and its potential influence on glaucoma management. These studies have been well received and highly cited in the field.
3. Drug delivery to the retina for neuroprotection
One of the main hurdles to translate basic research to clinical care for neuroprotective therapy is how to deliver the drugs efficiently in a long-lasting manner. Because elevated IOP is a main risk factor, all antiglaucoma drugs are to lower or control IOP; and studies suggested that controlled IOP slows down vision loss with glaucoma progression. Topical application of antiglaucoma drugs is considered the most desirable delivery method, but the bioavailability of drugs is low, and most drugs exhibit antiglaucoma effects shorter than a day. When multiple drugs are combined, they are unlikely to reach the eye in the amounts as prescribed. In other words, it remains a challenge to achieve a consistent and synchronized release of antiglaucoma drugs for optimal therapeutic outcomes.
In 2019, I established the collaboration with Dr. Yang while he was at the Virginia Commonwealth University to investigate novel drug delivery systems using animal glaucoma models. Our goal is to design and establish novel drug delivery systems to maximize antiglaucoma therapeutic benefits. We developed a new formulation system using the nanostructured dendrimer hydrogel particles (nDHPs) and tested the formulated drug(s) in controlling IOP in mouse models of glaucoma. Dr Yang’s group continues to optimize the nDHP-based monotherapy and fixed-combination formulations for anti-glaucoma drugs, and we will examine the formulated drugs on IOP regulation, neural and vision damage in our mouse glaucoma models. The current work is supported by an ongoing R01 (2023-2028) and will lead to new, versatile, and efficient formations for better glaucoma management.
https://www.ncbi.nlm.nih.gov/myncbi/xiaorong.liu.1/bibliography/public/