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Precision Medicine in Ocular Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (20 October 2022) | Viewed by 23661

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Dr. De-Kuang Hwang

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Guest Editor

Department of Medical Research, Taipei Veterans General Hospital, Taipei 112201, Taiwan
Interests: ocular inflammation (uveitis); retinal diseases; genes in ocular hereditary and inflammatory diseases; ophthalmic epidemiology; big data analysis; artificial intelligence
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Shih-Jen Chen

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Guest Editor

Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
Interests: diagnosis and treatments of retinal diseases; molecules and genes in ocular diseases; ophthalmic epidemiology; retinal stem cells; retinal prosthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, precision medicine has been widely investigated in many human diseases, including ophthalmology. Recent achievements in predicting drug responses and disease prognosis and stratifying patients according to their genetic makeup are remarkable and are slowly being implemented into clinical guidelines. Ocular diseases are found to possess a strong component of a genetic predisposition, where molecular advances in the understanding of genetic risk, molecular diagnosis, and pathophysiology will influence the patient outcome and derive novel leads for drug development where treatment strategies had been limited to symptom management of many ocular diseases. Furthermore, a greater understanding of the genetic architecture and genetic prevalence will allow active monitoring of the potential blinding of patients and promote effective treatment strategies.

This Special Issue is focused on the genetics of ophthalmic disease and its application into the clinic. Potential topics include, but are not limited, to the following: precision medicine, genetic statistics, polygenic risk score for all ocular pathologies (i.e., age-related macular degeneration, cataract, glaucoma, diabetic retinopathy, uveitis, Sicca syndrome, and inherited retinal dystrophy).

Dr. De-Kuang Hwang
Prof. Dr. Shih-Jen Chen
Guest Editors

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Keywords

precision medicine
statistical genetics
bioinformatics
ocular diseases
aged-related macular degeneration
cataract
diabetic retinopathy

Published Papers (11 papers)

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Research

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12 pages, 1423 KiB

Open AccessArticle

Origin of Retinal Oscillatory Potentials in the Mouse, a Tool to Specifically Locate Retinal Damage

by Fei Liao, Haitao Liu, Santiago Milla-Navarro, Pedro de la Villa and Francisco Germain

Int. J. Mol. Sci. 2023, 24(4), 3126; https://doi.org/10.3390/ijms24043126 - 4 Feb 2023

Cited by 4 | Viewed by 1836

Abstract

To determine the origin of oscillatory potentials (OPs), binocular electroretinogram (ERG) recordings were performed under light and dark adaptation on adult healthy C57BL/6J mice. In the experimental group, 1 μL of PBS was injected into the left eye, while the right eye was injected with 1 μL of PBS containing different agents: APB, GABA, Bicuculline, TPMPA, Glutamate, DNQX, Glycine, Strychnine, or HEPES. The OP response depends on the type of photoreceptors involved, showing their maximum response amplitude in the ERG induced by mixed rod/cone stimulation. The oscillatory components of the OPs were affected by the injected agents, with some drugs inducing the complete abolition of oscillations (APB, GABA, Glutamate, or DNQX), whereas other drugs merely reduced the oscillatory amplitudes (Bicuculline, Glycine, Strychnine, or HEPES) or did not even affect the oscillations (TPMPA). Assuming that rod bipolar cells (RBC) express metabotropic Glutamate receptors, GABA_A, GABA_C, and Glycine receptors and that they release glutamate mainly on Glycinergic AII amacrine cells and GABAergic A17 amacrine cells, which are differently affected by the mentioned drugs, we propose that RBC-AII/A17 reciprocal synapses are responsible for the OP generation in the ERG recordings in the mice. We conclude that the reciprocal synapses between RBC and AII/A17 are the basis of the ERG OP oscillations of the light response, and this fact must be taken into consideration in any ERG test that shows a decrease in the OPs’ amplitude. Full article

(This article belongs to the Special Issue Precision Medicine in Ocular Diseases)

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14 pages, 2371 KiB

Open AccessArticle

Electroretinography as a Biomarker to Monitor the Progression of Stargardt Disease

by Jana Sajovic, Andrej Meglič, Marko Hawlina and Ana Fakin

Int. J. Mol. Sci. 2022, 23(24), 16161; https://doi.org/10.3390/ijms232416161 - 18 Dec 2022

Cited by 2 | Viewed by 1509

Abstract

The aim of the present study is to determine how electroretinographic (ERG) responses reflect age-related disease progression in the Stargardt disease (STGD1). The prospective comparative cohort study included 8 patients harboring two null ABCA4 variants (Group 1) and 34 patients with other ABCA4 genotypes (Group 2). Age at exam, age at onset, visual acuity (VA) and ERG responses were evaluated. The correlation between ERG responses and age in each patient group was determined using linear regression. A Mann-Whitney U Test was used to compare the median values between the groups. Age of onset was significantly earlier in Group 1 than in Group 2 (8 vs. 18), while disease duration was similar (13 vs. 12 years, i.e., advanced stage). Group 1 had significantly worse VA and lower ERG responses. ERG responses that significantly correlated with age in Group 1 were DA 0.01 and 3.0 ERG, which represented a retinal rod system response. The only ERG response that significantly correlated with age in Group 2 was the S-cone ERG. The observed difference was likely due to early cone loss occurring in double-null patients and slower photoreceptor loss in patients with other genotypes. The results suggest that specific ERG responses may be used to detect double-null patients at an early stage and monitor STGD1 disease progression in patients with specific genotypes. Full article

(This article belongs to the Special Issue Precision Medicine in Ocular Diseases)

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11 pages, 1842 KiB

Open AccessArticle

Tear Proteomics Approach to Distinguishing Primary from Secondary Sjögren’s Syndrome for Dry Eye Patients with Long-Term Instillation of Eyedrops

by Yu-Ting Hsiao, Yu-Ting Huang, Hun-Ju Yu, Po-Chiung Fang and Ming-Tse Kuo

Int. J. Mol. Sci. 2022, 23(23), 15239; https://doi.org/10.3390/ijms232315239 - 3 Dec 2022

Cited by 4 | Viewed by 1275

Abstract

The diagnosis and monitoring of Sjögren syndrome (SS) is often difficult, requiring a multidisciplinary approach with invasive procedures. Our aim is to elucidate the tear protein alterations of dry eye disease (DED) with primary SS (pSS) and secondary SS (sSS) with the long-term instillation of eyedrops. We collected clinical demographics and tear fluid (TF) samples from DED patients with no autoimmune diseases (non-SS-DED), pSS-DED, and sSS-DED patients, followed by TF screening with tandem mass tagging-labeling gel-free proteomics assay. Bioinformatic analysis via Ingenuity Pathway Analysis was used to identify functional pathways and interacting networks. Validation of candidate proteins with enzyme-linked immunosorbent assay on the tear samples was done. The top functional pathways of the two comparisons (sSS-DED vs. pSS-DED and sSS-DED vs. non-SS-DED) were both associated with inflammation and stress-related signaling. After constructing an interaction network model with the selected candidate proteins, five proteins were identified. A Disintegrin and Metalloproteinase domain-containing protein 10 (ADAM10) was found to be an important candidate biomarker in all groups, followed by epidermal growth factor (EGF) in TF. This study revealed novel DED markers, ADAM10 and EGF, in differentiating between primary and secondary SS patients from tears by in-depth proteomic analysis. Full article

(This article belongs to the Special Issue Precision Medicine in Ocular Diseases)

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17 pages, 4840 KiB

Open AccessArticle

A New Organotypic 3D Slice Culture of Mouse Meibomian Glands Reveals Impact of Melanocortins

by Ingrid Zahn, Fabian Garreis, Martin Schicht, Vera Rötzer, Jens Waschke, Yuqiuhe Liu, Valerian L. Altersberger, Friedrich Paulsen and Jana Dietrich

Int. J. Mol. Sci. 2022, 23(23), 14947; https://doi.org/10.3390/ijms232314947 - 29 Nov 2022

Cited by 3 | Viewed by 1963

Abstract

The meibomian glands (MGs) within the eyelids produce a lipid-rich secretion that forms the superficial layer of the tear film. Meibomian gland dysfunction (MGD) results in excessive evaporation of the tear film, which is the leading cause of dry eye disease (DED). To develop a research model similar to the physiological situation of MGs, we established a new 3D organotypic slice culture (OSC) of mouse MGs (mMGs) and investigated the effects of melanocortins on exocrine secretion. Tissue viability, lipid production and morphological changes were analyzed during a 21-day cultivation period. Subsequently, the effects on lipid production and gene expression were examined after stimulation with a melanocortin receptor (MCR) agonist, α-melanocyte-stimulating hormone (α-MSH), and/or an MCR antagonist, JNJ-10229570. The cultivation of mMGs OSCs was possible without impairment for at least seven days. Stimulation with the MCR agonists induced lipid production in a dose-dependent manner, whereas this effect was tapered with the simultaneous incubation of the MCR antagonist. The new 3D OSC model is a promising approach to study the (patho-) physiological properties of MG/MGD while reducing animal studies. Therefore, it may accelerate the search for new treatments for MGD/DED and lead to new insights, such as that melanocortins likely stimulate meibum production. Full article

(This article belongs to the Special Issue Precision Medicine in Ocular Diseases)

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13 pages, 2732 KiB

Open AccessArticle

Diagnostic Odyssey in an Adult Patient with Ophthalmologic Abnormalities and Hearing Loss: Contribution of RNA-Seq to the Diagnosis of a PEX1 Deficiency

by Gerard Muñoz-Pujol, Socorro Alforja-Castiella, Ricardo Casaroli-Marano, Blai Morales-Romero, Judit García-Villoria, Vicente A. Yépez, Julien Gagneur, Mirjana Gusic, Holger Prokisch, Frederic Tort and Antonia Ribes

Int. J. Mol. Sci. 2022, 23(20), 12367; https://doi.org/10.3390/ijms232012367 - 15 Oct 2022

Cited by 1 | Viewed by 1689

Abstract

Peroxisomal biogenesis disorders (PBDs) are a heterogeneous group of genetic diseases. Multiple peroxisomal pathways are impaired, and very long chain fatty acids (VLCFA) are the first line biomarkers for the diagnosis. The clinical presentation of PBDs may range from severe, lethal multisystemic disorders to milder, late-onset disease. The vast majority of PBDs belong to Zellweger Spectrum Disordes (ZSDs) and represents a continuum of overlapping clinical symptoms, with Zellweger syndrome being the most severe and Heimler syndrome the less severe disease. Mild clinical conditions frequently present normal or slight biochemical alterations, making the diagnosis of these patients challenging. In the present study we used a combined WES and RNA-seq strategy to diagnose a patient presenting with retinal dystrophy as the main clinical symptom. Results showed the patient was compound heterozygous for mutations in PEX1. VLCFA were normal, but retrospective analysis of lysosphosphatidylcholines (LPC) containing C22:0–C26:0 species was altered. This simple test could avoid the diagnostic odyssey of patients with mild phenotype, such as the individual described here, who was diagnosed very late in adult life. We provide functional data in cell line models that may explain the mild phenotype of the patient by demonstrating the hypomorphic nature of a deep intronic variant altering PEX1 mRNA processing. Full article

(This article belongs to the Special Issue Precision Medicine in Ocular Diseases)

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20 pages, 2336 KiB

Open AccessArticle

An Extensive Study of Phenol Red Thread as a Novel Non-Invasive Tear Sampling Technique for Proteomics Studies: Comparison with Two Commonly Used Methods

by Gábor Kecskeméti, Edit Tóth-Molnár, Tamás Janáky and Zoltán Szabó

Int. J. Mol. Sci. 2022, 23(15), 8647; https://doi.org/10.3390/ijms23158647 - 3 Aug 2022

Cited by 2 | Viewed by 1762

Abstract

Tear samples are considered in recent publications as easily, noninvasively collectible information sources for precision medicine. Their complex composition may aid the identification of biomarkers and the monitoring of the effectiveness of treatments for the eye and systemic diseases. Sample collection and processing are key steps in any analytical method, especially if subtle personal differences need to be detected. In this work, we evaluate the usability of a novel sample collection technique for human tear samples using phenol red threads (cotton thread treated with the pH indicator phenol red), which are efficiently used to measure tear volume in clinical diagnosis. The low invasiveness and low discomfort to the patients have already been demonstrated, but their applicability for proteomic sample collection has not yet been compared to other methods. We have shown, using various statistical approaches, the qualitative and quantitative differences in proteomic samples collected with this novel and two traditional methods using either glass capillaries or Schirmer’s paper strips. In all parameters studied, the phenol red threads proved to be equally or even more suitable than traditional methods. Based on detectability using different sampling methods, we have classified proteins in tear samples. Full article

(This article belongs to the Special Issue Precision Medicine in Ocular Diseases)

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13 pages, 3494 KiB

Open AccessArticle

Use of OCT Angiography to Diagnose and Manage Atypical Presentations of Macular Telangiectasia Type 2

by John Moir, Shivam V. Amin, Saira Khanna, Rahul Komati, Lincoln T. Shaw, David Dao, Seenu M. Hariprasad and Dimitra Skondra

Int. J. Mol. Sci. 2022, 23(14), 7849; https://doi.org/10.3390/ijms23147849 - 16 Jul 2022

Cited by 2 | Viewed by 2170

Abstract

Macular telangiectasia Type 2 (MacTel) is a bilateral acquired retinal disease characterized by both vascular changes and atrophy of the retina. The purpose of this case series is to highlight the use of optical coherence tomography angiography (OCTA) as a non-invasive imaging modality to distinguish atypical MacTel from other macular conditions with similar presentations. We performed a retrospective review of patients referred to our academic retinal practice with unconfirmed or misdiagnosed MacTel between July 2017 and July 2021. Patients’ OCTA imaging findings were reviewed to guide the appropriate diagnosis and management of atypical MacTel. Fifteen eyes from eight patients were included in this study. Six patients were referred with previous diagnoses of either full-thickness macular hole, lamellar hole, vitreomacular traction (VMT), postoperative cystoid macular edema (CME), or diabetic macular edema (DME). Two patients were referred to us to confirm the diagnosis of MacTel. OCTA revealed telangiectatic vessels in the temporal parafovea of all 15 eyes. OCTA also highlighted previously undiagnosed subretinal neovascularization (SRNV) in seven eyes. OCTA imaging is a valuable imaging modality to distinguish MacTel from other macular conditions, whose treatment courses vary substantially. Due to its ease of use, it holds immense potential in the future as treatments for non-proliferative MacTel emerge. Full article

(This article belongs to the Special Issue Precision Medicine in Ocular Diseases)

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14 pages, 4901 KiB

Open AccessArticle

Layer-by-Layer Investigation of Ultrastructures and Biomechanics of Human Cornea

by Erick Rafael Dias Rates, Charles Duarte Almeida, Elaine de Paula Fiod Costa, Roberta Jansen de Mello Farias, Ralph Santos-Oliveira and Luciana Magalhães Rebelo Alencar

Int. J. Mol. Sci. 2022, 23(14), 7833; https://doi.org/10.3390/ijms23147833 - 15 Jul 2022

Cited by 6 | Viewed by 1850

Abstract

The cornea is an avascular, innervated, and transparent tissue composed of five layers: the epithelium, Bowman’s layer, stroma, Descemet’s membrane, and endothelium. It is located in the outermost fraction of the eyeball and is responsible for the refraction of two-thirds of light and protection from external mechanical damage. Although several studies have been done on the cornea on the macroscopic scale, there is a lack of studies on the micro-nanoscopic scale, especially an analysis evaluating the cornea layer by layer. In this study, atomic force microscopy (AFM) was employed to assess four layers that form the cornea, analyzing: adhesion, stiffness, and roughness. The results showed microvilli in the epithelial and endothelial layers, pores in the basement membrane, and collagen fibers in the Stroma. These data increase the knowledge about the human cornea layers’ ultrastructures and adds new information about its biophysical properties. Full article

(This article belongs to the Special Issue Precision Medicine in Ocular Diseases)

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16 pages, 2656 KiB

Open AccessArticle

The Potential Role of SP-G as Surface Tension Regulator in Tear Film: From Molecular Simulations to Experimental Observations

by Martin Schicht, Kamila Riedlová, Mercedes Kukulka, Wenyue Li, Aurelius Scheer, Fabian Garreis, Christina Jacobi, Friedrich Paulsen, Lukasz Cwiklik and Lars Bräuer

Int. J. Mol. Sci. 2022, 23(10), 5783; https://doi.org/10.3390/ijms23105783 - 21 May 2022

Cited by 2 | Viewed by 1942

Abstract

The ocular surface is in constant interaction with the environment and with numerous pathogens. Therefore, complex mechanisms such as a stable tear film and local immune defense mechanisms are required to protect the eye. This study describes the detection, characterization, and putative role of surfactant protein G (SP-G/SFTA2) with respect to wound healing and surface activity. Bioinformatic, biochemical, and immunological methods were combined to elucidate the role of SP-G in tear film. The results show the presence of SP-G in ocular surface tissues and tear film (TF). Increased expression of SP-G was demonstrated in TF of patients with dry eye disease (DED). Addition of recombinant SP-G in combination with lipids led to an accelerated wound healing of human corneal cells as well as to a reduction of TF surface tension. Molecular modeling of TF suggest that SP-G may regulate tear film surface tension and improve its stability through specific interactions with lipids components of the tear film. In conclusion, SP-G is an ocular surface protein with putative wound healing properties that can also reduce the surface tension of the tear film. Full article

(This article belongs to the Special Issue Precision Medicine in Ocular Diseases)

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Review

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13 pages, 811 KiB

Open AccessReview

New Insights into Treating Early and Advanced Stage Diabetic Retinopathy

by Rafael Simó and Cristina Hernández

Int. J. Mol. Sci. 2022, 23(15), 8513; https://doi.org/10.3390/ijms23158513 - 31 Jul 2022

Cited by 13 | Viewed by 2924

Abstract

Diabetic retinopathy (DR) is the leading cause of preventable blindness in the working-age population. The disease progresses slowly, and we can roughly differentiate two stages: early-stage (ESDR), in which there are mild retinal lesions and visual acuity is generally preserved, and advanced-stage (ASDR), in which the structural lesions are significant and visual acuity is compromised. At present, there are no specific treatments for ESDR and the current recommended action is to optimize metabolic control and maintain close control of blood pressure. However, in the coming years, it is foreseeable that therapeutic strategies based in neuroprotection will be introduced in the clinical arena. This means that screening aimed at identifying patients in whom neuroprotective treatment might be beneficial will be crucial. Regarding the treatment of ASDR, the current primary course is based on laser photocoagulation and intravitreal injections of anti-angiogenic factors or corticosteroids. Repeated intravitreal injections of anti-VEGF agents as the first-line treatment would be replaced by more cost-effective and personalized treatments based on the results of “liquid biopsies” of aqueous humor. Finally, topical administration (i.e., eye drops) of neuroprotective, anti-inflammatory and anti-angiogenic agents will represent a revolution in the treatment of DR in the coming decade. In this article, all these approaches and others will be critically discussed from a holistic perspective. Full article

(This article belongs to the Special Issue Precision Medicine in Ocular Diseases)

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21 pages, 1137 KiB

Open AccessReview

Tools and Biomarkers for the Study of Retinal Ganglion Cell Degeneration

by Ciriaco Corral-Domenge, Pedro de la Villa, Alicia Mansilla and Francisco Germain

Int. J. Mol. Sci. 2022, 23(8), 4287; https://doi.org/10.3390/ijms23084287 - 13 Apr 2022

Cited by 6 | Viewed by 3446

Abstract

The retina is part of the central nervous system, its analysis may provide an idea of the health and functionality, not only of the retina, but also of the entire central nervous system, as has been shown in Alzheimer’s or Parkinson’s diseases. Within the retina, the ganglion cells (RGC) are the neurons in charge of processing and sending light information to higher brain centers. Diverse insults and pathological states cause degeneration of RGC, leading to irreversible blindness or impaired vision. RGCs are the measurable endpoints in current research into experimental therapies and diagnosis in multiple ocular pathologies, like glaucoma. RGC subtype classifications are based on morphological, functional, genetical, and immunohistochemical aspects. Although great efforts are being made, there is still no classification accepted by consensus. Moreover, it has been observed that each RGC subtype has a different susceptibility to injury. Characterizing these subtypes together with cell death pathway identification will help to understand the degenerative process in the different injury and pathological models, and therefore prevent it. Here we review the known RGC subtypes, as well as the diagnostic techniques, probes, and biomarkers for programmed and unprogrammed cell death in RGC. Full article

(This article belongs to the Special Issue Precision Medicine in Ocular Diseases)

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