Thyroid eye disease is a complex inflammatory disorder of the orbit that has gained tremendous interest over the past years, and numerous scientific efforts have been deployed to elucidate its pathophysiology for novel drug development. Our manuscript will delve into the molecular dysregulations involved in the pathogenesis of thyroid eye disease that led to its clinical manifestations. Abnormalities within the apoptotic pathway, inflammatory cascade, and autoimmune regulatory systems will be covered. We will further discuss the challenges involved in its diagnosis and management and provide a summary of the current diagnostic tools (i.e., molecular biomarkers, diagnostic scores) from the perspective of clinicians. Finally, our comprehensive literature review will provide a thorough summary of most recent preclinical and clinical studies around the topic of thyroid eye disease, with an emphasis on the manuscripts published within the last five years. We believe our manuscript will bring novelty within the field by bridging the fundamental sciences with the clinical aspect of this disease. This review will be a great tool for clinicians in better understanding the pathogenesis of thyroid eye disease while providing an outlook on future perspectives (i.e., liquid biopsies, artificial intelligence).

With a common aim of restoring physiological function of defective cells, optogenetics and targeted gene therapies have shown great clinical potential and novelty in the branch of personalized medicine and inherited retinal diseases (IRDs). The basis of optogenetics aims to bypass defective photoreceptors by introducing opsins with light-sensing capabilities. In contrast, targeted gene therapies, such as methods based on CRISPR-Cas9 and RNA interference with noncoding RNAs (i.e., microRNA, small interfering RNA, short hairpin RNA), consists of inducing normal gene or protein expression into affected cells. Having partially leveraged the challenges limiting their prompt introduction into the clinical practice (i.e., engineering, cell or tissue delivery capabilities), it is crucial to deepen the fields of knowledge applied to optogenetics and targeted gene therapy. The aim of this in-depth and novel literature review is to explain the fundamentals and applications of optogenetics and targeted gene therapies, while providing decision-making arguments for ophthalmologists. First, we review the biomolecular principles and engineering steps involved in optogenetics and the targeted gene therapies mentioned above by bringing a focus on the specific vectors and molecules for cell signalization. The importance of vector choice and engineering methods are discussed. Second, we summarize the ongoing clinical trials and most recent discoveries for optogenetics and targeted gene therapies for IRDs. Finally, we then discuss the limits and current challenges of each novel therapy. We aim to provide for the first time scientific-based explanations for clinicians to justify the specificity of each therapy for one disease, which can help improve clinical decision-making tasks.

Intraocular malignant tumors are rare; however, they can cause serious life-threatening complications. Uveal melanoma (UM) and retinoblastoma (RB) are the most common intraocular tumors in adults and children, respectively, and come with a great disease burden. For many years, several different treatment modalities for UM and RB have been proposed, with chemotherapy for RB cases and plaque radiation therapy for localized UM as first-line treatment options. Extraocular extension, recurrence, and metastasis constitute the major challenges of conventional treatments. To overcome these obstacles, immunotherapy, which encompasses different treatment options such as oncolytic viruses, antibody-mediated immune modulations, and targeted immunotherapy, has shown great potential as a novel therapeutic tool for cancer therapy. These anti-cancer treatment options provide numerous advantages such as selective cancer cell death and the promotion of an anti-tumor immune response, and they prove useful in preventing vision impairment due to macular and/or optic disc involvement. Numerous factors such as the vector choice, route of administration, dosing, and patient characteristics must be considered when engineering an oncolytic virus or other forms of immunotherapy vectors. This manuscript provides an in-depth review of the molecular design of oncolytic viruses (e.g., virus capsid proteins and encapsulation technologies, vectors for delivery, cell targeting) and immunotherapy. The most recent advances in preclinical- and clinical-phase studies are further summarized. The recent developments in virus-like drug conjugates (i.e., AU011), oncolytic viruses for metastatic UM, and targeted immunotherapies have shown great results in clinical trials for the future clinical application of these novel technologies in the treatment algorithm of certain intraocular tumors.

Diabetic retinopathy (DR) remains the leading cause of preventable blindness among working-age adults worldwide, driven by the growing prevalence of diabetes mellitus. The aim of this comprehensive literature review is to provide an insightful analysis of recent advances in the pathogenesis of DR, followed by a summary of emerging technologies for its diagnosis and treatment. Recent studies have explored the roles of cell death pathways, immune activation, and lipid peroxidation in the pathology of DR. However, at the core of DR pathology lies neovascularization driven by vascular endothelial growth factor (VEGF), and mitochondrial damage due to dysregulated oxidative stress. These dysregulated pathways manifest clinically as DR, with specific subtypes including non-proliferative DR, proliferative DR and diabetic macular edema, which can be diagnosed through various imaging modalities. Recently, novel advances have been made using liquid biopsy and artificial (AI)-based algorithms with the goal of transforming DR diagnostics. AI models show distinct promise with the capacity to provide automated interpretation of retinal imaging. Furthermore, conventional anti-VEGF injectable agents have revolutionized DR treatment in the past decades. Today, as the pathogenesis of DR becomes better understood, new pathways, such as the ROS-VEGF loop, are being elucidated in greater depth, enabling the development of targeted therapies. In addition, new innovations such as intravitreal implants are transforming the delivery of DR-specific medication. This paper will discuss the current understanding of the pathogenesis of DR, which is leading to new diagnostic and therapeutic tools that will transform clinical management of DR.

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy and remains largely untreatable. This review summarizes RP pathogenesis and critically appraises emerging therapeutic strategies, including gene augmentation, gene editing, RNA-based therapies, gene-agnostic and neuroprotective approaches, stem-cell therapy and their delivery platforms. We compare these strategies according to mutation mechanism, disease stage, durability, delivery route, and current level of clinical evidence. Although several approaches have shown improved structural and functional outcomes in preclinical and early-phase studies, RPE65-directed gene augmentation (voretigen neparvovec) remains the only approved therapy, and even it does not halt degeneration. For most modalities, long-term efficacy, safety, durability and clinical validation are not yet established, and translation is further constrained by delivery, immunogenicity, manufacturing, and cost. Rather than a realized paradigm shift, current evidence points to a rapidly advancing but still largely investigational field with successful clinical translation remaining elusive.