Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and mitochondrial. These diseases are most often the result of defects in rod and/or cone photoreceptor and retinal pigment epithelium function, development, or both. The genes associated with these diseases, when mutated, produce altered protein products that have downstream effects in pathways critical to vision, including phototransduction, the visual cycle, photoreceptor development, cellular respiration, and retinal homeostasis. The aim of this manuscript is to provide a comprehensive review of the underlying molecular mechanisms of pathogenesis of IRDs by delving into many of the genes associated with IRD development, their protein products, and the pathways interrupted by genetic mutation.

Background: To evaluate the accuracy of Chat Generative Pre-Trained Transformer (ChatGPT), a large language model (LLM), to assist in diagnosing neuro-ophthalmic diseases based on case reports. Methods: We selected 22 different case reports of neuro-ophthalmic disorders from a publicly available online database. These cases included a wide range of chronic and acute diseases commonly seen by neuro-ophthalmologists. We inserted each case as a new prompt into ChatGPTs (GPT-3.5 and GPT-4) and asked for the most likely diagnosis. We then presented the exact information to 2 neuro-ophthalmologists and recorded their diagnoses, followed by comparing responses from both versions of ChatGPT. Results: GPT-3.5 and GPT-4 and the 2 neuro-ophthalmologists were correct in 13 (59%), 18 (82%), 19 (86%), and 19 (86%) out of 22 cases, respectively. The agreements between the various diagnostic sources were as follows: GPT-3.5 and GPT-4, 13 (59%); GPT-3.5 and the first neuro-ophthalmologist, 12 (55%); GPT-3.5 and the second neuro-ophthalmologist, 12 (55%); GPT-4 and the first neuro-ophthalmologist, 17 (77%); GPT-4 and the second neuro-ophthalmologist, 16 (73%); and first and second neuro-ophthalmologists 17 (77%). Conclusions: The accuracy of GPT-3.5 and GPT-4 in diagnosing patients with neuro-ophthalmic disorders was 59% and 82%, respectively. With further development, GPT-4 may have the potential to be used in clinical care settings to assist clinicians in providing accurate diagnoses. The applicability of using LLMs like ChatGPT in clinical settings that lack access to subspeciality trained neuro-ophthalmologists deserves further research.

Corneal penetration is a key rate limiting step in the bioavailability of topical ophthalmic formulations that incorporate poorly permeable drugs. Recent advances have greatly aided the ocular delivery of such drugs using colloidal drug delivery systems. Ribavirin, a poorly permeable BCS class-III drug, was incorporated in bioadhesive multiple W/O/W microemulsion (ME) to improve its corneal permeability. The drug-loaded ME was evaluated regarding its physical stability, droplet size, PDI, zeta potential, ultrastructure, viscosity, bioadhesion, in vitro release, transcorneal permeability, cytotoxicity, safety and ocular tolerance. Our ME possessed excellent physical stability, as it successfully passed several cycles of centrifugation and freeze–thaw tests. The formulation has a transparent appearance due to its tiny droplet size (10 nm). TEM confirmed ME droplet size and revealed its multilayered structure. In spite of the high aqueous solubility and the low permeability of ribavirin, this unique formulation was capable of sustaining its release for up to 24 h and improving its corneal permeability by 3-fold. The in vitro safety of our ME was proved by its high percentage cell viability, while its in vivo safety was confirmed by the absence of any sign of toxicity or irritation after either a single dose or 14 days of daily dosing. Our ME could serve as a vehicle for enhanced ocular delivery of drugs with different physicochemical properties, including those with low permeability.

Mononuclear phagocytes (MPs) play a crucial role in tissue homeostasis; however, MPs also contribute to tumor progression and resistance to immune checkpoint blockade (ICB). Targeting MPs could be an effective strategy to enhance ICB efficacy. We report that protein kinase C delta (PKCδ), a serine/threonine kinase, is abundantly expressed by MPs in human and mouse tumors. PKCδ ^−/− mice displayed reduced tumor progression compared to wild types, with increased response to anti–PD-1. Tumors from PKCδ ^−/− mice demonstrated T _H 1-skewed immune response including increased antigen presentation and T cell activation. Depletion of MPs in vivo altered tumor growth in control but not PKCδ ^−/− mice. Coinjection of PKCδ ^−/− M2-like macrophages with cancer cells into wild-type mice markedly delayed tumor growth and significantly increased intratumoral T cell activation compared to PKCδ ^+/+ controls. PKCδ deficiency reprogrammed MPs by activating type I and type II interferon signaling. Thus, PKCδ might be targeted to reprogram MPs to augment ICB efficacy.

Retinitis pigmentosa (RP) is a hereditary disease of the retina that results in complete blindness. Currently, there are very few treatments for the disease and those that exist work only for the recessively inherited forms. To better understand the pathogenesis of RP, multiple mouse models have been generated bearing mutations found in human patients including the human Q344X rhodopsin knock-in mouse. In recent years, the immune system was shown to play an increasingly important role in RP degeneration. By way of electroretinography, optical coherence tomography, funduscopy, fluorescein angiography, and fluorescent immunohistochemistry, we show degenerative and vascular phenotypes, microglial activation, photoreceptor phagocytosis, and upregulation of proinflammatory pathway proteins in the retinas of the human Q344X rhodopsin knock-in mouse. We also show that an FDA-approved pharmacological agent indicated for the treatment of rheumatoid arthritis is able to halt activation of pro-inflammatory signaling in cultured retinal cells, setting the stage for pre-clinical trials using these mice to inhibit proinflammatory signaling in an attempt to preserve vision. We conclude from this work that pro- and autoinflammatory upregulation likely act to enhance the progression of the degenerative phenotype of rhodopsin Q344X-mediated RP and that inhibition of these pathways may lead to longer-lasting vision in not only the Q344X rhodopsin knock-in mice, but humans as well.

Inherited retinal dystrophies (RDs) are heterogenous in many aspects including genes involved, age of onset, rate of progression, and treatments. While RDs are caused by a plethora of different mutations, all result in the same outcome of blindness. While treatments, both gene therapy-based and drug-based, have been developed to slow or halt disease progression and prevent further blindness, only a small handful of the forms of RDs have treatments available, which are primarily for recessively inherited forms. Using immunohistochemical methods coupled with electroretinography, optical coherence tomography, and fluorescein angiography, we show that in rhodopsin mutant mice, the involvement of both the innate and the autoimmune systems could be a strong contributing factor in disease progression and pathogenesis. Herein, we show that monocytic phagocytosis and inflammatory cytokine release along with protein citrullination, a major player in forms of autoimmunity, work to enhance the progression of RD associated with a rhodopsin mutation.