Update on Gene Therapy Clinical Trials for Eye Diseases.

P2X purinoceptor 7 receptor (P2X7R) is an ATP-gated ion channel that, upon activation by ATP, triggers the release of inflammatory mediators and induces apoptosis in cells. This channel plays a crucial role in the onset and progression of various diseases. Recently, there has been a growing body of research focused on the function of P2X7R receptors in ophthalmic conditions, particularly concerning retinal diseases such as age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa. This article is to provide a comprehensive review of the advancements in the study of P2X7R and its association with retinal diseases, elucidating its role in these conditions and identifying potential avenues for future research. Electronic databases, including PubMed, Web of Science, and Wan fang Data were searched for relevant literature. The following keywords were used: "P2X7R", Age-related macular degeneration", "Diabetic retinopathy", "Retinitis pigmentosa". Both preclinical and clinical studies were included to provide a holistic understanding of P2X7R's role in retinal pathology. P2X7R activation exacerbates retinal diseases by promoting inflammation and apoptosis. However, its role in disease progression and homeostasis complicates therapeutic targeting, highlighting the need for selective inhibitors and further research into its context-dependent functions. P2X7R plays a critical role in the pathogenesis of retinal diseases. At the same time, preclinical studies suggest that P2X7R inhibition holds promise as a therapeutic strategy. Future research should focus on developing selective P2X7R inhibitors, elucidating the receptor's role in different disease stages, and identifying biomarkers to guide personalized treatment. Addressing these challenges will be essential for translating P2X7R-targeted therapies into clinical practice and improving outcomes for patients with retinal diseases.

Cellular Transplants, 20 Years Later: The Pharma Initiative

Optogenetics, a cutting-edge tool in novel gene manipulation and drug discovery, holds significant therapeutic potential for a variety of neurological disorders, including retinal diseases. Retinal diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), significantly impair quality of life and cause severe visual impairment due to limited treatment options and a general lack of awareness. The increasing incidence of these degenerative conditions underscores the need for innovative solutions, such as optogenetics. Optogenetic therapy introduces genes coding for light-sensitive proteins, which are controlled by light signals to make neurons photosensitive. This precise targeting approach does not require specific gene intervention and can bypass dysfunctional photoreceptors, offering a treatment option for various degenerative and dystrophic eye diseases. Successful outcomes in patients with late-stage genetic retinal diseases and numerous clinical trials suggest that optogenetics could be an effective treatment for humans. This review provides an overview of the current landscape of optogenetic therapy, discusses its challenges, and summarizes the findings of ongoing clinical trials for neural and visual restoration.

Retinal diseases like age-related macular degeneration, diabetic retinopathy, and retinitis pigmentosa are major causes of vision loss. Stem cell therapy offers a regenerative approach, utilizing embryonic, induced pluripotent, mesenchymal, and retinal progenitor cells for retinal repair. This review explores advancements in stem cell therapy, highlighting its potential to restore vision while addressing challenges like ethical concerns, immune rejection, and delivery issues. With promising clinical trials and innovations in gene editing and biomaterials, stem cell therapy is poised to transform retinal disease management.

PurposeTo review the role of curcumin in retinal diseases, COVID era, modification of the molecule to improve bioavailability and its future scope.MethodsPubMed and MEDLINE searches were pertaining to curcumin, properties of curcumin, curcumin in retinal diseases, curcumin in diabetic retinopathy, curcumin in age-related macular degeneration, curcumin in retinal and choroidal diseases, curcumin in retinitis pigmentosa, curcumin in retinal ischemia reperfusion injury, curcumin in proliferative vitreoretinopathy and curcumin in current COVID era.ResultsIn experimental models, curcumin showed its pleiotropic effects in retinal diseases like diabetic retinopathy by increasing anti-oxidant enzymes, upregulating HO-1, nrf2 and reducing or inhibiting inflammatory mediators, growth factors and by inhibiting proliferation and migration of retinal endothelial cells in a dose-dependent manner in HRPC, HREC and ARPE-19 cells. In age-related macular degeneration, curcumin acts by reducing ROS and inhibiting apoptosis inducing proteins and cellular inflammatory genes and upregulating HO-1, thioredoxin and NQO1. In retinitis pigmentosa, curcumin has been shown to delay structural defects of P23H gene in P23H-rhodopsin transgenic rats. In proliferative vitreoretinopathy, curcumin inhibited the action of EGF in a dose- and time-dependent manner. In retinal ischemia reperfusion injury, curcumin downregulates IL-17, IL-23, NFKB, STAT-3, MCP-1 and JNK. In retinoblastoma, curcumin inhibits proliferation, migration and apoptosis of RBY79 and SO-RB50. Curcumin has already proven its efficacy in inhibiting viral replication, coagulation and cytokine storm in COVID era.ConclusionCurcumin is an easily available spice used traditionally in Indian cooking. The benefits of curcumin are manifold, and large randomized controlled trials are required to study its effects not only in treating retinal diseases in humans but in their prevention too.

Metformin is one of the most prescribed drugs in the world giving potential health benefits beyond that of type 2 diabetes (T2DM). Emerging evidence suggests that it may have protective effects for retinal/posterior segment diseases including diabetic retinopathy (DR), age-related macular degeneration (AMD), inherited retinal degeneration such as retinitis pigmentosa (RP), primary open angle glaucoma (POAG), retinal vein occlusion (RVO), and uveitis. Metformin exerts potent anti-inflammatory, antiangiogenic, and antioxidative effects on the retina in response to pathologic stressors. In this review, we highlight the broad mechanism of action of metformin through key preclinical studies on animal models and cell lines used to simulate human retinal disease. We then explore the sparse but promising retrospective clinical data on metformin's potential protective role in DR, AMD, POAG, and uveitis. Prospective clinical data is needed to clarify metformin's role in management of posterior segment disorders. However, given metformin's proven broad biochemical effects, favorable safety profile, relatively low cost, and promising data to date, it may represent a new therapeutic preventive and strategy for retinal diseases.

Introduction Sleep is important for optimal physical health and vitality. Recent studies have shown that individuals with visual impairments may be at risk for sleep problems. This research examines the prevalence of sleep problems among those with retinal disorders and the possibility of a genetic link. Methods Subjects with retinitis pigmentosa ( n = 33), Stargardt's disease ( n = 31) and age-related macular degeneration ( n = 43) were recruited from the ophthalmology department of Montreal Children's Hospital. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS). Genetic testing was conducted by the Radboud University Medical Center in Nijmegen, Netherlands. Retinal genes were identified as having retina only or pineal and retinal expression. Results The expression patterns of genes causing retinal disorders did not predict sleep quality. The PSQI indicated poor sleep quality in 56% of participants with retinitis pigmentosa, 48% of those with Stargardt's disease, and 53% of those with age-related macular degeneration. The ESS showed that daytime sleepiness was experienced by 20% of individuals with retinitis pigmentosa or Stargardt's disease, and by only one individual with age-related macular degeneration. Discussion Approximately 50% of people with retinal disease have sleep problems. This number compares with up to one-third of the general population. Gene expression did not correlate with sleep quality, and the explanation for such a large percentage of sleep disorders needs further investigation. Implications for practitioners Eye care and rehabilitation specialists need to be aware of the high prevalence of poor sleep quality in individuals with retinal disorders, since this situation may have an important impact on memory and learning, both of which are vital in successful rehabilitation.

A review on recent advancements in ophthalmology devices: Currently in market and under clinical trials

Re: Jaffe et al.: C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2/3 trial (Ophthalmology. 2021;128:576–586)

Retinal degenerative diseases include inherited pathologies such as retinitis pigmentosa (RP) and multifactorial diseases such as age-related macular degeneration (AMD). AMD, a leading cause of blindness in the Western world, typically causes visual distortion and loss of central vision. In those affected, RP causes early-onset loss of night vision, followed by loss of peripheral vision and ultimately blindness. Due to the need for more effective treatments with the eventual goal of preventing blindness, researchers are investigating new potential targets and technologies to address these diseases. In a preclinical setting, various animal models are available for evaluation of investigational therapies, and investigational drugs and drug delivery methods have shown promise in both preclinical and subsequent clinical trials. Recent efforts include research into the role of inflammation in AMD and RP, and the use of anti-inflammatory drugs in preventing or even reversing retinal damage. The aim of this manuscript is to review past and current works on models for these diseases, the inflammatory processes associated with them, and potential targets for pharmacotherapy as they relate to these progressive retinal dystrophies.

Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. Due to an aging population, its prevalence is expected to increase, making novel and optimized therapy options imperative. However, both late-stage forms of the disease, neovascular AMD (nAMD) and geographic atrophy (GA), exhibit considerable variability in disease progression and treatment response, complicating the evaluation of therapeutic efficacy and making it difficult to design clinical trials that are both inclusive and statistically robust. Traditional trial designs frequently rely on generalized endpoints that may not fully capture the nuanced benefits of treatment, particularly in diseases like GA, where functional improvements can be gradual or subtle. Artificial intelligence (AI) has the potential to address these issues by identifying novel, condition-specific biomarkers or endpoints, enabling precise patient stratification and improving recruitment strategies. By providing an overview of the advances and application of AI-based optical coherence tomography analysis in the context of AMD clinical trials, this review highlights the transformative potential of AI in optimizing clinical trial outcomes for patients with nAMD or GA secondary to AMD.

: The National Neurovision Research Institute (NNRI), the clinical arm of the Foundation Fighting Blindness (FFB), has established the National Eye Evaluation Research (NEER) Network composed of a collaborative group of five Clinical Treatment and Evaluation Centers (CTECs) and a support Clinical Coordinating Center. The intent of this new Network is to advance the science of therapeutic and preventive interventions for inherited orphan retinal degenerative diseases and dry age-related macular degeneration (AMD) through the conduct of clinical trials and other clinically relevant research. The scope of research to be carried out encompasses: (i) Phase I and Phase II clinical trials to evaluate the safety and efficacy of new therapeutic and preventive approaches, including devices, biopharmaceuticals, small molecules, nutritional supplements, and gene transfer approaches; natural history studies to develop standardized criteria to define disease stage, severity and progression; (iii) observational studies to enhance understanding of the natural history of these diseases for different genotypes and phenotypes; and (iv) evaluations of the reliability and validity of different available treatment outcomes measures to determine those that are most appropriate for various genotypes and phenotypes as well as for specific interventions. The NEER Network will also develop standard protocols for data collection, maintain and expand patient databases, classified by genotype and phenotype, to allow for the timely identification of eligible patients and facilitate patient access for clinical trial participation, and design and conduct, in collaboration with the Department of Defense, training programs for military ophthalmologists in the latest technologies and diagnostic and treatment regimens.

: The National Neurovision Research Institute (NNRI}, the clinical arm of the Foundation Fighting Blindness (FFB), has established the National Eye Evaluation Research (NEER) Network composed of a collaborative group of five Clinical Treatment and Evaluation Centers (CTECs) and a support Clinical Coordinating Center. The intent of this new Network is to advance the science of therapeutic and preventive interventions for inherited orphan retinal degenerative diseases and dry age-related macular degeneration (AMD) through the conduct of clinical trials and other clinically relevant research. The scope of research to be carried out encompasses: (i) Phase I and Phase II clinical trials to evaluate the safety and efficacy of new therapeutic and preventive approaches, including devices, biopharmaceuticals, small molecules, nutritional supplements, and gene transfer approaches; natural history studies to develop standardized criteria to define disease stage, severity and progression; (iii) observational studies to enhance understanding of the natural history of these diseases for different genotypes and phenotypes; and (iv) evaluations of the reliability and validity of different available treatment outcomes measures to determine those that are most appropriate for various genotypes and phenotypes as well as for specific interventions. The NEER Network will also develop standard protocols for data collection, maintain and expand standardized patient databases, classified by patient genotype and phenotype, to allow for the timely identification of eligible patients and facilitate patient access for clinical trial participation, and design and conduct, in collaboration with the Department of Defense, training programs for military ophthalmologists in the latest technologies and diagnostic and treatment regimens.

Wolfberry (Lycium barbarum) extracts have been used in the treatment of some retinal degenerative diseases, mostly associated with other antioxidants. The ones this chapter focuses on are retinitis pigmentosa and age-related macular degeneration. Hereditary retinal dystrophies are a broad (and growing) group of hereditary disorders affecting the retina. Retinitis pigmentosa is perhaps the best known of them and is sometimes (inaccurately) used as a synonym for some of the other conditions in this category. Although these two entities show completely different etiologies: The first one is a group of hereditary diseases in which photoreceptor death occurs due to different mutations, and in the second the loss of photoreceptors is associated to the aging process, in both oxidative damage has been claimed as a pathophysiological mechanism. The present chapter reviews the antioxidant chemical features of wolfberry and wolfberry extracts, the oxidative mechanisms involved in the pathophysiology of photoreceptor cell death, and the existing data on the use of wolfberry for retinal degenerations.

Cancer medicine continues to evolve into a more molecularly based discipline with many new treatments being developed aimed at specific cancer-related pathways and genetic alterations. In order to meet the challenges of the evolving science, new clinical trial designs and approaches for treatment trials are needed to evaluate the promise of these potential therapies. The National Cancer Institute (NCI) with the national NCI Clinical Trials Network (NCTN) Groups will launch two clinical research initiatives in lung cancer in 2014 that demonstrate innovative approaches to the design and conduct of clinical trials. The first initiative is the ALCHEMIST trial (Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial) which is aimed at patients with lung adenocarcinoma that has been entirely removed by surgery. In this study, samples of tumor tissue from thousands of patients will be tested for two specific genetic alterations, one in the EGFR gene, and the other in the ALK gene. These alterations are not common; about 10% of the lung cancer patient population in the US will have tumors with alterations in the EGFR gene and 5% will have alterations in the ALK gene. Rather than conduct a single trial for each alteration, the screening component of the ALCHEMIST trial will screen patients for both alterations at the same time. The ALCHEMIST is connected to 2 specific NCI-supported NCTN Group clinical treatment trials that are each testing a targeted agent specific for one of the alterations in conjunction with adjuvant therapy. Patients found to have tumors containing one of the alterations will be offered enrollment onto the appropriate clinical treatment trial. Every patient in the ALCHEMIST trial, including those without an EGFR or ALK alteration, will also be studied for cancer risk characteristics and their tumor tissue will be analyzed in a research genomics initiative conducted by the NCI Center for Cancer Genomics (CCG). This effort will employ next-generation sequencing technology to capitalize on the foundation of the CCG's earlier effort, the Cancer Genome Atlas. The second initiative, the Advanced Squamous Cell Carcinoma Lung Master Protocol, is a public-private effort made possible through collaboration with stakeholders including the NCI, NCTN Groups, FDA, NIH Foundation, the Friends of Cancer patient advocacy group, and the pharmaceutical industry. By pooling resources to screen tumor samples from about a thousand patients per year with advanced squamous cell carcinoma for multiple genetic alterations, this master protocol will enable several, randomized, phase II clinical trials with promising new agents to take place in parallel within a single study management framework. Agents will be evaluated rapidly and either be further evaluated in a phase III clinical trial or replaced by other new agents for phase II evaluation, without having to develop individual trials de novo each time. Compared with the usual process of developing clinical trials, these two new design approaches will hopefully allow more patients to be enrolled in trials with agents targeted for important molecular characteristics specific for their tumors and the trials will yield clinically useful results more rapidly. Citation Format: Margaret M. Mooney, Jack Welch, Jeffrey S. Abrams. Clinical trial design and master protocols in NCI clinical treatment trials. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr IA08.