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Gene Therapy Intervention in Neovascular Eye Disease: A Recent Update.

ABSTRACT: Aberrant growth of blood vessels (neovascularization) is a key feature of severe eye diseases that can cause legal blindness, including neovascular age-related macular degeneration (nAMD) and diabetic retinopathy (DR). The development of anti-vascular endothelial growth factor (VEGF) agents has revolutionized the treatment of ocular neovascularization. Novel proangiogenic targets, such as angiopoietin and platelet-derived growth factor (PDGF), are under development for patients who respond poorly to anti-VEGF therapy and to reduce adverse effects from long-term VEGF inhibition. A rapidly advancing area is gene therapy, which may provide significant therapeutic benefits. Viral vector-mediated transgene delivery provides the potential for continuous production of antiangiogenic proteins, which would avoid the need for repeated anti-VEGF injections. Gene silencing with RNA interference to target ocular angiogenesis has been investigated in clinical trials. Proof-of-concept gene therapy studies using gene-editing tools such as CRISPR-Cas have already been shown to be effective in suppressing neovascularization in animal models, highlighting the therapeutic potential of the system for treatment of aberrant ocular angiogenesis. This review provides updates on the development of anti-VEGF agents and novel antiangiogenic targets. We also summarize current gene therapy strategies already in clinical trials and those with the latest approaches utilizing CRISPR-Cas gene editing against aberrant ocular neovascularization.

SUBMITTER: Lin FL

PROVIDER: S-EPMC7544979 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Recent Developments in Gene Therapy for Neovascular Age-Related Macular Degeneration: A Review.

Project description:Age-related macular degeneration (AMD) is a complex and multifactorial disease and a leading cause of irreversible blindness in the elderly population. The anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionized the management and prognosis of neovascular AMD (nAMD) and is currently the standard of care for this disease. However, patients are required to receive repeated injections, imposing substantial social and economic burdens. The implementation of gene therapy methods to achieve sustained delivery of various therapeutic proteins holds the promise of a single treatment that could ameliorate the treatment challenges associated with chronic intravitreal therapy, and potentially improve visual outcomes. Several early-phase trials are currently underway, evaluating the safety and efficacy of gene therapy for nAMD; however, areas of controversy persist, including the therapeutic target, route of administration, and potential safety issues. In this review, we assess the evolution of gene therapy for nAMD and summarize several preclinical and early-stage clinical trials, exploring challenges and future directions.

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Gene Therapy for Parkinson's Disease, An Update.

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| S-EPMC6027861 | biostudies-other

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Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy.

Project description:Proliferative diabetic retinopathy (PDR), neovascular age-related macular degeneration (nvAMD), retinopathy of prematurity (ROP) and other eye diseases are characterized by retinal and/or choroidal neovascularization, ultimately causing vision loss in millions of people worldwide. nvAMD and PDR are associated with aging and the number of those affected is expected to increase as the global median age and life expectancy continue to rise. With this increase in prevalence, the development of novel, orally bioavailable therapies for neovascular eye diseases that target multiple pathways is critical, since current anti-vascular endothelial growth factor (VEGF) treatments, delivered by intravitreal injection, are accompanied with tachyphylaxis, a high treatment burden and risk of complications. One potential target is apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1). The multifunctional protein APE1/Ref-1 may be targeted via inhibitors of its redox-regulating transcription factor activation activity to modulate angiogenesis, inflammation, oxidative stress response and cell cycle in neovascular eye disease; these inhibitors also have neuroprotective effects in other tissues. An APE1/Ref-1 small molecule inhibitor is already in clinical trials for cancer, PDR and diabetic macular edema. Efforts to develop further inhibitors are underway. APE1/Ref-1 is a novel candidate for therapeutically targeting neovascular eye diseases and alleviating the burden associated with anti-VEGF intravitreal injections.

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Recent developments on dry eye disease treatment compounds.

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Eggs and Cardiovascular Disease Risk: An Update of Recent Evidence.

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| S-EPMC10285014 | biostudies-literature

An Update on Recent Advances of Photodynamic Therapy for Primary Cutaneous Lymphomas.

Project description:Primary cutaneous lymphomas are rare non-Hodgkin lymphomas consisting of heterogeneous disease entities. Photodynamic therapy (PDT) utilizing photosensitizers irradiated with a specific wavelength of light in the presence of oxygen exerts promising anti-tumor effects on non-melanoma skin cancer, yet its application in primary cutaneous lymphomas remains less recognized. Despite many in vitro data showing PDT could effectively kill lymphoma cells, clinical evidence of PDT against primary cutaneous lymphomas is limited. Recently, a phase 3 "FLASH" randomized clinical trial demonstrated the efficacy of topical hypericin PDT for early-stage cutaneous T-cell lymphoma. An update on recent advances of photodynamic therapy in primary cutaneous lymphomas is provided.

| S-EPMC10223676 | biostudies-literature

Neovascular Macular Degeneration: A Review of Etiology, Risk Factors, and Recent Advances in Research and Therapy.

Project description:Neovascular age-related macular degeneration (exudative or wet AMD) is a prevalent, progressive retinal degenerative macular disease that is characterized by neovascularization of the choroid, mainly affecting the elderly population causing gradual vision impairment. Risk factors such as age, race, genetics, iris color, smoking, drinking, BMI, and diet all play a part in nvAMD's progression, with anti-vascular endothelial growth factor (anti-VEGF) therapy being the mainstay of treatment. Current therapeutic advancements slow the progression of the disease but do not cure or reverse its course. Newer therapies such as gene therapies, Rho-kinase inhibitors, and levodopa offer potential new targets for treatment.

| S-EPMC7866170 | biostudies-literature

An Update on Gene Therapy Approaches for Parkinson's Disease: Restoration of Dopaminergic Function.

Project description:At present there is a significant unmet need for clinically available treatments for Parkinson's disease (PD) patients to stably restore balance to dopamine network function, leaving patients with inadequate management of symptoms as the disease progresses. Gene therapy is an attractive approach to impart a durable effect on neuronal function through introduction of genetic material to reestablish dopamine levels and/or functionally recover dopaminergic signaling by improving neuronal health. Ongoing clinical gene therapy trials in PD are focused on enzymatic enhancement of dopamine production and/or the restoration of the nigrostriatal pathway to improve dopaminergic network function. In this review, we discuss data from current gene therapy trials for PD and recent advances in study design and surgical approaches.

| S-EPMC8543243 | biostudies-literature

Genetics and Age-Related Eye Disease Study Formulation Interaction in Neovascular Age-Related Macular Degeneration.

Project description:PurposeThis work aims to determine whether previously defined genotype risk groups interact with Age-Related Eye Disease Study formulation (AREDS-F) use in progression to neovascular age-related macular degeneration (nvAMD).MethodsWe conducted a case-only study of 265 nvAMD patients. Patients were anonymously genotyped at the complement factor H and age-related maculopathy susceptibility 2 loci and segregated into genotype groups (GTGs) defined by specific combinations of risk alleles. Physicians, who were blind to patients' GTGs, obtained patients' AREDS-F use history. The facility performing genetic analysis was blind to the AREDS-F use history. We used logistic analysis to estimate the interaction coefficient between AREDS-F use and GTG 2 vs GTG 3 in a general-population model.ResultsThe odds ratio of numbers of patients reporting prior AREDS-F use to nonuse for GTG 2 vs GTG 3 was 4.18 (P = .001). Logistic regression, correcting for nongenetic risk factors, gave an estimate of the β for interaction of AREDS-F with genotype of 1.57 (P = .001). This estimates a corrected odds ratio associated with the effect of interaction of 4.81 between those in GTG 2 compared with those in GTG 3.ConclusionsOur data indicate an interaction between GTGs and AREDS-F use that is consistent in size and direction with previously published reports, which had found that using AREDS-F supplements significantly increases the risk of nvAMD for some users and significantly protects other users.

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