AAV-Based Strategies for Treatment of Retinal and Choroidal Vascular Diseases: Advances in Age-Related Macular Degeneration and Diabetic Retinopathy Therapies

Castro, Brenda F. M.; Steel, Jason C.; Layton, Christopher J.

doi:10.1007/s40259-023-00629-y

Cited by 3 publications

(5 citation statements)

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“…Promisingly, studies have showcased the potential of gene therapy in delaying or preventing retinal cell death, and potentially halting the progression of DR. For example, a gene therapy named AAV2-sFLT01 gene therapy, currently in clinical trials, seeks to block VEGF signaling and inhibit the formation of new blood vessels and retinal edema. By introducing a gene encoding this effect into the retina, this therapy aims to enhance the retinal neuron survival [227,228]. In the realm of the clinical trials testing gene therapy in vascular ocular disorders, important differences were observed in the INFINITY trial (NCT04418427), where the patients affected by diabetic macular edema and wet AMD treated with the AAV2.7m8 encoding aflibercept (ADVM-022) at the same dose ultimately displayed dose-limiting toxicity in DR, while encouraging results were reported in AMD, underscoring the detrimental impact of the diabetic condition on the ocular safety of AAV therapies [228,229].…”

Section: Gene and Cell Therapy Advancementsmentioning

confidence: 99%

“…By introducing a gene encoding this effect into the retina, this therapy aims to enhance the retinal neuron survival [227,228]. In the realm of the clinical trials testing gene therapy in vascular ocular disorders, important differences were observed in the INFINITY trial (NCT04418427), where the patients affected by diabetic macular edema and wet AMD treated with the AAV2.7m8 encoding aflibercept (ADVM-022) at the same dose ultimately displayed dose-limiting toxicity in DR, while encouraging results were reported in AMD, underscoring the detrimental impact of the diabetic condition on the ocular safety of AAV therapies [228,229].…”

Section: Gene and Cell Therapy Advancementsmentioning

confidence: 99%

“…Additionally, in the ALTITUDE clinical trial, while treating patients with DR without center-involved DME with a suprachoroidal injection of RGX-314, a molecule of AAV2/8 vectors encoding an anti-VEGF antibody fragment, the researchers obtained good tolerance at 6 months, with no drug-induced severe adverse events (NCT04567550; NCT05296447) [228,230]. The ALTITUDE trial is set to be completed in 2024, with the followup phase finishing in 2028 [228].…”

Section: Gene and Cell Therapy Advancementsmentioning

confidence: 99%

See 2 more Smart Citations

Diabetic Retinopathy: New Treatment Approaches Targeting Redox and Immune Mechanisms

Tang,

Buonfiglio,

Böhm

et al. 2024

Antioxidants

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Diabetic retinopathy (DR) represents a severe complication of diabetes mellitus, characterized by irreversible visual impairment resulting from microvascular abnormalities. Since the global prevalence of diabetes continues to escalate, DR has emerged as a prominent area of research interest. The development and progression of DR encompass a complex interplay of pathological and physiological mechanisms, such as high glucose-induced oxidative stress, immune responses, vascular endothelial dysfunction, as well as damage to retinal neurons. Recent years have unveiled the involvement of genomic and epigenetic factors in the formation of DR mechanisms. At present, extensive research explores the potential of biomarkers such as cytokines, molecular and cell therapies, antioxidant interventions, and gene therapy for DR treatment. Notably, certain drugs, such as anti-VEGF agents, antioxidants, inhibitors of inflammatory responses, and protein kinase C (PKC)-β inhibitors, have demonstrated promising outcomes in clinical trials. Within this context, this review article aims to introduce the recent molecular research on DR and highlight the current progress in the field, with a particular focus on the emerging and experimental treatment strategies targeting the immune and redox signaling pathways.

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Section: Gene and Cell Therapy Advancementsmentioning

confidence: 99%

Section: Gene and Cell Therapy Advancementsmentioning

confidence: 99%

Section: Gene and Cell Therapy Advancementsmentioning

confidence: 99%

See 1 more Smart Citation

Diabetic Retinopathy: New Treatment Approaches Targeting Redox and Immune Mechanisms

Tang,

Buonfiglio,

Böhm

et al. 2024

Antioxidants

View full text Add to dashboard Cite

show abstract

“… 26 ). Although other approaches can undoubtedly bring benefits to glaucoma and uveitis patients, AAV stands out as a promising technology given the possibility of optimisation of the delivery and expression methods, including regulation, targeting, specificity and multi-acting, in addition to a scalable manufacturing process (Refs 27 , 28 ). These distinctive features underscore the potential of AAV to address challenges associated with the management of prevalent, chronic, multifactorial and complex disorders (Ref.…”

Section: Introductionmentioning

confidence: 99%

“…These distinctive features underscore the potential of AAV to address challenges associated with the management of prevalent, chronic, multifactorial and complex disorders (Ref. 27 ).…”

Section: Introductionmentioning

confidence: 99%

AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?

Castro,

Steel,

Layton

2024

Expert Rev. Mol. Med.

Self Cite

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Glaucoma and uveitis are non-vascular ocular diseases which are among the leading causes of blindness and visual loss. These conditions have distinct characteristics and mechanisms but share a multifactorial and complex nature, making their management challenging and burdensome for patients and clinicians. Furthermore, the lack of symptoms in the early stages of glaucoma and the diverse aetiology of uveitis hinder timely and accurate diagnoses, which are a cause of poor visual outcomes under both conditions. Although current treatment is effective in most cases, it is often associated with low patient adherence and adverse events, which directly impact the overall therapeutic success. Therefore, long-lasting alternatives with improved safety and efficacy are needed. Gene therapy, particularly utilising adeno-associated virus (AAV) vectors, has emerged as a promising approach to address unmet needs in these diseases. Engineered capsids with enhanced tropism and lower immunogenicity have been proposed, along with constructs designed for targeted and controlled expression. Additionally, several pathways implicated in the pathogenesis of these conditions have been targeted with single or multigene expression cassettes, gene editing and silencing approaches. This review discusses strategies employed in AAV-based gene therapies for glaucoma and non-infectious uveitis and provides an overview of current progress and future directions.

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Preclinical development of a dual targeting bicistronic gene therapy approach for the treatment of wet age-related macular degeneration

Tam,

Joel,

Stampoulis

et al. 2024

Preprint

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Age-related macular degeneration (AMD) continues to be a leading cause of severe vision impairment affecting millions worldwide. The late stages of AMD are characterized by outer retinal atrophy (geographic atrophy, GA), or neovascularization associated with subretinal and/or intraretinal exudation (exudative neovascular or ‘wet’ AMD). Intravitreal (IVT) administration of anti-vascular endothelial growth factor (VEGF) therapies has dramatically improved vision preservation for wet AMD (wAMD) patients. However, current Standard of Care (SoC) has significant shortcomings and the benefits of anti-VEGF therapy in the real-world setting fall short of the vision gains observed in randomized clinical trials. This is thought to be attributable to drug burden to patients, lack of therapeutic durability due to progression of underlying macular atrophy and refractility to treatment. Vectorized anti-VEGF therapy has been shown to be effective in reducing drug burden clinically but is unlikely to address the progression of the underlying GA driven by complement-mediated inflammation. Here, we aim to address this unmet need by developing a bicistronic gene therapy vector co-expressing aflibercept and Factor H-like protein 1 (FHL-1) to target the pro-angiogenic and pro-inflammatory environment of wAMD. In vitro assays confirmed the anti-angiogenic and complement inhibitory properties of the bicistronic vector. Recombinant AAV8 (rAAV8)-mediated co-expression was detected for up to 4 weeks following subretinal delivery in wild type (WT) mice. In a mouse laser-induced choroidal neovascularization (CNV) model, subretinal delivery of bicistronic vectors significantly reduced both CNV leakage and lesion. These results demonstrate that a single subretinal administration of bicistronic vector may provide an effective treatment option for wAMD and may also prolong patient’s visual outcomes by preventing the underlying progression of GA.

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AAV-Based Strategies for Treatment of Retinal and Choroidal Vascular Diseases: Advances in Age-Related Macular Degeneration and Diabetic Retinopathy Therapies

Cited by 3 publications

References 123 publications

Diabetic Retinopathy: New Treatment Approaches Targeting Redox and Immune Mechanisms

Diabetic Retinopathy: New Treatment Approaches Targeting Redox and Immune Mechanisms

AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?

Preclinical development of a dual targeting bicistronic gene therapy approach for the treatment of wet age-related macular degeneration

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