Co-delivery of genes can be confounded by bicistronic vector design

Moradian, Hanieh; Gossen, Manfred; Lendlein, Andreas

doi:10.1557/s43579-021-00128-7

Cited by 2 publications

References 29 publications

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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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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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B and T Cell Bi-Cistronic Multiepitopic Vaccine Induces Broad Immunogenicity and Provides Protection Against SARS-CoV-2

Perdiguero,

Álvarez,

Marcos-Villar

et al. 2024

Vaccines

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Background: The COVID-19 pandemic, caused by SARS-CoV-2, has highlighted the need for vaccines targeting both neutralizing antibodies (NAbs) and long-lasting cross-reactive T cells covering multiple viral proteins to provide broad and durable protection against emerging variants. Methods: To address this, here we developed two vaccine candidates, namely (i) DNA-CoV2-TMEP, expressing the multiepitopic CoV2-TMEP protein containing immunodominant and conserved T cell regions from SARS-CoV-2 structural proteins, and (ii) MVA-CoV2-B2AT, encoding a bi-cistronic multiepitopic construct that combines conserved B and T cell overlapping regions from SARS-CoV-2 structural proteins. Results: Both candidates were assessed in vitro and in vivo demonstrating their ability to induce robust immune responses. In C57BL/6 mice, DNA-CoV2-TMEP enhanced the recruitment of innate immune cells and stimulated SARS-CoV-2-specific polyfunctional T cells targeting multiple viral proteins. MVA-CoV2-B2AT elicited NAbs against various SARS-CoV-2 variants of concern (VoCs) and reduced viral replication and viral yields against the Beta variant in susceptible K18-hACE2 mice. The combination of MVA-CoV2-B2AT with a mutated ISG15 form as an adjuvant further increased the magnitude, breadth and polyfunctional profile of the response. Conclusion: These findings underscore the potential of these multiepitopic proteins when expressed from DNA or MVA vectors to provide protection against SARS-CoV-2 and its variants, supporting their further development as next-generation COVID-19 vaccines.

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Co-delivery of genes can be confounded by bicistronic vector design

Cited by 2 publications

References 29 publications

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

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

B and T Cell Bi-Cistronic Multiepitopic Vaccine Induces Broad Immunogenicity and Provides Protection Against SARS-CoV-2

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