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Development of a novel PTD-mediated IVT-mRNA delivery platform for potential protein replacement therapy of metabolic/genetic disorders.

ABSTRACT: The potential clinical applications of the powerful in vitro-transcribed (IVT)-mRNAs, to restore defective protein functions, strongly depend on their successful intracellular delivery and transient translation through the development of safe and efficient delivery platforms. In this study, an innovative (international patent-pending) methodology was developed, combining the IVT-mRNAs with the protein transduction domain (PTD) technology, as an efficient delivery platform. Based on the PTD technology, which enables the intracellular delivery of various cargoes intracellularly, successful conjugation of a PTD to the IVT-mRNAs was achieved and evaluated by band-shift assay and NMR spectroscopy. In addition, the PTD-IVT-mRNAs were applied and evaluated in two protein-disease models, including the mitochondrial disorder fatal infantile cardioencephalomyopathy and cytochrome c oxidase (COX) deficiency (attributed to SCO2 gene mutations) and β-thalassemia. The PTD-IVT-mRNA of SCO2 was successfully transduced and translated to the corresponding Sco2 protein inside the primary fibroblasts of a SCO2/COX-deficient patient, whereas the PTD-IVT-mRNA of β-globin was transduced and translated in bone marrow cells, derived from three β-thalassemic patients. The transducibility and the structural stability of the PDT-IVT-mRNAs, in both cases, were confirmed at the RNA and protein levels. We propose that our novel delivery platform could be clinically applicable as a protein therapy for metabolic/genetic disorders.

SUBMITTER: Miliotou AN

PROVIDER: S-EPMC8517095 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Development of a novel PTD-mediated IVT-mRNA delivery platform for potential protein replacement therapy of metabolic/genetic disorders.

Miliotou Androulla N AN Pappas Ioannis S IS Spyroulias George G Vlachaki Efthimia E Tsiftsoglou Asterios S AS Vizirianakis Ioannis S IS Papadopoulou Lefkothea C LC

Molecular therapy. Nucleic acids 20210920

The potential clinical applications of the powerful <i>in vitro</i>-transcribed (IVT)-mRNAs, to restore defective protein functions, strongly depend on their successful intracellular delivery and transient translation through the development of safe and efficient delivery platforms. In this study, an innovative (international patent-pending) methodology was developed, combining the IVT-mRNAs with the protein transduction domain (PTD) technology, as an efficient delivery platform. Based on the PT ...[more]

PMID: 34703653

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Project description:Background: Skin aging can be classified into intrinsic and extrinsic types, with photoaging representing a significant form of extrinsic aging. Photoaging is caused by prolonged exposure to ultraviolet (UV) radiation, resulting in cellular damage, collagen degradation, and the development of wrinkles and pigmentation changes; severe cases can even lead to skin cancer. This condition affects individual aesthetics and health and imposes a broader societal burden, including increased healthcare costs and reduced quality of life. Addressing photoaging is critical, as effective treatments can enhance skin health, improve mental well-being, and alleviate the burden on healthcare systems, highlighting the importance of preventive and therapeutic strategies. Objective: This study aimed to develop a novel drug based on human type III collagen mRNA (hCOL3A1 mRNA) and to investigate its role in treating UVB-induced skin photoaging. Methods: We designed and synthesized the complete hCOL3A1 mRNA sequence and encapsulated it in lipid nanoparticles for skin delivery. The expression of the hCOL3A1 mRNA drug in human fibroblasts was examined by in vitro experiments, and its potential therapeutic effects on UVB-induced aging, oxidative stress, and inflammation were evaluated. In addition, we evaluated the efficacy of the hCOL3A1 mRNA drug on UVB-induced skin photoaging by an in vivo model. Results: It was found that the hCOL3A1 mRNA drug was effective in reducing UVB-induced skin photoaging, suggesting that the hCOL3A1 mRNA drug could be used as a therapeutic intervention for UVB-induced photoaging and also providing a novel approach to restore aging skin by increasing endogenous collagen production and reducing oxidative and inflammatory damage Conclusion: hCOL3A1 mRNA-LNP, as a novel protein therapeutic approach, overcomes the limitations of retinoic acid (RA) therapy, provides a simpler and more efficient therapeutic option, and is expected to be a new treatment for skin photoaging.

Dataset Information

Development of a novel PTD-mediated IVT-mRNA delivery platform for potential protein replacement therapy of metabolic/genetic disorders.

Publications

Development of a novel PTD-mediated IVT-mRNA delivery platform for potential protein replacement therapy of metabolic/genetic disorders.

Similar Datasets

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