Gene Therapy

Pozo-Rodríguez, Ana del; Rodríguez-Gascón, Alicia; Rodríguez-Castejón, Julen; Vicente-Pascual, Mónica; Gómez-Aguado, Itziar; Battaglia, Luigi; Solinís, Maria Ángelés

doi:10.1007/10_2019_109

Cited by 14 publications

(10 citation statements)

References 142 publications

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“…CNEs consist of a dispersion of an oil phase stabilized by an aqueous phase containing the cationic lipid. These nanoemulsions present a droplet size distribution of about 200 nm, and are mainly used to formulate mRNA vaccines [2,9]. For instance, a self-amplifying RNA (SAM) vaccine, expressing Human Immunodeficiency Virus (HIV) type 1 envelope, formulated in a CNE induced potent immune responses in rhesus macaques [99].…”

Section: Lipid-based Systemsmentioning

confidence: 99%

“…Up to date around 17 nucleic acid-based products have been approved worldwide, and almost 2700 gene therapy-based clinical trials have been completed, are ongoing or have been approved for a broad range of applications. It is expected that nucleic acid-based products will have a substantial impact on the biopharmaceutical market in the near future [2]. Gene therapy has been clinically implemented primarily through two different approaches: Ex vivo or in vivo.…”

Section: Introductionmentioning

confidence: 99%

“…Diverse nucleic acids are being used to address the development of these new medicinal products. DNA and messenger RNA (mRNA) induce protein expression, whereas, small interfering RNA (siRNA), microRNA, oligonucleotides or aptamers provide gene silencing [2]. Molecular scissor and gene editing approaches, such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR)-associated nuclease Cas9 (CRISPR/Cas9) are also being developed.…”

Section: Introductionmentioning

confidence: 99%

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Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives

et al. 2020

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The use of messenger RNA (mRNA) in gene therapy is increasing in recent years, due to its unique features compared to plasmid DNA: Transient expression, no need to enter into the nucleus and no risk of insertional mutagenesis. Nevertheless, the clinical application of mRNA as a therapeutic tool is limited by its instability and ability to activate immune responses; hence, mRNA chemical modifications together with the design of suitable vehicles result essential. This manuscript includes a revision of the strategies employed to enhance in vitro transcribed (IVT) mRNA functionality and efficacy, including the optimization of its stability and translational efficiency, as well as the regulation of its immunostimulatory properties. An overview of the nanosystems designed to protect the mRNA and to overcome the intra and extracellular barriers for successful delivery is also included. Finally, the present and future applications of mRNA nanomedicines for immunization against infectious diseases and cancer, protein replacement, gene editing, and regenerative medicine are highlighted.

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Section: Lipid-based Systemsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives

et al. 2020

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“…Recent innovations in biology, including next-generation sequencing (5,6), CRISPR-Cas9 gene editing (7,8), and induced pluripotent stem cell technology (9,10), are enabling treatment of diseases that were previously considered incurable (11)(12)(13). However, radiological studies based on anatomical imaging may not be effective in assessing the response to treatment.…”

Section: Preparation Of a Phantom Contrast Agent And In Vitro Phantomsmentioning

confidence: 99%

Human Organic Anion Transporting Polypeptide 1B3 Applied as an MRI-Based Reporter Gene

et al. 2020

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Objective: Recent innovations in biology are boosting gene and cell therapy, but monitoring the response to these treatments is difficult. The purpose of this study was to find an MRI-reporter gene that can be used to monitor gene or cell therapy and that can be delivered without a viral vector, as viral vector delivery methods can result in long-term complications. Materials and Methods: CMV promoter-human organic anion transporting polypeptide 1B3 (CMV-hOATP1B3) cDNA or CMV-blank DNA (control) was transfected into HEK293 cells using Lipofectamine. OATP1B3 expression was confirmed by western blotting and confocal microscopy. In vitro cell phantoms were made using transfected HEK293 cells cultured in various concentrations of gadoxetic acid for 24 hours, and images of the phantoms were made with a 9.4T micro-MRI. In vivo xenograft tumors were made by implanting HEK293 cells transfected with CMV-hOATP1B3 (n = 4) or CMV-blank (n = 4) in 8-week-old male nude mice, and MRI was performed before and after intravenous injection of gadoxetic acid (1.2 μL/g). Results: Western blot and confocal microscopy after immunofluorescence staining revealed that only CMV-hOATP1B3-transfected HEK293 cells produced abundant OATP1B3, which localized at the cell membrane. OATP1B3 expression levels remained high through the 25th subculture cycle, but decreased substantially by the 50th subculture cycle. MRI of cell phantoms showed that only the CMV-hOATP1B3-transfected cells produced a significant contrast enhancement effect. In vivo MRI of xenograft tumors revealed that only CMV-hOATP1B3-transfected HEK293 tumors demonstrated a T1 contrast effect, which lasted for at least 5 hours. Conclusion: The human endogenous OATP1B3 gene can be non-virally delivered into cells to induce transient OATP1B3 expression, leading to gadoxetic acid-mediated enhancement on MRI. These results indicate that hOATP1B3 can serve as an MRI-reporter gene while minimizing the risk of long-term complications.

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“…Gene therapy medicinal products generally consist of a vector or delivery formulation/system containing a genetic construct engineered to express a specific transgene (‘therapeutic sequence’) for the regulation, repair, replacement, addition, or deletion of a genetic sequence [ 4 ]. These products are expected to have a significant impact on the biopharmaceutical market shortly [ 5 ]. A significant number of studies have evaluated the potential of gene therapy to deliver specific anti-inflammatory factors to treat keratitis.…”

Section: Introductionmentioning

confidence: 99%

Topical Administration of SLN-Based Gene Therapy for the Treatment of Corneal Inflammation by De Novo IL-10 Production

et al. 2020

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One of the main challenges in gene therapy is the issue of delivery, and it is especially relevant for the success of gene therapy in the cornea. In the present work, eye drops containing biocompatible non-viral vectors based on solid lipid nanoparticles (SLNs) as gene delivery systems to induce the expression of interleukin 10 (IL-10) were designed to address the treatment of corneal inflammation. Two kinds of SLNs combined with different ligands (protamine, dextran, or hyaluronic acid (HA)) and formulated with polyvinyl alcohol (PVA) were prepared. SLN-based vectors were characterized in terms of size, adhesiveness, viscosity, and pH, before topical administration to wild type and IL-10 knock out (KO) mice. The formulations showed a homogenous particle size below 400 nm and a positive surface charge to favor bioadhesion; the incorporation of PVA improved the corneal penetration. After three days of treatment by topical instillation, SLN-based vectors mainly transfected corneal epithelial cells, HA-formulations being the most effective ones. IL-10 was capable of reaching even the endothelial layer. Corneal sections showed no histological change and formulations seemed to be well tolerated after repeated topical administration. These promising results highlight the possible contribution of non-viral gene augmentation therapy to the future clinical approach of corneal gene therapy.

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Gene Therapy

Cited by 14 publications

References 142 publications

Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives

Nanomedicines to Deliver mRNA: State of the Art and Future Perspectives

Human Organic Anion Transporting Polypeptide 1B3 Applied as an MRI-Based Reporter Gene

Topical Administration of SLN-Based Gene Therapy for the Treatment of Corneal Inflammation by De Novo IL-10 Production

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