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

Pharmaceutics ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 584 ◽  
Author(s):  
Mónica Vicente-Pascual ◽  
Itziar Gómez-Aguado ◽  
Julen Rodríguez-Castejón ◽  
Alicia Rodríguez-Gascón ◽  
Elisabetta Muntoni ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
De Novo ◽  
Topical Administration ◽  
Interleukin 10 ◽  
Viral Gene ◽  
Clinical Approach ◽  
Eye Drops ◽  
Knock Out ◽  
Corneal Inflammation

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.

scholarly journals mRNA-Based Nanomedicinal Products to Address Corneal Inflammation by Interleukin-10 Supplementation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1472
Author(s):  
Itziar Gómez-Aguado ◽  
Julen Rodríguez-Castejón ◽  
Marina Beraza-Millor ◽  
Mónica Vicente-Pascual ◽  
Alicia Rodríguez-Gascón ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Transfection Efficiency ◽  
Physicochemical Characterization ◽  
Topical Administration ◽  
Interleukin 10 ◽  
Eye Drops ◽  
Efficient Treatment ◽  
Corneal Inflammation ◽  
Transfection Efficacy

The anti-inflammatory cytokine Interleukin-10 (IL-10) is considered an efficient treatment for corneal inflammation, in spite of its short half-life and poor eye bioavailability. In the present work, mRNA-based nanomedicinal products based on solid lipid nanoparticles (SLNs) were developed in order to produce IL-10 to treat corneal inflammation. mRNA encoding green fluorescent protein (GFP) or human IL-10 was complexed with different SLNs and ligands. After, physicochemical characterization, transfection efficacy, intracellular disposition, cellular uptake and IL-10 expression of the nanosystems were evaluated in vitro in human corneal epithelial (HCE-2) cells. Energy-dependent mechanisms favoured HCE-2 transfection, whereas protein production was influenced by energy-independent uptake mechanisms. Nanovectors with a mean particle size between 94 and 348 nm and a positive superficial charge were formulated as eye drops containing 1% (w/v) of polyvinyl alcohol (PVA) with 7.1–7.5 pH. After three days of topical administration to mice, all formulations produced GFP in the corneal epithelium of mice. SLNs allowed the obtaining of a higher transfection efficiency than naked mRNA. All formulations produce IL-10, and the interleukin was even observed in the deeper layers of the epithelium of mice depending on the formulation. This work shows the potential application of mRNA-SLN-based nanosystems to address corneal inflammation by gene augmentation therapy.

scholarly journals How Far Are Non-Viral Vectors to Come of Age and Reach Clinical Translation in Gene Therapy?

2021 ◽  
Vol 22 (14) ◽  
pp. 7545
Author(s):  
Myriam Sainz-Ramos ◽  
Idoia Gallego ◽  
Ilia Villate-Beitia ◽  
Jon Zarate ◽  
Iván Maldonado ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Practice ◽  
Gene Delivery ◽  
Viral Vectors ◽  
Viral Vector ◽  
Clinical Success ◽  
Genetic Material ◽  
Viral Gene ◽  
Promising Alternative ◽  
Vector Systems

Efficient delivery of genetic material into cells is a critical process to translate gene therapy into clinical practice. In this sense, the increased knowledge acquired during past years in the molecular biology and nanotechnology fields has contributed to the development of different kinds of non-viral vector systems as a promising alternative to virus-based gene delivery counterparts. Consequently, the development of non-viral vectors has gained attention, and nowadays, gene delivery mediated by these systems is considered as the cornerstone of modern gene therapy due to relevant advantages such as low toxicity, poor immunogenicity and high packing capacity. However, despite these relevant advantages, non-viral vectors have been poorly translated into clinical success. This review addresses some critical issues that need to be considered for clinical practice application of non-viral vectors in mainstream medicine, such as efficiency, biocompatibility, long-lasting effect, route of administration, design of experimental condition or commercialization process. In addition, potential strategies for overcoming main hurdles are also addressed. Overall, this review aims to raise awareness among the scientific community and help researchers gain knowledge in the design of safe and efficient non-viral gene delivery systems for clinical applications to progress in the gene therapy field.

scholarly journals Long-Circulating Polymeric Nanovectors for Tumor-Selective Gene Delivery

2005 ◽  
Vol 4 (6) ◽  
pp. 615-625 ◽  
Author(s):  
Sushma Kommareddy ◽  
Sandip B. Tiwari ◽  
Mansoor M. Amiji
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Viral Vectors ◽  
High Efficiency ◽  
Transfection Efficiency ◽  
The United States ◽  
Medical Intervention ◽  
Hydrophilic Polymers ◽  
Circulation Time ◽  
Viral Gene

Significant advances in the understanding of the genetic abnormalities that lead to the development, progression, and metastasis of neoplastic diseases has raised the promise of gene therapy as an approach to medical intervention. Most of the clinical protocols that have been approved in the United States for gene therapy have used the viral vectors because of the high efficiency of gene transfer. Conventional means of gene delivery using viral vectors, however, has undesirable side effects such as insertion of mutational viral gene into the host genome and development of replication competent viruses. Among non-viral gene delivery methods, polymeric nanoparticles are increasingly becoming popular as vectors of choice. The major limitation of these nanoparticles is poor transfection efficiency at the target site after systemic administration due to uptake by the cells of reticuloendothelial system (RES). In order to reduce the uptake by the cells of the RES and improve blood circulation time, these nanoparticles are coated with hydrophilic polymers such as poly(ethylene glycol) (PEG). This article reviews the use of such hydrophilic polymers employed for improving the circulation time of the nanocarriers. The mechanism of polymer coating and factors affecting the circulation time of these nanocarriers will be discussed. In addition to the long circulating property, modifications to improve the target specificity of the particles and the limitations of steric protection will be analyzed.

scholarly journals Recent Advances in the Development of Bio-Reducible Polymers for Efficient Cancer Gene Delivery Systems

2019 ◽  
Vol 2 (1) ◽  
pp. 6-13 ◽  
Author(s):  
Kiel Sung Yong ◽  
◽  
Wan Kim Sung ◽  
◽  
◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Ribonucleic Acid ◽  
Viral Vectors ◽  
Delivery Systems ◽  
Host Cells ◽  
Viral Gene ◽  
Cancer Gene ◽  
Inherited Disorders ◽  
Messenger Ribonucleic Acid

Gene therapy is the unique method for the use of genetic materials such as Messenger ribonucleic acid (mRNA), plasmid deoxyribonucleic acid (pDNA), and small interfering ribonucleic acid (siRNA) into specific host-cells for the treatment of inherited disorders in any diseases. The successful way to utilize the gene therapy is to develop the efficient cancer gene delivery systems. In this paper, the successful and efficient gene delivery systems are briefly reviewed on the basis of bio-reducible polymeric systems for cancer therapy. The viral gene delivery systems such as RNA-based viral and DNA-based viral vectors are also discussed. The development of bio-reducible polymer for gene delivery system has briefly discussed for the efficient cancer gene delivery of viral vectors and non-viral vectors.

Current Non-Viral Gene Therapy Strategies for the Treatment of Glioblastoma

2021 ◽  
Vol 28 ◽  
Author(s):  
Antonela Sofía Asad ◽  
Alejandro Javier Nicola Candia ◽  
Nazareno González ◽  
Camila Florencia Zuccato ◽  
Adriana Seilicovich ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Blood Brain Barrier ◽  
Viral Vectors ◽  
Malignant Gliomas ◽  
Brain Parenchyma ◽  
Brain Barrier ◽  
Viral Gene ◽  
Normal Brain ◽  
Blood Brain ◽  
Transgene Delivery

Background: Glioblastoma constitutes the most frequent and aggressive primary malignant brain tumor in adults. Despite the advances in its treatment, its prognosis remains very poor. Gene therapy has been proposed as a complementary treatment, since it may overcome the problem of the blood-brain barrier for systemic therapies, allowing to target tumor cells and their tumor microenvironment locally, without affecting the normal brain parenchyma. In comparison with viral vectors, non-viral vectors became an attractive tool due to their reduced potential of biosafety risks, lower cost, higher availability and easy storage. Objective: In this article, we aimed to outline the current preclinical and clinical developments of non-viral delivery systems for therapeutic transgene delivery in malignant gliomas. Conclusion: Non-viral vectors are efficient tools for gene delivery since they exhibit reduced non-specific cytotoxicity and can go through several modifications in order to achieve high tumor tropism and the ability to cross the blood-brain barrier to access the tumor mass. However, further evaluations in preclinical models and clinical trials are required in order to translate it into the neuro-oncology clinic.

scholarly journals Novel molecular approaches to cystic fibrosis gene therapy

2005 ◽  
Vol 387 (1) ◽  
pp. 1-15 ◽  
Author(s):  
Tim W. R. LEE ◽  
David A. MATTHEWS ◽  
G. Eric BLAIR
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Gene Delivery ◽  
Viral Vectors ◽  
Bronchial Tree ◽  
Endosomal Escape ◽  
Host Cells ◽  
Cystic Fibrosis Gene ◽  
Viral Gene ◽  
Molecular Approaches

Gene therapy holds promise for the treatment of a range of inherited diseases, such as cystic fibrosis. However, efficient delivery and expression of the therapeutic transgene at levels sufficient to result in phenotypic correction of cystic fibrosis pulmonary disease has proved elusive. There are many reasons for this lack of progress, both macroscopically in terms of airway defence mechanisms and at the molecular level with regard to effective cDNA delivery. This review of approaches to cystic fibrosis gene therapy covers these areas in detail and highlights recent progress in the field. For gene therapy to be effective in patients with cystic fibrosis, the cDNA encoding the cystic fibrosis transmembrane conductance regulator protein must be delivered effectively to the nucleus of the epithelial cells lining the bronchial tree within the lungs. Expression of the transgene must be maintained at adequate levels for the lifetime of the patient, either by repeat dosage of the vector or by targeting airway stem cells. Clinical trials of gene therapy for cystic fibrosis have demonstrated proof of principle, but gene expression has been limited to 30 days at best. Results suggest that viral vectors such as adenovirus and adeno-associated virus are unsuited to repeat dosing, as the immune response reduces the effectiveness of each subsequent dose. Nonviral approaches, such as cationic liposomes, appear more suited to repeat dosing, but have been less effective. Current work regarding non-viral gene delivery is now focused on understanding the mechanisms involved in cell entry, endosomal escape and nuclear import of the transgene. There is now increasing evidence to suggest that additional ligands that facilitate endosomal escape or contain a nuclear localization signal may enhance liposome-mediated gene delivery. Much progress in this area has been informed by advances in our understanding of the mechanisms by which viruses deliver their genomes to the nuclei of host cells.

scholarly journals Viral therapies for glioblastoma and high-grade gliomas in adults: a systematic review

2021 ◽  
Vol 50 (2) ◽  
pp. E2
Author(s):  
Joshua L. Wang ◽  
Kristen M. Scheitler ◽  
Nicole M. Wenger ◽  
J. Bradley Elder
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Viral Vectors ◽  
Cytosine Deaminase ◽  
Treatment Strategies ◽  
Oncolytic Viruses ◽  
Phase Iii ◽  
Viral Gene ◽  
High Grade ◽  
High Grade Gliomas

OBJECTIVEHigh-grade gliomas (HGGs) inevitably recur and progress despite resection and standard chemotherapies and radiation. Viral therapies have emerged as a theoretically favorable adjuvant modality that might overcome intrinsic factors of HGGs that confer treatment resistance.METHODSThe authors present the results of systematic searches of the MEDLINE and ClinicalTrials.gov databases that were performed for clinical trials published or registered up to July 15, 2020.RESULTSFifty-one completed clinical trials were identified that made use of a virus-based therapeutic strategy to treat HGG. The two main types of viral therapies were oncolytic viruses and viral vectors for gene therapy. Among clinical trials that met inclusion criteria, 20 related to oncolytic viruses and 31 to gene therapy trials. No oncolytic viruses have progressed to phase III clinical trial testing, although there have been many promising early-phase results and no reported cases of encephalitis or death due to viral therapy. Three phase III trials in which viral gene therapy was used have been completed but have not resulted in any FDA-approved therapy. Recent efforts in this area have been focused on the delivery of suicide genes such as herpes simplex virus thymidine kinase and cytosine deaminase.CONCLUSIONSDecades of research efforts and an improving understanding of the immunomodulatory effects of viral therapies for gliomas are informing ongoing clinical efforts aimed at improving outcomes in patients with HGG. The available clinical data reveal varied efficacy among different virus-based treatment strategies.

scholarly journals Viral Gene Therapy for Glioblastoma Multiforme: A Promising Hope for the Current Dilemma

2021 ◽  
Vol 11 ◽  
Author(s):  
Junsheng Li ◽  
Wen Wang ◽  
Jia Wang ◽  
Yong Cao ◽  
Shuo Wang ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Glioblastoma Multiforme ◽  
Brain Tumors ◽  
Therapeutic Approach ◽  
Viral Vectors ◽  
Viral Gene ◽  
Target Cells ◽  
Antitumor Effects ◽  
Promising Therapeutic Approach ◽  
Viral Gene Therapy

Glioblastoma multiforme (GBM), as one of the most common malignant brain tumors, was limited in its treatment effectiveness with current options. Its invasive and infiltrative features led to tumor recurrence and poor prognosis. Effective treatment and survival improvement have always been a challenge. With the exploration of genetic mutations and molecular pathways in neuro-oncology, gene therapy is becoming a promising therapeutic approach. Therapeutic genes are delivered into target cells with viral vectors to act specific antitumor effects, which can be used in gene delivery, play an oncolysis effect, and induce host immune response. The application of engineering technology makes the virus vector used in genetics a more prospective future. Recent advances in viral gene therapy offer hope for treating brain tumors. In this review, we discuss the types and designs of viruses as well as their study progress and potential applications in the treatment of GBM. Although still under research, viral gene therapy is promising to be a new therapeutic approach for GBM treatment in the future.

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