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Background Uveal melanoma (UM) is the prevailing malignant tumor that develops within the eye in adults, and it has a bleak outlook because of the few treatment choices available and the high likelihood of returning after treatment. Currently, surgical intervention, radiation therapy, and a combination of both modalities are available therapeutic modalities for controlling UM. However, these techniques are associated with notable adverse effects and have limited efficacy. Therefore, there is a lack of sufficient and reliable therapies for UM, especially for advanced and metastatic UM forms. This review aims to summarize the clinical features and current therapies of UM and highlight recent progress in gene therapy approaches. Recent Findings Significant developments in gene therapy have introduced multiple strategies for targeting UM. Gene silencing using siRNA and shRNA has shown efficacy in downregulating oncogenic pathways. CRISPR/Cas9‐based editing has enabled selective disruption of tumor‐promoting genes, sensitizing tumor cells to targeted inhibitors. Restoration of tumor‐suppressive miRNAs has reduced proliferation, migration, and invasion of UM cells in preclinical models. Suicide gene therapy has demonstrated potent cytotoxicity in xenografts. Moreover, oncolytic viruses and stem‐cell–associated delivery systems provide novel mechanisms for tumor‐selective gene expression and immune activation. Although challenges persist—such as delivery efficiency, immune responses, and genetic heterogeneity—ongoing innovations in vector design, non‐viral nanoformulations, and mutation‐guided therapies continue to enhance clinical feasibility. Conclusion Gene therapy provides improved safety profiles and the possibility of tailored treatment strategies by integrating information on gene expression patterns and DNA alterations. In the future, gene therapy has the potential to improve the treatment of UM by targeting specific genetic mutations driving tumor growth and may offer new hope for patients with advanced stages of UM.

Transplantation of mesenchymal stem cells (MSCs) derived from adult bone marrow has been proposed as a potential therapeutic approach for post‐infarction left ventricular (LV) dysfunction. However, age‐related functional decline of stem cells has restricted their clinical benefits after transplantation into the infarcted myocardium. The limitations imposed on patient cells could be addressed by genetic modification of stem cells. This study was designed to improve our understanding of genetic modification of human bone marrow derived mesenchymal stem cells (hMSCs) by polyethylenimine (PEI, branched with Mw 25 kD), one of non‐viral vectors that show promise in stem cell genetic modification, in the context of cardiac regeneration for patients. We optimized the PEI‐mediated reporter gene transfection into hMSCs, evaluated whether transfection efficiency is associated with gender or age of the cell donors, analysed the influence of cell cycle on transfection and investigated the transfer of therapeutic vascular endothelial growth factor gene (VEGF). hMSCs were isolated from patients with cardiovascular disease aged from 41 to 85 years. Optimization of gene delivery to hMSCs was carried out based on the particle size of the PEI/DNA complexes, N/P ratio of complexes, DNA dosage and cell viability. The highest efficiency with the cell viability near 60% was achieved at N/P ratio 2 and 6.0 μg DNA/cm2. The average transfection efficiency for all tested samples, middle‐age group (<65 years), old‐age group (>65 years), female group and male group was 4.32%, 3.85%, 4.52%, 4.14% and 4.38%, respectively. The transfection efficiency did not show any correlation either with the age or the gender of the donors. Statistically, there were two subpopulations in the donors; and transfection efficiency in each subpopulation was linearly related to the cell percentage in S phase. No significant phenotypic differences were observed between these two subpopulations. Furthermore, PEI‐mediated therapeutic gene VEGF transfer could significantly enhance the expression level.

Oligonucleotide-based therapies are a promising approach for treating a wide range of hard-to-treat diseases, particularly genetic and rare diseases. These therapies involve the use of short synthetic sequences of DNA or RNA that can modulate gene expression or inhibit proteins through various mechanisms. Despite the potential of these therapies, a significant barrier to their widespread use is the difficulty in ensuring their uptake by target cells/tissues. Strategies to overcome this challenge include cell-penetrating peptide conjugation, chemical modification, nanoparticle formulation, and the use of endogenous vesicles, spherical nucleic acids, and smart material-based delivery vehicles. This article provides an overview of these strategies and their potential for the efficient delivery of oligonucleotide drugs, as well as the safety and toxicity considerations, regulatory requirements, and challenges in translating these therapies from the laboratory to the clinic.

Background Efficient gene transfer is a major challenge for non‐viral gene therapy. Understanding how non‐viral vectors initiate gene expression could lead to the development of new future vectors with enhanced efficacy. Methods Linear or branched polyethylenimine (PEI)/DNA complexes were generated in varying salt conditions and their transfection efficiencies were compared in vitro and in vivo using reporter genes, luciferase and green fluorescent protein, and rhodamine labeled DNA (pGeneGrip™). Results The transfection efficiency of linear PEI22/DNA in vitro was generally greater than that of branched PEI/DNA when complexes were generated in salt containing buffer. However, PEI complexes generated under salt‐free conditions generally had low transfection activity in vitro. In contrast, PEI22/DNA salt‐free complexes were highly active in vivo. Branched PEI/DNA and salt containing PEI22/DNA complexes were generally 10–100‐fold less active than the salt‐free PEI22/DNA complexes. Salt‐free PEI22/DNA complexes were small, but subsequently grew into aggregates when salt was added. In contrast, PEI25/DNA complexes remained small even after salt was added under the same conditions. Furthermore, PEI22/pGeneGrip™ complexes formed large aggregates associated with the cell membrane, cytoplasm and nucleus, while branched PEI complexes remained as small distinct particles associated with the cell membrane or in the cytoplasm. Conclusions Branched and linear PEI/DNA complexes differ in their ability to transfect cells. The greater efficiency of linear PEI might be due to an inherent kinetic instability under salt conditions. Understanding how to employ this kinetic instability of linear PEI could help in designing future vectors with greater flexibility and transfection efficiency in vivo. Copyright © 2001 John Wiley & Sons, Ltd.

Background Every cancer therapy appears to be transiently effective for cancer regression, but cancers gradually transform to be resistant to the therapy. Cancers also develop machineries to resist chemotherapy. Short interfering RNA (siRNA) has been evaluated as an attractive and effective tool for suppressing a target protein by specifically digesting its mRNA. Suppression of the machineries using siRNA may enhance the sensitivity to chemotherapy in cancers when combined with an effective delivery system. Methods To enhance the anti‐cancer effect of chemotherapy, we transferred siRNA against Rad51 into various human cancer cells using the HVJ (hemagglutinating virus of Japan, Sendai virus) envelope vector in the presence or absence of cis‐diamminedichloroplatinum(II) (CDDP, cisplatin). The inhibition of cell growth was assessed by a modified MTT assay, counting cell number, or fluorescence‐activated cell sorting (FACS) analysis after Annexin V labeling. The synthetic Rad51 siRNA was also introduced into subcutaneous tumor masses of HeLa cells in SCID mice with or without intraperitoneal injection of CDDP, and tumor growth was monitored. Results When synthetic Rad51 siRNA was delivered into HeLa cells using the HVJ envelope vector, no Rad51 transcripts were detected on day 2, and Rad51 protein completely disappeared for 4 days after siRNA transfer. When HeLa cells were incubated with 0.02 µg/ml CDDP for 3 h after siRNA transfer, the number of colonies decreased to approximately 10% of that with scrambled siRNA. The sensitivity to CDDP was enhanced in various human cancer cells, but not in normal human fibroblasts. When Rad51 siRNA was delivered into tumors using the HVJ envelope vector, the Rad51 transcript level was reduced to approximately 25%. Rad51 siRNA combined with CDDP significantly inhibited tumor growth when compared to siRNA or CDDP alone. Conclusions Rad51 siRNA could enhance the sensitivity to CDDP in cancer cells both in vitro and in vivo. Our results suggest that the combination of CDDP and Rad51 siRNA will be an effective anti‐cancer protocol. Copyright © 2005 John Wiley & Sons, Ltd.

Gene therapy is manipulation in/of gene expression in specific cells/tissue to treat diseases. This manipulation is carried out by introducing exogenous nucleic acids, such as DNA or RNA, into the cell. Because of their negative charge and considerable larger size, the delivery of these molecules, in general, should be mediated by gene vectors. Non-viral vectors, as promising delivery systems, have received considerable attention due to their low cytotoxicity and non-immunogenicity. As research continued, more and more functional non-viral vectors have emerged. They not only have the ability to deliver a gene into the cells but also have other functions, such as the performance of fluorescence imaging, which aids in monitoring their progress, targeted delivery, and biodegradation. Recently, many reviews related to non-viral vectors, such as polymers and cationic lipids, have been reported. However, there are few reviews regarding functional non-viral vectors. This review summarizes the common functional non-viral vectors developed in the last ten years and their potential applications in the future. The transfection efficiency and the transport mechanism of these materials were also discussed in detail. We hope that this review can help researchers design more new high-efficiency and low-toxicity multifunctional non-viral vectors, and further accelerate the progress of gene therapy.

The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system is a gene-editing technology. Nanoparticle delivery systems have attracted attention because of the limitations of conventional viral vectors. In this review, we assess the efficiency of various nanoparticles, including lipid-based, polymer-based, inorganic, and extracellular vesicle-based systems, as non-viral vectors for CRISPR/Cas9 delivery. We discuss their advantages, limitations, and current challenges. By summarizing recent advancements and highlighting key strategies, this review aims to provide a comprehensive overview of the role of non-viral delivery systems in advancing CRISPR/Cas9 technology for clinical applications and gene therapy.

Vaccines have proven effective in the treatment and prevention of numerous diseases. However, traditional attenuated and inactivated vaccines suffer from certain drawbacks such as complex preparation, limited efficacy, potential risks and others. These limitations restrict their widespread use, especially in the face of an increasingly diverse range of diseases. With the ongoing advancements in genetic engineering vaccines, DNA vaccines have emerged as a highly promising approach in the treatment of both genetic diseases and acquired diseases. While several DNA vaccines have demonstrated substantial success in animal models of diseases, certain challenges need to be addressed before application in human subjects. The primary obstacle lies in the absence of an optimal delivery system, which significantly hampers the immunogenicity of DNA vaccines. We conduct a comprehensive analysis of the current status and limitations of DNA vaccines by focusing on both viral and non-viral DNA delivery systems, as they play crucial roles in the exploration of novel DNA vaccines. We provide an evaluation of their strengths and weaknesses based on our critical assessment. Additionally, the review summarizes the most recent advancements and breakthroughs in pre-clinical and clinical studies, highlighting the need for further clinical trials in this rapidly evolving field.

Gene-based therapies have emerged as a new modality for combating a myriad of currently incurable diseases. However, the fragile nature of gene therapeutics has significantly hampered their biomedical applications. Correspondingly, the development of gene-delivery vectors is of critical importance for gene-based therapies. To date, a variety of gene-delivery vectors have been created and utilized for gene delivery. In general, they can be categorized into viral- and non-viral vectors. Due to safety issues associated with viral vectors, non-viral vectors have recently attracted much more research focus. Of these non-viral vectors, polymeric vectors, which have been preferred due to their low immunogenicity, ease of production, controlled chemical composition and high chemical versatility, have constituted an ideal alternative to viral vectors. In particular, biodegradable polymers, which possess advantageous biocompatibility and biosafety, have been considered to have great potential in clinical applications. In this context, the aim of this review is to introduce the recent development and progress of biodegradable polymers for gene delivery applications, especially for their chemical structure design, gene delivery capacity and additional biological functions. Accordingly, we first define and categorize biodegradable polymers, followed by describing their corresponding degradation mechanisms. Various types of biodegradable polymers resulting from natural and synthetic polymers will be introduced and their applications in gene delivery will be examined. Finally, a future perspective regarding the development of biodegradable polymer vectors will be given.