Current Issue : October-December Volume : 2025 Issue Number : 4 Articles : 5 Articles
Introduction: Adeno-associated virus (AAV) vectors are promising tools for cancer gene therapy, yet their clinical application in head and neck squamous cell carcinoma (HNSCC) is hindered by suboptimal transduction efficiency and off-target risks. Bioengineered AAV capsids require optimization to enhance tumor-specific targeting while minimizing systemic toxicity. Methods: We employed a directed evolution strategy combining DNA shuffling and site-directed mutagenesis to generate AAV variants. Five rounds of in vitro selection were performed using HNSCC cell lines (SCC-090, SCC-152, FaDu), followed by validation through in vitro transduction assays and in vivo studies in HNSCC xenograft mouse models. AAVzy9-3, a lead capsid variant, was further tested for a2d1-targeted gene silencing efficacy. Results: This capsid demonstrated superior transduction efficiency in SCC-090, SCC-152 and FaDu cells when compared to the most efficient parental capsid. The validation of AAVzy9–3 targeting of HNSCC cells was validated through both in vitro and in vivo methods, employing a transplanted tumor mouse model. The results showed that AAVzy9–3 was more effective at infecting HNSCC cells than the wild type, while demonstrating reduced infectious potential toward other cells and organs. Additionally, the study used AAVzy9-3 to knockdown a2d1 expression in a mouse model of HNSCC transplanted tumors, resulting in reduced tumor size. Discussion: The development of AAVzy9-3, a novel AAV variant with HNSCCspecific tumor tropism, addresses critical limitations of conventional AAVs. The in vivo antitumor activity validates its therapeutic potential for HNSCC....
Hematopoietic stem/progenitor cell (HSPC)-based anti-HIV- 1 gene therapy holds promise to provide life-long remission following a single treatment. Here we report a multi-pronged anti-HIV-1 HSPC-based gene therapy designed to defend against and attack HIV-1 infection. We developed a lentiviral vector capable of co-expressing three anti-HIV-1 genes. Two are designed to prevent infection, including a short hairpin RNA (shRNA) (CCR5sh1005) to knock down HIV-1 co-receptor CCR5 and a membrane-anchored HIV-1 fusion inhibitor (C46). The third gene is a CD4-based chimeric antigen receptor (CAR) designed to attack HIV-1-infected cells. Our vector also includes a non-signaling truncated human epidermal growth factor receptor (huEGFRt) which acts as a negative selection-based safety kill switch against transduced cells. Anti-HIV-1 vector-transduced human CD34+ HSPC efficiently reconstituted multi-lineage human hematopoietic cells in humanized bone marrow/liver/thymus (huBLT) mice. HIV-1 viral load was significantly reduced (1-log fold reduction, p < 0.001) in transplanted huBLT mice. Anti-huEGFR monoclonal antibody cetuximab (CTX) administration significantly reduced huEGFRt+ vector-modified cells (>4-fold reduction, p < 0.01) in huBLT mice. These results demonstrate that our strategy is highly effective for HIV-1 inhibition, and that CTX-mediated negative selection can deplete anti-HIV- 1 vector-modified cells in the event of unwanted adverse effects in huBLT mice....
Gene therapy, a pivotal cornerstone in biomedical research, has emerged as a transformative approach for addressing a wide spectrum of dermatologic conditions, including hereditary disorders, chronic wounds, and immune related skin diseases. The skin, with its expansive surface area and regenerative capacity, serves as an ideal platform for localized gene delivery. However, conventional gene therapy strategies face critical limitations, such as high costs, suboptimal transfection efficiency, immunogenicity, and off-target effects. In this context, gene hydrogels have emerged as an innovative paradigm, offering tailored physicochemical and biological functionalities to overcome these challenges. Gene hydrogels are distinguished by their tunable morphologies (e.g., particulate or bulk gel configurations), which enable precise control over therapeutic release kinetics and spatial distribution. Their three-dimensional polymeric networks recapitulate the extracellular matrix, functioning as bioactive scaffolds that enhance tissue regeneration, facilitate cell migration, and accelerate wound healing. By integrating stimuli-responsive polymers, these hydrogels achieve spatiotemporal control of gene delivery, improving target specificity while minimizing systemic exposure. Furthermore, their inherent biocompatibility and biodegradability mitigate immunogenic risks and prevent long-term residue accumulation, addressing pivotal safety concerns in clinical translation. This review systematically examines the multifaceted advantages of gene hydrogels, including their ability to bypass the stratum corneum barrier, protect genetic payloads from enzymatic degradation, and sustain localized therapeutic effects over extended periods. Recent advancements in “smart” hydrogels, responsive to pathological cues such as pH fluctuations or matrix metalloproteinase overexpression, further underscore their potential in personalized medicine. By synergizing material science with gene-editing technologies, gene hydrogels represent a revolutionary leap toward precision dermatologic therapies. Future challenges, such as scalable manufacturing and dynamic regulatory mechanisms, are critically analyzed alongside opportunities in intelligent material design and interdisciplinary innovation. This comprehensive analysis positions gene hydrogels as a cornerstone for next-generation dermatologic therapeutics, bridging the gap between laboratory innovation and clinical impact....
Aging is characterized by a progressive decline in organ and tissue structure and function, significantly increasing the risk of many chronic diseases. Developing interventions to delay aging holds the potential to reduce the burden of age-associated diseases and promote healthy longevity. Gene therapy has emerged as a clinically transformable approach, leveraging advanced gene editing and delivery systems to target the molecular underpinnings of aging. This review systematically explores the potential of gene therapy strategies in aging intervention, focusing on approaches that enhance genomic and epigenetic stability, restore metabolic homeostasis, modulate immune responses, and rejuvenate senescent cells. By providing a comprehensive overview and forward-looking insights, this article aims to inform future research directions and translational applications of gene therapy in mitigating aging-related decline....
Objective ‒ Data mining was applied to explore the expression, functional enrichment, and signal pathway of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) gene in non-small cell lung cancer (NSCLC) and its relationship with patient prognosis. Methods ‒ The expression of MTHFD2 gene in NSCLC and its adjacent tissues was studied by bioinformatics data analysis. The biological function and signal pathway of MTHFD2 gene were enriched, and the MTHFD2 protein– protein interaction (PPI) network was constructed in the string database. The relationship between MTHFD2 expression and overall survival (OS), disease free survival (DFS) of NSCLC patients was analyzed in GEPIA database. Results ‒ In NSCLC patients, the expression level of MTHFD2 in cancer tissues was significantly higher than that in adjacent normal tissues (P < 0.05). There were 21 related proteins in the PPI network, and the interaction relationship between proteins was 173 with the average local clustering coefficient of 0.881. The biological process of MTHFD2 and relevant genes was mainly enriched in tetrahydrofolate metabolic process, onecarbon metabolic process, and folic acid metabolic process. The KEGG pathway of MTHFD2 and relevant genes wasmainly enriched in one carbon pool by folate, metabolic pathways, and antifolate resistance pathway. The OS of patients with high expression of MTHFD2 gene in lung adenocarcinoma (LUAD) was significantly lower than that of patients with low expression (hazard ratio [HR] = 1.6, P = 0.0041), while the expression level of MTHFD2 was not related to DFS of LUAD (HR = 1.4, P = 0.05), lung squamous cell carcinoma (LUSC; HR = 1.3, P = 0.16), and OS of LUSC (HR = 0.82, P = 0.15). MTHFD2 expression level was correlated with B cells, CD8+ T (r = 0.143, P < 0.05) and CD4+ T lymphocyte infiltration. Conclusion ‒ MTHFD2 gene is highly expressed in NSCLC and participates in the metabolism of folic acid and one carbon unit. Its high expression is related to the poor prognosis of patients and may apply as a potential new target for therapy of NSCLC. However, the primary findings are derived from bioinformatic analyses, which, while valuable, necessitate further validation through further empirical methods....
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