Current gene therapy最新文献

Introduction: There is an urgent and ongoing need to develop effective therapeutic strategies for lung cancer. CCR2 is considered a valid target for lung cancer treatment. However, singletarget- oriented monotherapy frequently fails to yield satisfactory results, and multi-target therapy has become the current trend. IL-21 exerts anti-tumor effects across various cancers, including lung cancer. Whether the combination of CCR2-targeted therapy and IL-21 exerts a stronger anti-tumor effect remains to be verified.

Methods: Mouse Lewis lung cancer cells and pre-constructed IL-21-siRNA-CCR2 plasmid were used. Annexin V-FITC, flow cytometry, Western blot, Ki67 IHC, immunofluorescence, and TUNEL assay were used to analyze apoptosis, immune cells, proteins, and proliferation.

Results: Compared with single-agent treatments, combination treatment significantly inhibited CCR2 expression, enhanced IL-21 expression, and slowed tumor growth in mouse lung cancer tissues. Further analysis demonstrated that this treatment effectively increased the infiltration of CD4⁺ and CD8⁺ T lymphocytes in tumor tissues, elevated the proportion of M1 macrophages while reducing that of M2 macrophages, and notably increased the percentages of CD4+ T lymphocytes and NK cells in mouse spleens.

Discussion: The combination treatment not only directly suppressed the proliferation of tumor cells but also enhanced the overall anti-tumor immune response in tumor-bearing mice. In subsequent studies, it will be further verified that the efficacy of this treatment is in a variety of tumor cell lines.

Conclusion: The combination of IL-21 and CCR2 blockade exerts a synergistic anti-lung-cancer effect.

Background: The battle against cancer has gained the interest of various researchers, scientists, pharmacologists, and pharmaceutical intervenors in China. Cancer is a leading cause of death worldwide, and the exploration of Traditional Chinese medicine plays an active role in modern medicine and patients with tumors.

Method: The literature search was done in PubMed, Web of Science, Scopus, PubChem, Google Scholar, SCI, and various online data sources. The review summarizes the pharmacology and applications of TCM as an adjuvant cancer therapeutic.

Results: More than 75% of cancer cases are treated using herbal remedies and alternative therapies like TCM in China. Researchers have focused on Western medicines for inhibiting cancer cell growth, apoptosis, and metastasis, with applications of TCM medicines in cancer patients. Furthermore, the complementary and alternative therapies used for cancer patients in China are helpful for cancer-fatigue patients with a combination of chemotherapy and radiotherapy.

Discussion: TCM is a promising strategy for researchers and provides a solid foundation for formulating future hypotheses for studies on TCM-based cancer therapy with fewer side effects and improving patient health.

Conclusion: TCM anticancer progress regulates immune responses and the role of natural killer cells, T and B cells, innate immunity, macrophages, and CD4+ lymphocytes. Additionally, chemopreventive measures in TCM nanotherapeutics shed light on underlying cancer mechanisms and cancer-suppressing genes, promoting the survival of cancer-affected patients in China. Further, it provides newer insights into the therapeutic effects of traditional Chinese medicine in controlling cancer cell growth, cancer stem cells, DNA methylation, apoptosis, and improving patient compliance, promoting health.

Introduction: 5-alpha reductase deficiency is an inherited autosomal recessive disorder that can present with severe masculinization defects and ambiguous genitalia. Up to more than 100 mutations have been reported, but phenotype and genotype associations have not been directly evidenced. Testosterone-to-dihydrotestosterone (T/DHT) ratio is a clinically diagnostic test, and the cut-off value is expected to be higher than 10.

Case presentation: This brief report of 4 patients with SRD5A2 deficiency in the same family has focused on the clinical and biochemical features of patients with the same mutation. A 14-year-old patient with c193G>C, p. Ala65Pro in SRD5A2 gene had primary amenorrhea and bilateral palpable mass in the inguinal canal. After a detailed physical examination and karyotype analysis, the patient was diagnosed with SRD5A2 deficiency with a 46, XY karyotype. In addition, the other affected siblings had the same clinical phenotype and low masculinization score. T/DHT ratio of all siblings was 14.5, 2.1, 3.7, and 19.2, respectively. Although all of them had the same genetic mutations with a homozygous pattern (c193G>C, p. Ala65Pro), a different T/DHT ratio was observed in our study.

Conclusion: The definitive diagnosis of SRD5A2 deficiency requires molecular testing, but it is currently not available in some centers. Therefore, clinical phenotype and biochemical screening, especially the T/DHT ratio, should be used for evaluating this hereditary syndrome. However, we must consider that the diagnostic sensitivity of the stimulated T/DHT ratio can be affected by various factors, such as age, ethnicity, or the presence of residual enzyme activity.

Exosomes represent the smallest size among extracellular vesicles, which also include apoptotic bodies and microvesicles. Exosomes are natural nanocarriers that play a key role in intracellular communication, consisting of a hydrophobic lipid bilayer membrane and a hydrophilic core. The membrane compositions of exosomes are similar to those of the parent cells from which they are generated. Normally, the exosome membrane contains diacylglycerol, ceramide, cholesterol, and various surface proteins, including tetraspanins and Lamb2. Almost all cell types secrete exosomes into body fluids through exocytosis, including stem cells, epithelial cells, endothelial cells, immune cells, tumor cells, neurons, mast cells, oligodendrocytes, reticulocytes, macrophages, platelets, and astrocytes. Every cell type expresses a distinct type of exosomes carrying various bioactive molecules. Exosomes are major transporters of bioactive cargo, including enzymes, receptors, growth and transcription factors, nucleic acids, lipids, and other metabolites, which strongly affect the physiology of recipient cells. Exosomes are not only potent drug and gene delivery nanocarriers, but also have potential for disease diagnosis, tissue regeneration, and immunomodulation. Exosomes are present in various body fluids, including plasma, serum, saliva, milk, nasal secretions, urine, amniotic fluid, semen, and cerebrospinal fluid, among others. Stem cell-made exosomes are potential natural therapeutics, which is due to their rejuvenating cargo and ability to cross biological barriers. However, natural exosomes' inefficient cargo transfer and short lifespan in the bloodstream have hindered their progress in therapeutic interventions. Genetic engineering of the parent cell allows for loading specific therapeutic cargo into the lumen of newly generated exosomes and/or displaying certain homing peptides or ligands at their surface, leading to extension of their lifespan and precise delivery to specific organs or tissues. This minireview explores the creation of designer exosomes through parent cell engineering and their utilization for guiding the delivery of tailored therapeutic cargo to specific organs while evading the host's innate immune response.

One of the most significant issues facing the world today is antibiotic resistance, which makes it increasingly difficult to treat bacterial infections. Regular antibiotics no longer work against many bacteria, affecting millions of people. A novel approach known as CRISPR-phage therapy may be beneficial. This technique introduces a technology called CRISPR into resistant bacteria using bacteriophages. The genes that cause bacteria to become resistant to antibiotics can be identified and cut using CRISPR. This enables antibiotics to function by inhibiting the bacteria. This approach is highly precise, unlike conventional antibiotics, so it doesn't damage our bodies' beneficial bacteria. Preliminary studies and limited clinical trials suggest that this technique can effectively target drug-resistant bacteria such as Klebsiella pneumoniae and Methicillinresistant Staphylococcus aureus (MRSA). However, challenges in phage engineering, host delivery, and the growing threat of bacterial CRISPR resistance demand urgent and strategic innovation. Our perspective underscores that without proactive resolution of these hurdles, the current hopefulness could disappear. Looking ahead, integrating next-generation Cas effectors, non-DSB editors, and resistance monitoring frameworks could transform CRISPR-phage systems from an experimental novelty into a clinical mainstay. This shift will require not only scientific ingenuity but also coordinated advances in regulatory, translational, and manufacturing efforts.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder with a complex genetic basis involving both rare mutations and common variants. This review provides a comprehensive synthesis of established and emerging genetic risk factors implicated in AD pathogenesis. Mendelian forms are strongly associated with mutations in APP, PSEN1, and PSEN2, whereas the APOE ε4 allele remains the most robust genetic risk factor for late-onset AD. Recent Genome- Wide Association Studies (GWAS) have uncovered additional susceptibility loci, including TREM2, CLU, ABCA7, and SORL1, which reflect diverse biological pathways such as amyloid metabolism, lipid regulation, and immune response. The review also highlights the roles of epigenetic mechanisms such as DNA methylation and histone modifications, as well as geneenvironment interactions in modulating disease risk and progression. Although substantial progress has been made in identifying genetic contributors, translating these findings into clinical applications remains challenging. This article underscores the need for integrative, multi-omic approaches and population-diverse studies to enhance risk prediction and enable personalized interventions for prevention and therapy in AD.

Introduction: Identifying potential biomarkers for the detection, diagnosis, and monitoring of cervical cancer (CC) constitutes a key area for future research.

Methods: Differentially expressed genes (DEGs) and survival-associated DEGs (SDEGs) were identified using the GEPIA2 database through the TCGA-CESC dataset. The 3D structures of target proteins were predicted using trRosetta and validated via SAVES v6.0. Phytocompounds were retrieved from the PubChem database, and docking studies were performed using AutoDock Vina. The miRNAs regulating HK2 and MAP7 were also predicted by implementing miRNetv2.0 and the CancerMIRNome database. Finally, the anticancer activity of these compounds was validated individually and in combination using the ME180 and SiHa CC cell lines.

Results: The present study identified the top five most hazardous novel biomarkers through DEGs (5763) and SDEGs (500) (P-value ≤ 0.05). The phytocompounds EGCG and myricetin interacted with HK2 with binding affinities of -8.3 and -8.1 kcal/mol and RMSDs of 1.369Å and 1.452Å, respectively. Similarly, EGCG (-9.1 kcal/mol) and myricetin (-7.9 kcal/mol), with the RMSD of 1.682Å and 1.148Å, showed strong bonding with the MAP7. EGCG and myricetin treatment synergistically inhibited ME180 (IC50 = 63.49μM) and SiHa (IC50 = 81.54μM) cell-proliferation. miRNAs regulating HK2 and MAP7 were identified, including hsa-mir-484 (HK2) and hsa-mir-17-5p, hsa-mir-93-5p, hsa-mir-106b-5p, among others (MAP7).

Discussion: EGCG and myricetin, in combination, showed a synergistic effect on the ME180 cell line compared to the SiHa cell line.

Conclusion: More in vitro and cell- and patient-derived xenograft models studies are needed to support the synergistic effect of EGCG and myricetin.

Introduction: Pancreatic Cancer (PC) is recognized as a highly aggressive malignancy and is anticipated to become the second leading cause of cancer-associated deaths across the United States by 2030. Owing to its late-stage diagnosis and the substantial risk of metastasis, current therapeutic strategies exhibit limited efficacy, resulting in a five-year survival rate below 10%. Consequently, identifying reliable biomarkers and therapeutic approaches remains imperative for enhancing treatment effectiveness.

Methods: In this study, using the data of Cancer Genome Atlas (TCGA) and Genome-Wide Association Study (GWAS), we identified macrophage subsets and key gene arrb2 closely related to the progression of Pancreatic Adenocarcinoma (PAAD) via the scpagwas method combined with single- cell and bulk transcriptome analysis.

Results: The results showed that in macrophage subpopulations closely related to disease progression, the ARRB2 gene was significantly associated with the prognosis of patients, and low expression suggested poor survival outcomes. The high-expression subgroup of ARRB2 exhibited higher sensitivity to a variety of drugs, and i-bet-762 showed strong molecular binding ability with ARRB2. The experimental detection further confirmed the low expression of ARRB2 in PAAD tissue, which provided the basis for its use as a prognostic marker and potential therapeutic target.

Discussion: The results of this study suggest that ARRB2 is not only a prognostic biomarker of PAAD but may also be involved in the regulation of metabolic and immune pathways, thereby affecting drug responsiveness. There was a significant difference in drug sensitivity between the high and low-expression subgroups of ARRB2, suggesting that there may be a potential mechanism between the signal pathway and the therapeutic effect, which warrants further functional research. Considering the heterogeneity of the macrophage population and its dual role in tumor promotion and inhibition, in-depth analysis of the context-dependent function of ARRB2 in the immune-rich microenvironment is expected to provide new insights for the development of combination therapy, especially the potential of combining it with BET inhibitors (such as i-bet-762).

Conclusion: Macrophages, along with ARRB2, serve an essential function in the progression of PAAD and immune regulation. The identification of ARRB2 as a prognostic biomarker and its involvement in critical oncogenic pathways furnish a theoretical foundation for targeted therapeutic interventions. These discoveries contribute to the ongoing exploration of diagnostic, prognostic, and treatment strategies for PAAD.

Gene therapy has revolutionized the therapeutic landscape for hemophilia A and B, offering the prospect for persistent endogenous production of coagulation factors VIII and IX. Recent advances in adeno-associated virus (AAV)-mediated gene transfer, particularly the approvals of valoctocogene roxaparvovec (Roctavian) and etranacogene dezaparvovec (Hemgenix), mark significant milestones in hemophilia care. This mini-review synthesizes emerging clinical data from phase I-III trials published between 2022 and 2025, emphasizing efficacy, durability, and immunogenicity profiles of leading AAV-based therapies. Innovations in vector design, such as liverspecific promoters, codon-optimized constructs, and novel capsids (e.g., AAVhu37, AAVrh10, AAV-Spark100), have improved transgene expression and expanded eligibility. Despite notable success, challenges persist, including immune-mediated transaminitis, declining factor activity over time, particularly in hemophilia A, and limitations posed by preexisting neutralizing antibodies. Additionally, CRISPR-Cas9 and non-viral delivery systems are emerging as complementary strategies, potentially enhancing therapeutic precision and overcoming AAV-related barriers. The review also addresses the critical need for equitable access and scalable production models to ensure global availability of gene therapies. With ongoing innovation and multidisciplinary collaboration, gene therapy is poised to transition from experimental intervention to mainstream curative care in hemophilia and other hematologic diseases.