Current gene therapy最新文献

Introduction: Hereditary forms of diabetes, including Maturity-Onset Diabetes of the Young (MODY) and Neonatal Diabetes Mellitus (NDM), are rare monogenic disorders caused by mutations in genes involved in pancreatic development, beta-cell function, and insulin secretion. Unlike the polygenic nature of type 1 and type 2 diabetes, these forms provide a unique model for precision medicine.

Methods: A comprehensive literature review was conducted to explore the molecular genetics, clinical features, diagnostic advancements, and therapeutic strategies related to MODY and NDM. Particular focus was placed on genotype-phenotype correlations and responsiveness to targeted treatments.

Results: Distinct gene mutations such as GCK, HNF1A, and HNF4A in MODY, and KCNJ11, ABCC8, and INS in NDM are associated with specific clinical characteristics and treatment responses. Genetic testing plays a crucial role in early diagnosis and management. For instance, sulfonylurea therapy has effectively replaced insulin in some cases of NDMre with KATP channel mutations. In MODY, accurate genetic classification helps guide the use of oral hypoglycemics or dietary interventions instead of unnecessary insulin therapy.

Discussion: Understanding the genetic basis of MODY and NDM has enabled clinicians to personalize treatment plans, improving disease outcomes. Genetic diagnosis not only facilitates better classification but also informs prognosis and guides family screening. Despite these advances, challenges remain in access to testing and awareness among healthcare providers.

Conclusion: Molecular insights into MODY and NDM have revolutionized their diagnosis and treatment. Gene-based therapeutic approaches enhance glycemic control and quality of life, marking a significant step toward precision medicine in diabetes care. Ongoing research will be key to further optimizing individualized treatment strategies.

Crohn's disease (CD), a chronic inflammatory disorder of the gastrointestinal tract, presents significant challenges in clinical medicine due to its multifactorial etiology and varied therapeutic responses. This review examines the diverse causes of CD, including genetic predispositions identified through genome-wide association studies (GWAS), which involve scanning the genome for single-nucleotide polymorphisms associated with CD risk, as well as environmental triggers, such as diet and alterations in the microbiome. Biomarkers, such as fecal calprotectin and Creactive protein (CRP), as well as genetic markers like NOD2 mutations, provide critical tools for diagnosis and treatment stratification. Advances in computational methodologies, including multiomics analyses and machine learning, have enhanced our understanding of CD pathophysiology and therapeutic outcomes. Traditional treatments, including immunomodulators and biologics, such as anti-TNF agents, have laid the groundwork for novel cytokine-targeted therapies, such as IL-12/23 inhibitors (e.g., ustekinumab) and integrin inhibitors (e.g., vedolizumab), which aim to improve mucosal healing and reduce relapse rates. However, integrating personalized medicine into clinical practice remains challenging due to the heterogeneity of CD and limitations in biomarker validation. The integration of predictive biomarkers with computational tools enables clinicians to tailor therapy at the individual level, improving remission rates, minimizing adverse effects, and enhancing long-term disease control. These personalized strategies show promise in shifting CD management toward a more effective, patient-specific model of care. This review underscores the potential of personalized therapeutic strategies, leveraging molecular and computational insights, to optimize disease management and improve patient outcomes in CD.

Introduction: Diabetic Nephropathy (DN) is a leading cause of chronic kidney disease and end-stage renal failure, highlighting the need for improved diagnostic and therapeutic strategies. This review examines the emerging roles of exosomal microRNAs (miRNAs) and epigenetic modifications in disease, with a focus on their diagnostic and therapeutic potential.

Methods: A comprehensive analysis of the current literature was conducted, focusing on exosomal miRNAs-particularly miR-21, miR-192, and miR-29-and their impact on inflammatory pathways, such as IL-6 and NF-κB. The role of epigenetic alterations, including DNA methylation, histone modification, and noncoding RNAs, in DN progression is also discussed. Techniques for miRNA detection and exosome isolation are briefly reviewed.

Results: Exosomal miRNAs contribute to DN pathophysiology by promoting oxidative stress, inflammation, and fibrosis. Their stability and noninvasive detectability make them promising early biomarkers. Epigenetic modifications further modulate gene expression relevant to disease progression.

Discussion: These molecular changes offer novel targets for early diagnosis and therapeutic intervention in DN. The interplay between miRNAs and epigenetic regulation may provide insights into disease heterogeneity and progression. However, limitations exist regarding the standardization of detection techniques and clinical translation, necessitating further research.

Conclusion: Exosomal miRNAs and epigenetic markers present valuable tools for advancing the diagnosis and personalized treatment of DN. Enhancing detection techniques and understanding their molecular roles could pave the way for more effective clinical applications.

Cerebral Cavernous Malformations (CCMs) are vascular anomalies in the central nervous system that arise from both genetic and non-genetic factors, and can cause hemorrhage, seizures, and neurological deficits. Approximately 80% of CCMs are sporadic, while 20% are Familial (FCCMs), an autosomal dominant, monogenic disorder characterized by multiple lesions and severe clinical manifestations. Over the past three decades, linkage analyses have identified KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3 as major pathogenic genes in FCCMs. However, existing surgical and pharmacological treatments have not adequately prevented disease progression, underscoring the need for more effective strategies. Recent advancements in gene editing tools and delivery systems have transformed gene therapy from a laboratory concept to a clinical reality, offering renewed hope for FCCM patients. Given the multifactorial nature, complexity, and neurological comorbidities of FCCMs, exploring non-surgical gene therapies provides a promising approach for addressing these cerebrovascular lesions. This review summarizes the latest progress in gene editing for FCCMs and examines its therapeutic potential, while acknowledging both the promising benefits and the remaining uncertainties in this evolving field.

Introduction: Lung cancer, specifically non-small cell lung cancer (NSCLC), is a leading cause of cancer-related mortality worldwide. TP53, a crucial tumor suppressor gene, is often mutated in various cancers, including lung cancer. This study focuses on the differences in transcriptomic profiles between TP53-mutated (TP53+) and TP53-wildtype (TP53-) NSCLC tumor samples, aiming to develop a gene signature that can predict overall survival and immune response, particularly in the context of immunotherapy. It aims to identify differentially expressed genes (DEGs) associated with TP53 status in non-small cell lung cancer and develop a gene signature that can predict overall survival and immune response.

Method: Gene expression profiles from TP53-positive and TP53-negative NSCLC tumor samples were analyzed. Data were sourced from the GEO database (GSE8569, n = 69) and the TCGA database (n = 1026). Differential expression analysis was conducted to identify DEGs, which were further analyzed using LASSO regression to develop a prognostic gene signature. Quantitative PCR (qPCR) was performed to validate the expression of selected genes.

Results: A total of 535 DEGs (168 up-regulated, 367 down-regulated) were identified in TP53+ samples. Further analysis with TCGA data narrowed this down to 29 genes, from which 12 were identified as prognostic features using LASSO analysis. This 12-gene signature effectively stratified patients into low- and high-risk groups for overall survival. Differences in immune cell infiltration and immune pathway activity were significant between these groups, indicating the potential of the gene signature to predict immune response. Among the genes analyzed, BMP2, LPXN, IER3, ANLN, TNNT1, OGT, KRT8, BARX2, PRC1, and SNX30 showed statistically significant differences in qPCR results.

Discussion: The 12-gene signature demonstrates robust predictive capability for survival outcomes and immune response patterns in NSCLC patients, suggesting its potential clinical utility in precision oncology. The observed correlation between TP53 mutation status and immune microenvironment alterations provides valuable insights into the mechanistic basis of immunotherapy resistance and response.

Conclusion: This study identifies a TP53-associated transcriptomic signature that is significantly associated with overall survival in lung cancer patients. The gene signature also correlates with differences in immune cell infiltration patterns between risk groups, offering potential insights into the tumor immune microenvironment. These findings may contribute to future efforts to stratify patients and guide immunotherapy decisions, pending further experimental validation.

Introduction: The discovery of the gene as the primary unit of inheritance marked the beginning of intensive research into targeted genome modifications for treating rare genetic diseases. Despite conventional approaches such as continuous factor replacement or novel non-factor therapies, the need for a one-time infusion and long-term sustenance of clotting factors is evident. This review focuses on gene therapies discovered to treat patients with hemophilia. This narrative review seeks to highlight the current potential of gene therapies for hemophilia, elucidate their mode of action, and assess their long-term effectiveness and clinical significance.

Methods: A literature search in PubMed, Embase, Google Scholar, and Scopus databases was done using search terms like gene therapy, viral vectors, Roctavian, hemophilia, etranacogene dezaparvovec, AAV, and FIX-Padua variant.

Results: Following intensive clinical trials and successful outcomes, the currently available FDAapproved gene therapies include valoctocogene roxaparvovec (Roctavian) for hemophilia A and etranacogene dezaparvovec (Hemgenix), and fidanacogene elaparvovec (Beqvez) for hemophilia B, and an antibody-based therapy, Marstacimab (Hympavzi) for both hemophilia A and B.

Discussion: Decades of clinical research on introducing gene therapy as a potential therapy for hemophilia A and B have paved the way for successful discovery to overcome the long-term burden of factor replacement and other adjunct therapies. Gene therapy has shown persistent success in hemophilia, with clinical trials demonstrating long-term expression of functional clotting factors (Factor VIII or IX). This has reduced bleeding episodes remarkably and the need for regular factor replacement therapy. Yet the drugs need to be studied further to assess long term safety and efficacy following administration.

Conclusions: Gene therapy has shown new possibilities in hemophilia, with many patients achieving near-normal levels of clotting factors and experiencing a significant reduction in bleeding episodes. However, challenges remain, including potential declines in Factor VIII levels over time, immune responses to viral vectors, and high treatment costs. Ongoing research is focused on improving durability, expanding eligibility, and exploring alternative delivery methods.

The fusion of nanotechnology with gene editing promises a revolutionary strategy in combating cancer, providing the possibility of precise and focused treatments. This review examines the synergistic integration of these two potent technologies, specifically emphasising their combined effectiveness in oncological therapies. Nanotechnology offers a flexible framework for administering gene-editing tools, improving their accuracy, and reducing unintended side effects, all of which are significant obstacles in existing cancer treatments. Nanoparticles can improve the effectiveness of therapies, lower the risk of systemic toxicity, and allow the simultaneous manipulation of many genetic pathways involved in cancer growth by delivering CRISPR-Cas9 and other gene-editing systems directly to tumour sites. We conduct a thorough analysis of recent progress in this burgeoning field, emphasising significant advancements in the design of nanoparticles and gene-editing techniques that propel the development of next-generation cancer medicines. In addition, we address the present obstacles and constraints, such as the effectiveness of delivery, apprehensions over safety, and regulatory obstacles, while suggesting potential areas of future research to surmount these barriers. This study thoroughly examines the promise of nano-precision gene editing as a transformative approach to cancer treatment by incorporating findings from recent clinical trials and case studies. By highlighting recent clinical advancements and emerging innovations, this review underscores the potential of nano-precision gene editing as a groundbreaking approach in next-generation cancer therapy.

PAK1, a serine-threonine kinase, acts as an effector of Rac, Ras, and CDC42, which are pivotal in oncogenic signaling pathways. Its involvement spans critical cellular processes like cell cycle regulation, angiogenesis, and metastasis. PAK1 also influences therapeutic resistance mechanisms in various cancers. Serving as a linchpin in diverse signaling pathways pivotal to cancer progression, PAK1 positions itself as a promising therapeutic target. The comprehensive understanding of PAK1's roles in cancer biology underscores its potential for targeted interventions and offers prospects for improved cancer diagnostics and treatment strategies.

Introduction: Kidney injury molecule 1 (KIM-1) is a cell-surface glycoprotein expressed in the proximal tubules and encoded by the hepatitis A virus cellular receptor 1 (HAVCR1) gene. It is also expressed in renal cell carcinoma (RCC).

Objective: This study examined the immune landscape of clear cell RCC in association with HAVCR1 expression.

Methods: Next-generation sequencing (NGS) data from ccRCC tumor samples of patients from The Cancer Genome Atlas (TCGA) were interrogated for enrichment of immune infiltrates and checkpoints in tumors harboring high HAVCR1 mRNA expression or/and amplification.

Results: HAVCR1 mRNA expression was positively associated with presence of CD8 (r = 0.254, p = 3.03 x 10-8) and CD4 T-cells (r = 0.329, p = 3.98 x 10-13), while it was negatively associated with T-regulatory (T-regs) (r = ̶ 0.2, p = 1.47 x 10-5) and myeloid-derived suppressor cells (MDSCs) (r = ̶.0.285, p = 4.92 x 10-10). HAVCR1 amplification was also associated with CD8 (p = 0.0019), CD4 T cells (p = 0.0002) while expression of HAVCR1 gene was positively associated with immune checkpoints PD-L1 (CD274) (r = 0.331, p = 4.64 x 10-15) and CTLA4 mRNA expression (r = 0.085, p = 0.05). HAVCR1 transcript levels were directly correlated with those of Polybromo-1 (PBRM1) (r = 0.276, p = 9.36 x 10-11) while inversely related with BRCA-associated protein 1 (BAP1) gene expression (r = ̶ 0.134, p = 1.94 x 10-3).

Discussion: The study reveals that high HAVCR1 (KIM-1) expression in clear cell RCC is associated with a distinct immune profile characterized by increased CD8/CD4 T-cell infiltration and immune checkpoint expression, suggesting a potential role in predicting immunotherapy response, though the observational nature and reliance on TCGA data limit causal inference.

Conclusions: Collectively, a potential immune-regulatory role of KIM-1 in clear cell RCC is implicated. This could be exploited for predicting benefit from adjuvant immunotherapy.

Alzheimer's Disease (AD) represents a significant global health challenge, distinguished by a complex pathology that involves the accumulation of abnormal proteins in the brain, leading to neuronal loss and brain atrophy. Recent research has indicated a potential association between various pathogens and the development of AD, suggesting that infectious pathogens may play a role in its pathology. The study focuses on the exploration of pathogens linked to AD. It aims to enhance the understanding of the disease's etiopathogenesis, which refers to the causes and development of the condition. The findings from this analysis have the potential to contribute to improved diagnostic methods and treatment strategies for AD. Overall, the manuscript highlights the importance of exploring infectious pathogens relating to neurodegenerative disorders. This comprehensive literature review was conducted using databases such as PubMed and Scopus, focusing on research published up to March 2025. Articles were searched based on keywords related to reviews and research exploring the association/link between different pathogens and AD, emerging interventions, preventive strategies, and limitations in study design. This study indicates that various viruses, bacteria, and fungi are significant contributors to the condition, while parasites and prions play a lesser role. Notably, the variability in pathogen species among patients could provide insights into the evolution and severity of clinical symptoms associated with the disease. Additionally, some studies propose that after modification, certain fungi may actually reduce the amyloid burden in Alzheimer's patients. However, it is crucial to emphasize that there is currently no definitive evidence supporting the notion that treating infections alone can prevent or cure AD. The prevention and treatment of pathogens, including viruses, bacteria, and fungi, as well as infectious prions, may play a significant role in reducing the risk of AD. Effective management of these pathogens can help to control and prevent further damage in individuals who have already been diagnosed with AD. There is a pressing need for additional pre-clinical and clinical research to deepen the understanding of the pathophysiological connections between pathogens and AD.