Human gene therapy最新文献

{"title":"Interview with Chiara Bonini, MD.","authors":"Thomas Gallagher","doi":"10.1089/hum.2025.050","DOIUrl":"10.1089/hum.2025.050","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"937-940"},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hepatocyte Growth Factor-Modified Dental Pulp Stem Cells Potentially Regulate Novel Renal Fibrosis-Associated Gene via PI3K/AKT/GSK3β Pathway to Alleviate Renal Fibrosis.","authors":"Jingyuan Shao, Weiming Xu, Ning Tao, Haitao Du, Zhichao He, Liang Wang, Chu-Tse Wu, Hua Wang","doi":"10.1089/hum.2025.044","DOIUrl":"10.1089/hum.2025.044","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is a major global health problem characterized by renal fibrosis, for which effective therapeutic options are still lacking. Mesenchymal stem cells (MSCs) have emerged as potential candidates for treating fibrosis due to their paracrine effects. This study first compared the antifibrotic capacities of umbilical cord-derived MSCs (UCMSCs) and dental pulp stem cells (DPSCs). The results showed that DPSCs exhibited superior effects in suppressing fibrosis markers and improving the fibrotic microenvironment. Thus, subsequent studies focused on DPSC and their hepatocyte growth factor (HGF)-modified counterpart (HGF-DPSC). Using an <i>in vivo</i> unilateral ureteral obstruction (UUO) mouse model and an <i>in vitro</i> Transforming Growth Factor-Beta 1(TGF-β1)-induced Human Renal Proximal Tubule Epithelial Cell (HK-2 cell) model, this study systematically evaluated the promising antifibrotic effects and mechanisms of DPSC. The results demonstrated that HGF-DPSC significantly improved the fibrotic microenvironment by regulating the Phosphoinositide 3-Kinase/Protein Kinase B/Glycogen Synthase Kinase 3 Beta (PI3K/AKT/GSK3β) signaling pathway and suppressing β-catenin activation. We confirmed direct protein-protein interaction between HGF and Iodothyronine Deiodinase 2 (DIO2) through co-immunoprecipitation (Co-IP), which suggested a novel molecular mechanism by which HGF-DPSC exerts its antifibrotic effects. These findings highlight the multitarget mechanism of HGF-DPSC in the treatment of renal fibrosis and provide new insights and possibilities for the treatment of CKD.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"956-975"},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Highly Precise Method for the Quantitation of rAAV Cellular Uptake by ddPCR.","authors":"Albert Kiladjian, Prerana Pathak, Marina Feschenko, Svetlana Bergelson, Cullen Mason, Yu Wang","doi":"10.1089/hum.2025.023","DOIUrl":"10.1089/hum.2025.023","url":null,"abstract":"<p><p>Recombinant adeno-associated virus (rAAV) has emerged as a leading vehicle for human gene therapy. An accurate and precise infectious titer assay is critical for assessing rAAV quality, potency, and product stability. The current gold standard for measuring rAAV infectivity is the median tissue culture infectivity dose (TCID50) method, which is laborious and highly variable. In the past several years, the droplet digital PCR (ddPCR) technology has made profound impacts on gene therapy analytics as it provides absolute DNA copy quantitation and is more accurate and precise than qPCR. In this article, we leveraged the ddPCR technology and developed a method to quantify rAAV cellular uptake <i>in vitro</i>. The results demonstrated that our method is consistent with TCID50 but is significantly more precise. Utilizing a stable AAV receptor (AAVR) cell line, this method can be implemented as a platform approach for various AAV serotypes and target genes. Moreover, the method is stability indicating, as desired for a potency assay. In conclusion, a novel rAAV uptake assay has been developed which reflects the mechanism of action of rAAV, and is accurate, precise and sensitive to product quality; thus overcoming many of the challenges of the traditional TCID50 method. It is particularly useful for initial rAAV product quality assessment and can contribute to a robust assay matrix with other product-specific potency assays for late-stage programs.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"1004-1011"},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144158324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATOH-1 Gene Therapy in Acquired Sensorineural Hearing Loss: A Meta-Analysis and Bioinformatic Analysis of Preclinical Studies.","authors":"Ahmad Saeed, Osama Younis, Nada Al-Awamleh, Fares Qubbaj, Zeid Al-Sharif, Samia Sulaiman, Mohammad Al-Taher, Lubna Khreesha","doi":"10.1089/hum.2025.013","DOIUrl":"10.1089/hum.2025.013","url":null,"abstract":"<p><p>Sensorineural hearing loss (SNHL) is the most common sensory deficit globally. Acquired SNHL results from ototoxic damage to cochlear hair cells (HCs) and is typically irreversible due to their limited regenerative capacity. While no cure currently exists, targeting the underlying pathology offers potential. Preclinical studies have investigated transcription factors like ATOH1, which can induce non-sensory cells to transdifferentiate into HCs. Gene therapy using viral vectors to deliver <i>ATOH1</i> is emerging as a promising regenerative approach. PubMed, Web of Science, and Embase were systematically searched. The review was conducted following the Systematic Review Center for Laboratory Animal Experimentation guidelines. Random-effects meta-analysis was conducted using R's \"meta\" and \"metafor\" packages. To corroborate our findings, differential gene expression (DEG) analysis was performed on the GEO dataset GSE127683 using DESeq2. K-means clustering and gene set enrichment analysis (GSEA) were conducted using iDEP 2.0 and Enrichr, respectively. Four studies including 52 rodents were included. <i>ATOH1</i> gene therapy significantly reduced Auditory Brainstem Response thresholds (<i>MD = -21.37</i> dB SPL, CI: [-40.19; -2.54], <i>p</i> = 0.027), indicating improved hearing. DEG analysis showed upregulation of genes crucial for hair cell differentiation and functioning, including GFI1, PTPRQ, OTOF, USH2A, and POU4F3. GSEA highlighted key upregulated pathways related to inner ear development, auditory receptor cell differentiation and sensory perception of sound. <i>ATOH1</i> gene therapy shows promise for treating acquired SNHL. However, further clinical trials are essential to confirm these preclinical findings and advance towards a potential cure.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"989-1003"},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FDA Names Prasad CBER Director, Sparking Gene Therapy Review Concerns.","authors":"Alex Philippidis","doi":"10.1089/hum.2025.097","DOIUrl":"10.1089/hum.2025.097","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"941-944"},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144266136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AAV8-<i>LDLR</i> Gene Therapy in <i>Ldlr</i>-KO and Homozygous <i>Ldlr</i> p.W483X Mice.","authors":"Qingao Li, Muyun Tang, Ye Jin, Gengchen Su, Yufan Li, Kaide Ju, Shijie Zhang, Shuyang Zhang, Xiaodong Luan","doi":"10.1089/hum.2024.164","DOIUrl":"10.1089/hum.2024.164","url":null,"abstract":"<p><p>The low-density lipoprotein receptor (LDLR) plays a crucial role in cholesterol regulation and lipoprotein transport. Variations in the <i>LDLR</i> gene can cause familial hypercholesterolemia (FH), with homozygous familial hypercholesterolemia (HoFH) being the most severe form. HoFH is marked by elevated low-density lipoprotein cholesterol (LDL-C) levels and early onset of cardiovascular disease, often with a poor prognosis. Current treatment options for HoFH are limited by insufficient effectiveness and restricted availability. Gene therapy, which involves the delivery of functional <i>LDLR</i> genes, offers a promising and innovative approach that could significantly improve outcomes for patients with HoFH. In this study, the adeno-associated virus serotype 8 (AAV8) vector was used to deliver the <i>LDLR</i> gene specifically to hepatocytes. The vector was designed using the pAAV-TBG plasmid, incorporating a hepatocyte-specific thyroid hormone-binding globulin (TBG) promoter. Viral packaging was performed in HEK 293T cells, followed by virus collection, purification, and titration. Mice, including C57BL/6J, <i>Ldlr</i>-KO, and homozygous <i>Ldlr</i> p.W483X mice, were injected with low, medium, or high doses of the virus via the tail vein. The efficacy and safety of the AAV8-<i>LDLR</i> gene therapy were assessed through Western blot analysis, lipid profiling, and liver pathology. AAV8-mediated <i>LDLR</i> delivery effectively improved lipid levels in both <i>Ldlr</i>-KO and homozygous <i>Ldlr</i> p.W483X mice. LDL-C levels showed a sustained reduction over the 2-month observation period. Western blot analysis confirmed the expression of LDLR protein in the liver, while lipid profiling demonstrated significant reductions in total cholesterol, triglycerides, LDL-C, and high-density lipoprotein cholesterol levels. Liver histopathology revealed no significant differences in non-alcoholic fatty liver disease scores between groups, indicating a favorable safety profile, particularly at low and medium doses. AAV8-<i>LDLR</i> gene therapy shows considerable promise as an effective treatment for HoFH. Our results indicate that this therapy significantly reduces lipid levels while maintaining a favorable safety profile.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"976-988"},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recombinant Adeno-Associated Virus Integration Profiles in Nonhuman Primates and Gene Therapy Participants after Treatment with Valoctocogene Roxaparvovec.","authors":"Chris B Russell, Christian Vettermann, Suresh Agarwal, Evan Witt, Wyatt Clark, Jeremy Arens, Raffaele Fronza, Kristin M Obrochta Moss, Theresa Kasprzyk, Tara M Robinson, Huyen Tran, Gili Kenet, Priyanka Raheja, Will Lester, Kevin Eggan, Stephen Zoog","doi":"10.1089/hum.2024.236","DOIUrl":"10.1089/hum.2024.236","url":null,"abstract":"<p><p>Recombinant adeno-associated viruses (AAVs) are clinically relevant vectors for gene therapy that persist largely as extrachromosomal episomes but also infrequently integrate into host genomes. Valoctocogene roxaparvovec is an approved AAV-based gene therapy for severe hemophilia A. We present a molecular characterization of the vector integration profiles in 5 human biopsy samples from valoctocogene roxaparvovec clinical trials as well as in samples from valoctocogene roxaparvovec-treated nonhuman primates (NHPs). The number of genomic integrations was substantially below the previously reported number of transgene-expressing cells, and integration profiles were similar between human and NHP samples. The integration profiles were polyclonal, similarly distributed across the genome, and demonstrated a small bias toward regions of open chromatin and actively transcribed genes, with no relative enrichment in cancer-associated genes. These observations were replicated between species and support the concept that preclinical assessment of AAV vector integration in NHPs is representative of outcomes in humans.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"945-955"},"PeriodicalIF":3.9,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autologous Production: The Future of Sustainable Antibody Treatments.","authors":"Steevens Bouaziz, Florence Rouleux-Bonnin, Stéphanie David, Guillermo Carvajal Alegria, Florence Velge-Roussel","doi":"10.1089/hum.2025.052","DOIUrl":"https://doi.org/10.1089/hum.2025.052","url":null,"abstract":"<p><p>Antibody gene transfer offers a promising solution to the high cost and frequent administration of monoclonal antibodies (mAbs), enabling the body to produce its own drugs economically and sustainably. This review addresses the challenges faced by antibody therapies, including economic and environmental impacts, as well as patient-related issues such as efficacy and tolerance. We propose that direct <i>in vivo</i> protein production, or autologous production, via plasmid DNA (pDNA) injection may address some of these challenges. This pDNA-based strategy provides a cost-effective alternative while maintaining flexibility and adaptability for various proteins, making it suitable for a wide range of pathological contexts. Additionally, gene therapy with plasmids could reduce the need for frequent injections, improving patient compliance. In this review, we provide an overview of the pioneering studies that introduced the use of pDNA for <i>in vivo</i> protein production. We focus on key factors for successful autologous production, such as plasmid design, vectorization, and methods of administration. Finally, we explore various applications where autologous production could serve as a promising alternative for therapeutic antibody treatments.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144527693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The β-Hemoglobinopathies as a Model for the Development of Nonviral, Episomal Vectors for Gene Therapy.","authors":"Aglaia Athanassiadou, Argyro Sgourou, Meletios Verras","doi":"10.1089/hum.2025.034","DOIUrl":"https://doi.org/10.1089/hum.2025.034","url":null,"abstract":"<p><p>The study of β-hemoglobinopathies and associated β-globin genes has revealed that genetic elements, such as the Locus Control Region (LCR) or the replication Initiation Region (IR) of the β-globin gene locus, are essential for the regulation of β-globin genes replication and expression. The LCR at 5' of the β-globin genes plays major role in the intricate regulation of transcription of the \"β-like globin genes\" expression <i>in situ</i> and in gene therapy protocols by viral gene transfer, ensuring globin gene expression independent from integration site and exerting a critical role in chromatin organization and boundary formation. The IR element, located at the 5' site of the <i>HBB</i> gene promoter, functions as the initiation point for physiological, bidirectional DNA replication, both <i>in situ</i> and within an episomal vector, and induces replication in positions that do not possess such capacity. It enhances plasmid replication, establishment, and transgene expression in the descendants of transfected human CD34+ cells during colony-forming cell assays. A third required genetic element is the promoter of the transgene(s). This is either the <i>HBB</i> gene native promoter or the CD34+ cell-functional ubiquitous promoter spleen focus-forming virus. Both promoters, in <i>in vitro</i> studies, can direct accurate, efficient transcription from episomal, S/MAR-based vectors. Mutations in the <i>HBB</i> gene native promoter as well as in LCR and IR lead to β-thalassemia. Another genetic element, the S/MAR, deriving from the 5' of the human β-interferon gene, ensures plasmid nonintegration and long-term nuclear retention in the prototype episomal vector pEPI-1 and derivative episomal vectors. Such S/MAR-based episomal vectors form the basis from which the genetic elements collectively- <i>HBB gene</i> promoter, LCR, and IR-represent a comprehensive model for the design of efficient episomal vectors with efficient transcription, replication, and long-term nuclear retention of vector for gene therapy applications for the β-hemoglobinopathies within the context of <i>gene addition</i> strategy.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144527694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"10-Month-Old Boy Makes History as World's First Patient Treated with Personalized CRISPR Therapy.","authors":"Alex Philippidis","doi":"10.1089/hum.2025.124","DOIUrl":"https://doi.org/10.1089/hum.2025.124","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144474979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}