Human gene therapy最新文献

{"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}

{"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":"https://doi.org/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":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-12","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":"https://doi.org/10.1089/hum.2025.097","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-11","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":"Progress Toward a Cure for All Patients with Cystic Fibrosis: An Interview with Patrick Thibodeau, PhD.","authors":"","doi":"10.1089/hum.2025.105","DOIUrl":"https://doi.org/10.1089/hum.2025.105","url":null,"abstract":"","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257923","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":"https://doi.org/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":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-04","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":"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":"https://doi.org/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":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-04","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":"https://doi.org/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":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-04","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":"Periostin Exon 17 Skipping Enhances the Efficacy of Local Adeno-Associated Viral-Microdystrophin Administration in a Fibrotic Model of Duchenne Muscular Dystrophy.","authors":"Jessica Trundle, Alexis Boulinguiez, Ngoc Lu-Nguyen, James March, Alberto Malerba, Linda Popplewell","doi":"10.1089/hum.2024.256","DOIUrl":"https://doi.org/10.1089/hum.2024.256","url":null,"abstract":"<p><p>Duchenne muscular dystrophy (DMD) is a severe, progressive genetic disorder primarily affecting boys, characterized by muscle degeneration due to mutations in the DMD gene encoding dystrophin, a crucial protein for muscle fiber integrity. The disease leads to significant muscle weakness and eventually to loss of ambulation. Adeno-associated viral (AAV)-microdystrophin (MD) gene therapy shows promise in preclinical and clinical settings. However, muscle fibrosis, a consequence of chronic inflammation and extracellular matrix remodeling, exacerbates disease progression and may hinder therapeutic efficacy. Periostin, a matricellular protein involved in fibrosis, is upregulated in DMD rodent models and correlates with collagen deposition. We previously developed an antisense oligonucleotide strategy to induce exon 17 skipping and so reduce periostin expression and collagen accumulation in the fibrotic D2.<i>mdx</i> mouse model of DMD. Here, we investigated the combined effects of periostin modulation and AAV-MD1 treatment. We found that systemic periostin splicing modulation significantly improved muscle function, assessed by forelimb grip strength and treadmill performance. Importantly, periostin exon skipping increased the MD protein expression. These findings suggest that targeting periostin in conjunction with MD therapy could represent a valid therapeutic strategy for DMD.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215695","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":"Limitation of Assay Sensitivity Revealed by the Improvement of Cell-Based Assay Against Various Adeno-Associated Virus Serotypes.","authors":"Ryota Watano, Kenji Ohba, Yoshihide Sehara, Yuka Hayashi, Yasushi Saga, Masashi Urabe, Tsukasa Ohmori, Hiroaki Mizukami","doi":"10.1089/hum.2024.261","DOIUrl":"10.1089/hum.2024.261","url":null,"abstract":"<p><p>Gene therapy using adeno-associated virus (AAV) vectors is currently expanding to broad clinical applications. As the presence of a neutralizing antibody (NAb) against AAV capsids significantly restrains their efficacy, an accurate evaluation of NAb status is crucial for selecting appropriate candidates for gene therapy. Notably, cell-based NAb assays may not be sufficiently sensitive for detecting low-titer NAb, and few assays can evaluate multiple AAV serotypes using a commonly available cell. In this study, we developed a sensitive NAb assay against various AAV serotypes using commonly available HEK293 and Huh-7 cells. We found that adding glucose efficiently enhanced transgene expression across various AAV serotypes without causing cell damage. In addition, by combining a highly sensitive reporter gene, NanoLuc, the necessary dose of AAV vector was significantly reduced. The reduction of AAV dose resulted in the increased sensitivity of NAb detection as low as 100 vector genomes/cell. At the lower vector doses, sensitivity improvement was not observed regardless of serotypes, suggesting the limit of assay sensitivity of the cell-based NAb assay. These findings provide a highly sensitive methodology for assessing NAb titers and offer insights into conditions to attain maximal sensitivity in the cell-based NAb assay.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"914-924"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101788","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":"Oncolytic Adenovirus Armoring with <i>CXCL9</i> and <i>IL15</i> Shows Potent Antitumor Activity and Boosts CAR-T Therapy for Prostate Cancer.","authors":"Lin Fang, Xueyan Wang, Yi Zhang, Chen Zhang, Xiaoxiao Liu, Wanjing Li, Yuxin Zhang, Nan Sun, Junnian Zheng, Gang Wang","doi":"10.1089/hum.2024.254","DOIUrl":"10.1089/hum.2024.254","url":null,"abstract":"<p><p>Chimeric antigen receptor T cell (CAR-T) therapy has achieved great success and progress for treatment of hematological malignancy, but it still cannot overcome the obstacles in solid tumors. The hostile tumor microenvironment (TME), such as dense extracellular matrix, hypoxia, low pH, and tumor-derived metabolites, largely impedes CAR-T function. Oncolytic virus, as a form of immunotherapy, provides a way to antagonize the TME and improve the efficacy of CAR-T cells in solid tumors. In this study, the chemokine <i>CXCL9</i> and interleukin 15 (<i>IL15</i>) genes were genetically integrated into adenoviral vector to construct oncolytic adenovirus (OAV) Ad-CXCL9-IL15, which could infect tumor cells to express and secrete CXCL9 and IL15. Ad-CXCL9-IL15 showed potent antitumor activity in xenografted prostate cancer model and augmented the tumor infiltration of CD45⁺CD3⁺ T and CD8⁺ T cells in immunocompetent mice. Moreover, Ad-CXCL9-IL15 treatment decreased Treg cells in tumor mass and increased CD44⁺CD62L⁺ T cells in spleen. Indicating that Ad-CXCL9-IL15 modified the TME and augmented antitumor immune responses <i>in vivo</i>. Furthermore, administration of Ad-CXCL9-IL15 dramatically promoted infiltration and survival of B7H3-targeting CAR-T cells, improved the therapeutic efficacy, and prolonged the survival time of prostate cancer-bearing mice. Therefore, cytokine-armored OAV Ad-CXCL9-IL15 could be used as a bioenhancer to modify TME and boost immunotherapy for solid tumors.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":"884-901"},"PeriodicalIF":3.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998268","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}