Human gene therapy最新文献

{"title":"Long-Term Functional Correction of Pompe Disease and Increased α-Glucosidase Expression after Gene Therapy with Novel Combinations of Muscle-Targeted Transcriptional <i>Cis</i>-Regulatory Elements.","authors":"Quang Hong Pham, Venkata Anudeep Bheemsetty, Phuong Anh Nguyen, Ermira Samara-Kuko, Fangye Gao, Marinee K Chuah, Thierry VandenDriessche","doi":"10.1177/10430342251359989","DOIUrl":"https://doi.org/10.1177/10430342251359989","url":null,"abstract":"<p><p>The development of efficient and safe muscle-directed gene therapy is an unmet medical need. One of the bottlenecks in muscle-directed gene therapy is the high levels of muscle-targeted transcription required in these afflicted target tissues. To circumvent this problem, novel transcriptional cis-regulatory elements (CREs) were identified by transcriptome-wide data-mining that led to a significant increase of transgene expression in skeletal muscle, heart, and diaphragm after adeno-associated viral vector 9 (AAV9) gene transfer. The expression achieved with this CRE arrays outperformed that obtained with several quintessential muscle-targeted promoters, such as the synthetic SPc5-12 and MHCK7 promoters, used in various muscle-targeted gene therapy clinical trials. Incorporation of these CRE arrays led up to a robust 20- to 30-fold increase in luciferase reporter gene expression when compared with the SPc5-12 and MHCK7 promoters. To validate their therapeutic efficacy, AAV9 vectors containing CREs and encoding α-glucosidase (<i>GAA</i>) were administered to <i>GAA</i>-/- knockout mice that mimic Pompe disease (glycogen storage disease type II) in human subjects. The CRE arrays resulted in a significant 25-fold increase in GAA protein and <i>GAA</i> mRNA expression in different skeletal muscles, leading to GAA activity levels comparable with those of wild-type mice. Subsequently, this led to a significant decrease in glycogen accumulation and a restoration of centronuclear localization similar to those of wild-type levels. Most importantly, long-term correction of skeletal muscle, diaphragm, and cardiac function was achieved in <i>GAA</i>-/- knockout mice treated with the CRE-containing AAV9 vectors yielding normal phenotypes indistinguishable from wild type. This robust phenotypic correction was demonstrated based on grip and hanging tests, cardiac conductance assays as reflected by PR interval prolongation, and diaphragm contractility function tests. The current study has broad implications for improving outcomes of future clinical trials in Pompe patients and other genetic disorders that affect skeletal muscle, heart, and diaphragm.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659047","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 Lived Experience of Pediatric Gene Therapy Clinical Trial in Duchenne Muscular Dystrophy: Exploring Perceptions of Parents and Professionals Using Social Representation Method.","authors":"Shotaro Tachibana, Dominique Vincent-Genod, Pascal Rippert, Carole Vuillerot, Silvana De Lucia","doi":"10.1177/10430342251359998","DOIUrl":"https://doi.org/10.1177/10430342251359998","url":null,"abstract":"<p><p>In recent decades, medical and scientific advances have led to the development of new therapeutic approaches for Duchenne muscular dystrophy (DMD), including gene therapy (GT), which is currently being evaluated. Recruiting enough children in clinical trials remains a challenge, depending on parental decisions. Numerous studies have already been carried out to understand these decision-making factors. To date, no study in Europe has been conducted among the various stakeholders lived experience in a DMD GT trial. Our qualitative study explored participants' perceptions using a social representation method and compared them. We recruited 42 participants, divided into 2 groups comprising 21 parents and 21 professionals participating in GNT-014, a DMD natural history study. Each participant was interviewed on four questions about clinical trials, GT, and the facilitators and barriers of the clinical trial pathway. A prototypical and categorical analysis was carried out using \"Pointe-au-Sel\" software to analyze the data quantitatively. This method highlights which perceptions are shared within the same group and brings out the most important and most frequently evoked terms. We exported the data as a superimposed scatterplot of the representations of both groups for each question. We obtained a total of 453 evocations for the parents' group and a total of 611 evocations for the professionals' group. For clinical trial and GT, <i>hope and scientific progress</i> are common to the core of both groups but are not at the same level of representation. Parents evoked <i>human contact</i> as the main facilitator and what their child may undergo and become for barriers. For professionals, the facilitators and barriers are centered on the terms that can influence the proper conduct of the trial. These comparative results imply that the vision of the different stakeholders is not totally shared in trial participation. On the contrary, the term GT may also have an influence on professionals, including caregivers.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144636926","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 Responsible Development of Adeno-Associated Virus Gene Therapies.","authors":"James M Wilson, Arthur L Caplan","doi":"10.1177/10430342251359668","DOIUrl":"https://doi.org/10.1177/10430342251359668","url":null,"abstract":"<p><p>Several unexpected fatalities in patients who received adeno-associated virus (AAV)-based gene therapies have recently occurred. These tragic events have cast a pall over the entire sector with some stakeholders suggesting that AAV is patently unsafe as a gene delivery platform and ought not to be pursued. This conclusion is not warranted.</p>","PeriodicalId":13007,"journal":{"name":"Human gene therapy","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608181","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":"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}