Gene Therapy最新文献_第5页

Vaccine elicitation of HIV broadly neutralizing antibodies from genome-edited B cells in non-human primates and derived lymphoid organoids 在非人类灵长类动物和衍生的淋巴样器官中从基因组编辑的B细胞中获得HIV广泛中和抗体的疫苗。

IF 5.9 3区医学

Gene Therapy Pub Date : 2026-04-10 DOI: 10.1038/s41434-026-00610-8

Mary Tenuta, Morgan Bravo, Alex Olson, Celia L. Saney, Jason Weinfurter, Elana Ben-Akiva, Disha Bhange, Christopher A. Cottrell, Logan Vosler, Kimberly Weisgrau, Dennis R. Burton, Darrell J. Irvine, William R. Schief, Eva Rakasz, Chester J. Joyner, James E. Voss

{"title":"Vaccine elicitation of HIV broadly neutralizing antibodies from genome-edited B cells in non-human primates and derived lymphoid organoids","authors":"Mary Tenuta, Morgan Bravo, Alex Olson, Celia L. Saney, Jason Weinfurter, Elana Ben-Akiva, Disha Bhange, Christopher A. Cottrell, Logan Vosler, Kimberly Weisgrau, Dennis R. Burton, Darrell J. Irvine, William R. Schief, Eva Rakasz, Chester J. Joyner, James E. Voss","doi":"10.1038/s41434-026-00610-8","DOIUrl":"10.1038/s41434-026-00610-8","url":null,"abstract":"HIV broadly neutralizing antibodies (bnAbs) are promising reagents for prevention and therapy of disease; however, their elicitation is constrained by genetic limitations of the human B cell antigen-receptor (BCR) repertoire. Precision genome-editing offers a potential solution by enabling bnAb genes to be programmed into the BCR repertoire as IgH-modified B cells. Such cells can be vaccinated to elicit durable bnAb memory responses in mice; however, extending this success to non-human primates (NHPs) would be a major advance towards clinical translation. Here, we show that ex vivo reprogrammed NHP B cells can survive autologous infusion and respond to immunization, differentiating into antibody-secreting cells (ASCs) that can produce up to 1 µg/ml of a bnAb in serum following vaccination prime. Although durable transgenic memory responses were not generated, vaccination of engineered cells in secondary lymphoid organoid (SLO) cultures recapitulated transient ASC responses in vitro. These findings suggest that NHP-derived SLOs could provide a platform to optimize engineering and vaccination conditions that drive germinal center maturation of IgH-reprogrammed B cells in a clinically relevant NHP model, supporting the development of engineered B-cell vaccines that generate durable bnAb responses as a potential functional cure for HIV.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"33 5","pages":"541-558"},"PeriodicalIF":5.9,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-026-00610-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147653969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The poly-(HA-GMA) hydrogel carrying AAV8-sTβRII alleviates scar formation in mice skin wound healing by inhibiting fibrosis 携带aav8 - st - β rii的聚（HA-GMA）水凝胶通过抑制纤维化减轻小鼠皮肤创面愈合过程中的瘢痕形成。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-04-01 DOI: 10.1038/s41434-026-00608-2

Jinhao Chen, Lijun Zhan, Jinyan Duan, Tianning Wang, Zenan Meng, Qianru Wang, Jianlin Yang, Xiaofei Huang, Yue Liao, Xinyu Song, Chunyu Cao

{"title":"The poly-(HA-GMA) hydrogel carrying AAV8-sTβRII alleviates scar formation in mice skin wound healing by inhibiting fibrosis","authors":"Jinhao Chen, Lijun Zhan, Jinyan Duan, Tianning Wang, Zenan Meng, Qianru Wang, Jianlin Yang, Xiaofei Huang, Yue Liao, Xinyu Song, Chunyu Cao","doi":"10.1038/s41434-026-00608-2","DOIUrl":"10.1038/s41434-026-00608-2","url":null,"abstract":"Effective scar control requires selectively suppressing late-stage fibrosis without compromising early wound closure. We developed a localized, time-staged delivery system. A poly-(HA-GMA) hydrogel serves as a short-term depot, loaded with AAV8-sTβRII and applied directly along the wound margin. Materials characterization showed a water-rich porous network that rapidly imbibes and releases vector primarily by diffusion. In vivo, the hydrogel naturally degrades in ~3 days, enabling local enrichment in early healing without excessive retention. In a mouse full-thickness skin-wound model, this approach achieved efficient transduction of the cutaneous and fascial layers while markedly reducing hepatic exposure. From postoperative day 6 onward it accelerated closure and produced a thinner dermis, more orderly collagen organization, and a lower collagen area fraction. Mechanistically, Flag-sTβRII was detected within scar tissue. Phospho-Smad2/3 and α-SMA were reduced, whereas total Smad2/3 was largely unchanged, indicating that inhibition occurs at the activation step of the TGF-β/Smad pathway. Moreover, adding exogenous TGF-β1 reversed the macroscopic and histological benefits, strengthening the evidence for pathway specificity. Compared with direct intradermal injection, hydrogel delivery simultaneously increased local expression and limited systemic spillover. Using the AAV8 capsid provided the most favorable balance—high in skin, low in liver. Safety readouts—including body weight, serum transaminases, and histology of major organs—showed no abnormalities. To our knowledge, the “HA-GMA × AAV8-sTβRII” strategy precisely aligns pathway antagonism with the escalation phase of fibrosis, yielding improvements from molecular and cellular phenotypes to tissue remodeling and healing. It offers a generalizable, materials–biology integrated platform for anti-fibrotic gene therapy at the wound edge.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"33 3","pages":"330-344"},"PeriodicalIF":4.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147591670","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}

引用次数: 0

First-in-human nuclease-free homologous recombination-dependent gene editing in pediatric patients with methylmalonic acidemia: results of a phase 1/2 study 甲基丙二酸血症儿童患者的首次人类无核酸酶同源重组依赖基因编辑：1/2期研究的结果

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-03-30 DOI: 10.1038/s41434-026-00609-1

Jirair K. Bedoyan, Thomas Morgan, Angela Sun, Hong Li, Daniel Gruskin, Marie Payton, Frederic Chereau, Eugene Scott Swenson, Qun Lin, Mark A. Kay, Jerry Vockley

{"title":"First-in-human nuclease-free homologous recombination-dependent gene editing in pediatric patients with methylmalonic acidemia: results of a phase 1/2 study","authors":"Jirair K. Bedoyan, Thomas Morgan, Angela Sun, Hong Li, Daniel Gruskin, Marie Payton, Frederic Chereau, Eugene Scott Swenson, Qun Lin, Mark A. Kay, Jerry Vockley","doi":"10.1038/s41434-026-00609-1","DOIUrl":"10.1038/s41434-026-00609-1","url":null,"abstract":"Gene-based editing can potentially correct the genetic defect in methylmalonic acidemia (MMA). SUNRISE, a first-in-human phase 1/2 open-label study, evaluated the safety/tolerability (primary endpoints) of liver-targeted hLB-001 in four pediatric participants (ages 20-114 months) with mitochondrial methylmalonyl-CoA mutase (MMUT)–deficient MMA. We designed a single-infusion adeno-associated viral capsid (hLB-001) to nondisruptively integrate functional MMUT at the 3′ end of the albumin (ALB) locus to produce both albumin and MMUT. All four participants experienced at least one treatment-emergent adverse event. Three participants had treatment-emergent serious adverse events of cytokine release syndrome (one participant) and thrombotic microangiopathy (two participants); all resolved during the trial. Biologic activity, clinical efficacy, and 1-year survival were secondary endpoints. MMUT expression (measured by 2A-tagged ALB biomarker expression) increased in two participants over two years, confirming homology-based integration and positive selection of transgenic cells. However, serum methylmalonic acid (sMMA), serum FGF21, serum methylcitric acid (sMCA), and propionate oxidation remained abnormal in all four participants. All participants were alive at 1 year and at database lock. SUNRISE was terminated due to lack of efficacy. These results provide proof-of-concept for use of liver-targeted gene editing without nucleases for MMA and other genetic metabolic disorders. ClinicalTrials.gov identifier: NCT04581785 Target journal: Gene Therapy (Springer Nature)","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"33 3","pages":"345-357"},"PeriodicalIF":4.5,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-026-00609-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147581094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CJ-1: an optimized mRNA platform with enhanced protein expression and minimal immunogenicity for therapeutic applications CJ-1：一个优化的mRNA平台，具有增强的蛋白质表达和最小的免疫原性，用于治疗应用。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-03-13 DOI: 10.1038/s41434-026-00606-4

Seyoung Kim, Min Ju Jo, Min Seon Jeong, Minki Ha, Youngwook Ham, Jiye Hong, Daeyong Kim, Kyuha Yum, Jaewook Yeon, Sang-Bae Han, Seok-Beom Yong, Sungchan Cho

{"title":"CJ-1: an optimized mRNA platform with enhanced protein expression and minimal immunogenicity for therapeutic applications","authors":"Seyoung Kim, Min Ju Jo, Min Seon Jeong, Minki Ha, Youngwook Ham, Jiye Hong, Daeyong Kim, Kyuha Yum, Jaewook Yeon, Sang-Bae Han, Seok-Beom Yong, Sungchan Cho","doi":"10.1038/s41434-026-00606-4","DOIUrl":"10.1038/s41434-026-00606-4","url":null,"abstract":"Messenger RNA therapeutics offer broad potential across various diseases, yet achieving sustained and efficient protein expression remains a central challenge. In this study, we report CJ-1, a novel mRNA construct engineered through systematic optimization of major regulatory elements, including the 5′ and 3′ untranslated regions and poly (A) tail. CJ-1 consistently outperformed first-generation mRNA constructs in protein expression across multiple cell types and in vivo mouse models. Moreover, CJ-1 elicited markedly lower cytokine responses, indicating reduced innate immune activation. To evaluate its therapeutic applicability, erythropoietin (EPO)-encoding CJ-1 mRNA was encapsulated in a Pfizer-BioNTech lipid nanoparticle formulation and administered intraperitoneally in mice. This resulted in elevated, sustained serum EPO levels and significant increases in reticulocyte counts and hematocrit. These findings support CJ-1 as a promising mRNA platform with enhanced expression and minimal immunogenicity, advancing the development of safer and more effective mRNA-based therapies.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"33 2","pages":"164-175"},"PeriodicalIF":4.5,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-026-00606-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147456627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Building a gene editing lexicon: a model for rare and inherited disorders 构建基因编辑词典：罕见和遗传性疾病的模型。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-03-13 DOI: 10.1038/s41434-026-00596-3

Leonard A. Valentino, Cedric Hermans, Donna Coffin, Wolfgang Miesbach, Maria Elisa Mancuso, Carmen Unzu, Micheala Jones, David E. Gutstein, William McKeown, Craig M. Kessler

{"title":"Building a gene editing lexicon: a model for rare and inherited disorders","authors":"Leonard A. Valentino, Cedric Hermans, Donna Coffin, Wolfgang Miesbach, Maria Elisa Mancuso, Carmen Unzu, Micheala Jones, David E. Gutstein, William McKeown, Craig M. Kessler","doi":"10.1038/s41434-026-00596-3","DOIUrl":"10.1038/s41434-026-00596-3","url":null,"abstract":"As more advanced cell and gene therapies, including gene editing technologies, progress through drug development, there is increased emphasis on the importance of stakeholders, including people living with disease, caregivers, and healthcare professionals, to communicate using clear, accurate, and consistent language. Lexicons explaining advanced gene therapies will support patients’ and clinicians’ understanding, enabling shared decision-making and informed consent for clinical trial participation and, in the future, healthcare choice. Early lexicon development is crucial for standardizing communication across clinical sites, geographies, clinicians, and patients. A lexicon for clustered regularly interspaced short palindromic repeats-associated protein 9 (CRISPR-Cas9) gene editing for hemophilia was developed using comprehensive methodologies, gathering insight through qualitative research and in-depth interviews, language audits, and workshops, with input from lived experience experts, leading clinicians in hemophilia, gene therapy experts, and scientific and patient organizations. This lexicon serves as a gold standard template for future comprehensive patient lexicon development strategy and could be applied to other therapeutic areas where treatments are being developed and standardized, or where accessible vocabulary for patients, healthcare professionals, and the affected community is lacking. This communication highlights the need for lexicon development for advanced gene editing treatments across therapeutic areas to support standardized understanding and enhance communication.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"33 3","pages":"310-315"},"PeriodicalIF":4.5,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-026-00596-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147456675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Seroprevalence of anti-AAV antibodies in a healthy adult Spanish population: findings from the SAAVIA study 抗aav抗体在西班牙健康成人人群中的血清流行率：来自SAAVIA研究的结果

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-03-12 DOI: 10.1038/s41434-026-00597-2

Rafael Parra, Assumpció Bosch, Angela Sánchez, Cristina Caparros, Hae Kyung Kim, Nadia Lwoff

{"title":"Seroprevalence of anti-AAV antibodies in a healthy adult Spanish population: findings from the SAAVIA study","authors":"Rafael Parra, Assumpció Bosch, Angela Sánchez, Cristina Caparros, Hae Kyung Kim, Nadia Lwoff","doi":"10.1038/s41434-026-00597-2","DOIUrl":"10.1038/s41434-026-00597-2","url":null,"abstract":"Adeno-associated virus (AAV) vectors are essential tools for gene therapy (GT), yet preexisting immunity can hinder their efficacy. This study examines the seroprevalence of total binding IgG against AAV serotypes 2, 5, 6, 8, and 9, and neutralizing antibodies (NAb) against AAV 6, 8, and 9 serotypes in a healthy adult Spanish population. Using enzyme-linked immunosorbent assays (ELISA) for IgG and luciferase-based assays for NAb, we found that IgG seroprevalence was highest for AAV6 (84.4%), followed by AAV2 (74.4%) and AAV8 (60.0%), with the lowest prevalence observed for AAV9 (51.2%) and AAV5 (40.4%). For NAb, AAV6 showed the highest prevalence (62.8%), followed by AAV8 (60.4%) and AAV9 (52.4%). Co-prevalence analysis revealed high rates among all IgG-AAV serotypes tested (ranging from 46.4% to 97.0%) and significant co-occurrence of NAb against AAV6, AAV8, and AAV9 (83.0% to 91.0%). High NAb levels correlated with high IgG levels in all samples. The variability in seroprevalence across populations highlights the importance of personalized and validated testing to optimize treatment outcomes and ensure the safety of AAV-based gene therapies.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"33 2","pages":"156-163"},"PeriodicalIF":4.5,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147443453","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}

引用次数: 0

Topical application of Cas9 ribonucleoproteins inhibits corneal neovascularization in a mouse model of alkali burn injury 局部应用Cas9核糖核蛋白抑制碱烧伤小鼠角膜新生血管。

IF 5.9 3区医学

Gene Therapy Pub Date : 2026-03-12 DOI: 10.1038/s41434-026-00607-3

Seok Jae Lee, Bae-Geun Nam, Sung-Ah Hong, Dong Hyun Jo, Sang-Mok Lee, Sangsu Bae, Jeong Hun Kim

{"title":"Topical application of Cas9 ribonucleoproteins inhibits corneal neovascularization in a mouse model of alkali burn injury","authors":"Seok Jae Lee, Bae-Geun Nam, Sung-Ah Hong, Dong Hyun Jo, Sang-Mok Lee, Sangsu Bae, Jeong Hun Kim","doi":"10.1038/s41434-026-00607-3","DOIUrl":"10.1038/s41434-026-00607-3","url":null,"abstract":"Corneal neovascularization is a sight-threatening condition for which current treatments such as anti-VEGF agents are limited by invasiveness and side effects. We present the first non-viral, CRISPR/Cas9-based gene therapy delivered via topical eye drops that penetrates the cornea and inhibits pathological neovascularization. Cas9 ribonucleoproteins (RNPs) targeting the Vegfa gene were complexed with a liposomal carrier (lipofectamine) and administered to mice after alkali burn injury to the cornea. This approach achieved approximately 2% gene editing at the Vegfa locus in vivo, which significantly reduced local VEGF-A expression. Consequently, treated corneas showed markedly decreased macrophage infiltration and robust suppression of both hemangiogenesis and lymphangiogenesis compared to untreated controls. These findings demonstrate that even modest in vivo gene editing can yield a strong therapeutic effect, highlighting a clinically relevant strategy for controlling corneal angiogenesis. Our study introduces a feasible and safe topical CRISPR therapy for corneal diseases, offering a potential alternative to invasive or virus-based gene delivery methods.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"33 4","pages":"1-13"},"PeriodicalIF":5.9,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147443366","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}

引用次数: 0

Securitization as a means to pay for cell and gene therapies for orphan diseases: a simulation study 作为支付孤儿疾病细胞和基因治疗手段的证券化：一项模拟研究。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-03-11 DOI: 10.1038/s41434-026-00604-6

John M. Lu, Avi J. Cherla, Alexander W. Carter, Elias A. Mossialos

{"title":"Securitization as a means to pay for cell and gene therapies for orphan diseases: a simulation study","authors":"John M. Lu, Avi J. Cherla, Alexander W. Carter, Elias A. Mossialos","doi":"10.1038/s41434-026-00604-6","DOIUrl":"10.1038/s41434-026-00604-6","url":null,"abstract":"Cell and gene therapies may provide life-extending treatments for patients. However, paying for these therapies using a single upfront payment will be challenging because of uncertainty about long-term clinical effectiveness and affordability. Developers, recognizing the challenges of paying for these therapies, have offered payers 5-year outcomes-based installment plans. The short length of these plans, however, does little to address uncertainties about the cost-effectiveness of paying for these therapies. Instead, we propose to offer 30-year performance-based annuities that shift payments to match the expected accrual of clinical benefits more closely. Using securitization techniques combined with long-term performance-based annuities, we demonstrate that in the case of the gene therapy Zolgensma, this mechanism is effective at mitigating concerns over value and affordability for payers. In summary, our proposal for financing cell and gene therapies creates a viable incentive for developers, while also balancing long-term effectiveness and budget impact concerns from payers and access challenges for patients.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"33 2","pages":"138-143"},"PeriodicalIF":4.5,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-026-00604-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147432418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spatial transcriptomics and single-nucleus RNA sequencing reveal rAAV2- and rAAV9-specific transduction signatures in the mouse liver 空间转录组学和单核RNA测序揭示了小鼠肝脏中rAAV2-和raav9特异性转导特征。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-03-11 DOI: 10.1038/s41434-026-00600-w

Bettina Amberg, Fabian Köchl, Nadine Kumpesa, Megana Prasad, Filip Bochner, Mar Hernández-Obiols, Michael B. Otteneder, Lucas Stalder, Frances Shaffo, Ali Nowrouzi, David Markusic, Hélène Haegel, Rebecca Xicluna, Marc Sultan, Björn Jacobsen, Sven Rottenberg, Alberto Valdeolivas, Petra C. Schwalie, Kerstin Hahn

{"title":"Spatial transcriptomics and single-nucleus RNA sequencing reveal rAAV2- and rAAV9-specific transduction signatures in the mouse liver","authors":"Bettina Amberg, Fabian Köchl, Nadine Kumpesa, Megana Prasad, Filip Bochner, Mar Hernández-Obiols, Michael B. Otteneder, Lucas Stalder, Frances Shaffo, Ali Nowrouzi, David Markusic, Hélène Haegel, Rebecca Xicluna, Marc Sultan, Björn Jacobsen, Sven Rottenberg, Alberto Valdeolivas, Petra C. Schwalie, Kerstin Hahn","doi":"10.1038/s41434-026-00600-w","DOIUrl":"10.1038/s41434-026-00600-w","url":null,"abstract":"The liver is a primary target for recombinant adeno-associated viral (rAAV) vectors, yet the influence of serotype, sex, and liver zonation on transduction and transcriptomic changes remains incompletely understood. This proof-of-concept study employs spatial transcriptomics alongside single-nucleus RNA sequencing to map the spatial distribution and impacts of rAAV2- and rAAV9-CMV-EGFP vectors in male and female mouse livers. Spatial transcriptomics provided precise transgene mapping and highlighted that CMV-EGFP rAAV vectors deregulate hepatocellular lipid metabolism, the circadian clock, and the immune/stress response with sex specific differences. Lipid metabolism genes (Elovl3, Chka, Irs2, Ppard), were consistently deregulated across all zones of the liver lobule in male and female rAAV2- and rAAV9-CMV-EGFP-treated mice, while Srebf1, Tlcd4, Cpt2, and Acot1 exhibited sex-specific patterns. Circadian clock modulators (Dbp, Tef, Arntl, Nfil3, Nr1d1/Nr1d2) were altered independently of zonation. The study found sex-specific downregulation of immune and stress-response genes and pathways, including Gadd45g and hypoxia pathways. TGF-β and EGFR pathways were upregulated sex-independently. Spatial transcriptomics further enabled examination of transgene and rAAV entry factor co-expression, identifying known and novel factors like Rpsa, Dpp4, Sdc1, and solute carrier proteins, highlighting its role in supporting targeted screening. Our findings demonstrate spatial transcriptomics as a powerful tool in gene therapy research and reveal novel rAAV vector effects on liver biology.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"33 3","pages":"316-329"},"PeriodicalIF":4.5,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41434-026-00600-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147432348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AAV-mediated gene replacement therapy for LRAT-associated retinitis pigmentosa: a proof-of-concept study in a patient-based rat model aav介导的lrat相关性视网膜色素变性基因替代疗法：基于患者的大鼠模型的概念验证研究

IF 5.9 3区医学

Gene Therapy Pub Date : 2026-03-10 DOI: 10.1038/s41434-026-00601-9

A. M. El-Kalaani, J. B. Ten Brink, C. J. F. Boon, C. Koster

{"title":"AAV-mediated gene replacement therapy for LRAT-associated retinitis pigmentosa: a proof-of-concept study in a patient-based rat model","authors":"A. M. El-Kalaani, J. B. Ten Brink, C. J. F. Boon, C. Koster","doi":"10.1038/s41434-026-00601-9","DOIUrl":"10.1038/s41434-026-00601-9","url":null,"abstract":"Retinitis pigmentosa (RP) is an inherited retinal disease that causes progressive vision loss, ultimately leading to blindness. Currently, RP is mostly untreatable, and patients can only manage their symptoms through supportive measures such as visual aids and psychotherapy. Mutations in the lecithin: retinol acyltransferase (LRAT) gene, which encodes an essential protein in the visual cycle, can cause early-onset retinitis pigmentosa. In a Dutch RP patient cohort, the c.12delC mutation in the LRAT gene was identified as the most common cause of LRAT-associated RP. Gene replacement therapy is a promising treatment strategy for these patients. To test the feasibility of this approach, we used a Brown Norway rat strain with a homologous mutation to the aforementioned patient group (c.12delA) in the rat Lrat gene, and treated them with adeno-associated virus (AAV2)-based human LRAT cDNA delivery. We combined in vivo and ex vivo techniques to determine the treatment’s potential. Supplementation of the LRAT gene in the subretinal space led to morphological improvements of the retina, significantly increased the electrical response to light, and enhanced functional vision compared to sham-treated controls. Our results provide strong proof-of-concept for AAV-mediated gene replacement as a potential treatment for LRAT-associated RP.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":"33 4","pages":"398-412"},"PeriodicalIF":5.9,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147432420","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}

引用次数: 0