Gene Therapy最新文献

Clinical response to systemic AAV gene therapy in a large animal model of late-stage lysosomal storage disease. 晚期溶酶体贮积病大型动物模型对系统性AAV基因治疗的临床反应

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-05-04 DOI: 10.1038/s41434-026-00618-0

Jacqueline E Hunter, Caitlyn M Molony, Dana L Clarke, Wojciech Panek, Charles H Vite, Sanjeev Chawla, Harish Poptani, John H Wolfe

{"title":"Clinical response to systemic AAV gene therapy in a large animal model of late-stage lysosomal storage disease.","authors":"Jacqueline E Hunter, Caitlyn M Molony, Dana L Clarke, Wojciech Panek, Charles H Vite, Sanjeev Chawla, Harish Poptani, John H Wolfe","doi":"10.1038/s41434-026-00618-0","DOIUrl":"https://doi.org/10.1038/s41434-026-00618-0","url":null,"abstract":"The benefit of early diagnosis and treatment has been demonstrated in animal models of several lysosomal storage diseases. In a clinical setting, however, diagnoses are often not made until after patients become symptomatic. The lysosomal storage disease alpha-mannosidosis is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions throughout the brain and other tissues. In a feline model of alpha-mannosidosis, we previously demonstrated complete correction of the brain following delivery of AAVhu.32-fMANB via the carotid artery in the early symptomatic stage. Here, we investigate the efficacy of AAV gene therapy on globally distributed storage lesions in animals with advanced disease. Some improvements in clinical parameters were observed, however these improvements were less than in animals with less advanced disease. Although the treated animals were improved compared to untreated animals, increasing the vector dose did not further improve clinical outcomes. These results further demonstrate the importance of early detection and treatment of a lysosomal storage disease to successful outcomes. Despite this, partial correction extended the lifespan of diseased cats and may be medically beneficial to patients by slowing or stabilizing the progressive degenerative course of disease.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837164","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

AAV2 capsid clearance and neuronal trafficking dynamics in the central nervous system. 中枢神经系统AAV2衣壳清除和神经元运输动力学。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-04-30 DOI: 10.1038/s41434-026-00617-1

Thanvi Gullapalli, Jake W Willows, Ahmad Karkhah, Vikas Munjal, Abigail Nimmo, Kaya E Ceyhan, Meika Travis, Allison O'Brien, Matthew T Rocco, Anitvir S Taunque, Kristy L Townsend, Lluis Samaranch

{"title":"AAV2 capsid clearance and neuronal trafficking dynamics in the central nervous system.","authors":"Thanvi Gullapalli, Jake W Willows, Ahmad Karkhah, Vikas Munjal, Abigail Nimmo, Kaya E Ceyhan, Meika Travis, Allison O'Brien, Matthew T Rocco, Anitvir S Taunque, Kristy L Townsend, Lluis Samaranch","doi":"10.1038/s41434-026-00617-1","DOIUrl":"https://doi.org/10.1038/s41434-026-00617-1","url":null,"abstract":"Adeno-associated virus serotype 2 (AAV2) remains one of the most common vectors for CNS gene delivery. Yet, its long-term intraparenchymal trafficking and the relationship between capsid persistence and transgene expression remain poorly understood. In this study, we tracked the spatial and temporal patterns of AAV2 following direct striatal infusion in rats, analyzing tissue at 3 days, 3 weeks, 12 weeks, 30 weeks, and 67 weeks after injection. Using immunofluorescence for the human aromatic L-amino acid decarboxylase (AADC) transgene and an epitope detecting intact AAV2 capsids (A20), we mapped capsid localization, clearance, and axonal transport over more than a year. Following direct striatal infusion, AAV2 capsids rapidly localized to striatal neurons, with early accumulation in the substantia nigra pars reticulata (SNpr) detectable by 3 days post-infusion, but without evidence of nigral neuron transduction. Transgene expression increased over time and peaked locally at 12 weeks, with a delayed yet robust AADC signal in striatonigral terminals by 30 weeks. By 67 weeks, capsid signal was minimal while AADC expression remained stable. These findings clarify the long-term dynamics of AAV2 distribution, capsid persistence, and axonal transport in the adult brain, informing our understanding of vector behavior and durability following intraparenchymal AAV2 gene delivery.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147769146","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

Correction: Genetic mutations in HSV-1 replication-defective vectors: Implications for their safety in gene therapy applications. 修正：HSV-1复制缺陷载体的基因突变：对其在基因治疗应用中的安全性的影响。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-04-20 DOI: 10.1038/s41434-026-00615-3

Stefano Cattaneo, Barbara Bettegazzi, Selene Ingusci, Gianluca Verlengia, Anna Sofia Tascini, Silvia Zucchini, Franca Codazzi, Marco J Morelli, Marco Marzulli, Joseph C Glorioso, Michele Simonato

引用次数: 0

Beneficial bystander-enhanced cryptic splice rescue of cardiac-type Fabry GLA IVS4+919G>A by adenine base editing in patient fibroblasts. 通过腺嘌呤碱基编辑在患者成纤维细胞中有益的旁观者增强隐剪接挽救心脏型Fabry GLA IVS4+919G>A。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-04-18 DOI: 10.1038/s41434-026-00612-6

Hua-Chuan Chao, Yu-Ying Lu, Yu-Ting Chiang, Yun-Ru Chen, Ching-Tzu Yen, Chun-Ying Huang, Sheng-Kai Chang, Yen-Fu Cheng, Yung-Hsiu Lu, Dau-Ming Niu

{"title":"Beneficial bystander-enhanced cryptic splice rescue of cardiac-type Fabry GLA IVS4+919G>A by adenine base editing in patient fibroblasts.","authors":"Hua-Chuan Chao, Yu-Ying Lu, Yu-Ting Chiang, Yun-Ru Chen, Ching-Tzu Yen, Chun-Ying Huang, Sheng-Kai Chang, Yen-Fu Cheng, Yung-Hsiu Lu, Dau-Ming Niu","doi":"10.1038/s41434-026-00612-6","DOIUrl":"https://doi.org/10.1038/s41434-026-00612-6","url":null,"abstract":"The IVS4+919G>A mutation in the GLA gene, prevalent in East Asian populations, causes cardiac-type Fabry disease by creating an abnormal splice site. This results in the insertion of a 57-nucleotide segment between exon 4 and exon 5, introducing a premature stop codon and leading to a truncated, non-functional α-Gal A protein. We evaluated whether adenine base editing (ABEmax) can modulate this allele-induced cryptic splice event in patient-derived fibroblasts in vitro as a proof-of-concept. Two ABEmax/sgRNA constructs targeting intron 4 (ABEmax-sgRNA1 and ABEmax-sgRNA2) were tested; both induced on-target +919 A → G conversion with frequent bystander edits at +918/+920. Edited bulk populations and single-cell-derived clones showed restoration of correctly spliced GLA mRNA with reduced aberrant transcripts, increased GLA protein, higher α-Gal A activity (approaching wild-type levels in some clones), and reduced intracellular Gb3 signal. A focused next-generation sequencing panel identified a low-frequency intronic change at one predicted off-target locus without predicted coding consequences. These findings demonstrate in vitro splice rescue of a deep intronic, cardiac-type Fabry disease variant by adenine base editing and suggest that bystander edits in non-coding sequence can further enhance correction by suppressing cryptic splicing, with concordant improvements in α-Gal A activity and Gb3 signals.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716525","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

Retraction Note: Local administration of transcription factor decoy oligonucleotides to nuclear factor-κB prevents carrageenin-induced inflammation in rat hind paw. 注：局部给药核因子-κB转录因子诱饵寡核苷酸可预防卡拉胶诱导的大鼠后爪炎症。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-04-15 DOI: 10.1038/s41434-026-00614-4

F D'Acquisto, A Ialenti, A Ianaro, R Di Vaio, R Carnuccio

引用次数: 0

CRISPR/Cas9-mediated gene correction of Wilson disease H1069Q point mutation in patient-specific induced pluripotent stem cells. 患者特异性诱导多能干细胞中威尔森病H1069Q点突变的CRISPR/ cas9介导的基因纠正

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-04-14 DOI: 10.1038/s41434-026-00611-7

Viktoria Iwan, Oksana Nadzemova, Matthias Weiand, Andree Zibert, Hartmut H Schmidt, Phil-Robin Tepasse, Robert Schierwagen, Jonel Trebicka, Vanessa Sandfort

{"title":"CRISPR/Cas9-mediated gene correction of Wilson disease H1069Q point mutation in patient-specific induced pluripotent stem cells.","authors":"Viktoria Iwan, Oksana Nadzemova, Matthias Weiand, Andree Zibert, Hartmut H Schmidt, Phil-Robin Tepasse, Robert Schierwagen, Jonel Trebicka, Vanessa Sandfort","doi":"10.1038/s41434-026-00611-7","DOIUrl":"https://doi.org/10.1038/s41434-026-00611-7","url":null,"abstract":"The innovative clustered regularly interspaced short palindromic repeats (CRISPR) associated nuclease 9 (Cas9) gene editing technique may represent a suitable therapeutic opportunity for the treatment of inherited diseases such as Wilson disease (WD). This monogenetic liver disease is based on a mutation of the ATP7B gene and leads to a functional deterioration in copper (Cu) excretion. Excess Cu accumulations in organs such as the liver and brain lead to severe cytotoxicity, followed by acute or chronic liver failure and/or neurological symptoms, and even death, which makes cellular Cu excretion indispensable for any potential WD therapy, e.g., gene therapy. A life-long treatment with zinc or chelators such as D-penicillamine may improve the course of the disease, but serious side effects have been observed in a significant portion of patients. In this study, isolated urinary epithelial cells from a WD patient carrying the ATP7B H1069Q mutation were reprogrammed into induced pluripotent stem cells (iPSCs). Using the CRISPR/Cas9 technology, ATP7B H1069Q was corrected by the additional use of single-stranded oligo DNA nucleotides (ssODNs). After differentiation into hepatocyte-like cells (HLCs), a high resistance to Cu was observed, plus a recovery of ATP7B trafficking. This is the first study to confirm that CRISPR/Cas9-mediated correction of the ATP7B point mutation H1069Q is possible and could open new possibilities for future applications.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147689785","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

Antimicrobial resistance and gene therapy: emerging molecular strategies for a global health threat. 抗微生物药物耐药性和基因治疗：应对全球健康威胁的新兴分子策略。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-04-13 DOI: 10.1038/s41434-026-00613-5

A Vitiello, M Boccellino, A Zovi, M Bassetti

引用次数: 0

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 4.5 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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/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":" ","pages":""},"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":"https://doi.org/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: NCT04581785Target journal: Gene Therapy (Springer Nature).","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0