Gene Therapy最新文献_第2页

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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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 4.5 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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":4.5,"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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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 4.5 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":"https://doi.org/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":" ","pages":""},"PeriodicalIF":4.5,"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

First pilot study of intravenous rAAV-PAX6 gene therapy increases retinal-ganglion-cell-layer thickness and Notch1 transcription in a mouse model of aniridia. 在无虹膜小鼠模型中，静脉注射rAAV-PAX6基因治疗增加视网膜神经节细胞层厚度和Notch1转录的首次初步研究。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-03-09 DOI: 10.1038/s41434-026-00605-5

Diana Djaksigulova, Sif G Kaad, Andrea J Korecki, Siu Ling Lam, Tess C Lengyell, Elizabeth M Simpson

{"title":"First pilot study of intravenous rAAV-PAX6 gene therapy increases retinal-ganglion-cell-layer thickness and Notch1 transcription in a mouse model of aniridia.","authors":"Diana Djaksigulova, Sif G Kaad, Andrea J Korecki, Siu Ling Lam, Tess C Lengyell, Elizabeth M Simpson","doi":"10.1038/s41434-026-00605-5","DOIUrl":"https://doi.org/10.1038/s41434-026-00605-5","url":null,"abstract":"Aniridia is a rare congenital vision-loss disorder that is caused primarily by heterozygous loss-of-function variants in the PAX6 gene. There is currently no curative treatment. Gene therapy has emerged as a powerful strategy for treating inherited retinal diseases. Here, we aim to establish a systemic PAX6 gene-augmentation therapy capable of addressing retinal pathologic phenotypes in a preclinical Sey mouse model of aniridia. We evaluated the intravenous delivery of FLAG-tagged PAX6 packaged in the AAV-PHP.eB capsid. Treatment was administered on postnatal day 21 to mimic the average age at diagnosis and the likely early therapeutic window in humans. The transcript levels of the virally-delivered PAX6 were 7.1% at 1 month, and 8.9% at 5 months, of Wt endogenous levels. These transcripts produced PAX6 protein in the ganglion (GCL) and inner nuclear cell layers. Importantly, in this pilot study, a significant increase in GCL thickness at 5 months post-injection was also observed. Furthermore, this structural change in the Sey retina was preceded by a significant increase in Notch1 transcription at 1-month post-injection. Thus, we demonstrated the first successful viral-mediated augmentation of PAX6 in the retina in a preclinical mouse model of aniridia, resulting in a phenotypic change at the structural and molecular levels.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147377102","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

In vitro and in vivo rescue of dopaminergic neurons in Parkinson's disease models after Parkin gene therapy. 帕金森基因治疗后帕金森病模型多巴胺能神经元的体外和体内修复。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-03-05 DOI: 10.1038/s41434-026-00599-0

Takeshi Hioki, Masaaki Nishimura, Xiuxia Sun, Sarah Melissa Jacobo, Miyu Nakayama, Mitsuhiro Nishihara, Kimio Tohyama, Po-Ting Liu, Takuro Okai, Maiko Tanaka, Gabriele Proetzel

{"title":"In vitro and in vivo rescue of dopaminergic neurons in Parkinson's disease models after Parkin gene therapy.","authors":"Takeshi Hioki, Masaaki Nishimura, Xiuxia Sun, Sarah Melissa Jacobo, Miyu Nakayama, Mitsuhiro Nishihara, Kimio Tohyama, Po-Ting Liu, Takuro Okai, Maiko Tanaka, Gabriele Proetzel","doi":"10.1038/s41434-026-00599-0","DOIUrl":"https://doi.org/10.1038/s41434-026-00599-0","url":null,"abstract":"Young-onset Parkinson's disease (PD), the most common autosomal recessive familial PD, is caused by gene mutations in Parkin (PRKN). These mutations result in Parkin protein loss and reduced enzymatic activity, leading to severe degeneration of dopamine-producing neurons in the substantia nigra pars compacta (SNpc). Adeno-associated virus (AAV) gene therapy can directly address the cause of PRKN-PD by expressing Parkin protein at levels comparable to those observed in healthy humans. AAV9 vectors with different promoters were engineered to deliver PRKN cDNA with efficient human Parkin (hParkin) expression in dopaminergic (DA) neurons as shown in PRKN-null human induced pluripotent stem cell (iPSC) derived DA neurons. Further, we show that AAV9-PRKN treatment can protect nigral DA neurons in two mouse PD models, the 6-hydroxydopamine (6-OHDA)-lesion and the α-synuclein (α-Syn) pre-formed fibrils (PFFs)-lesion model. In summary, AAV9-PRKN gene therapy demonstrates neuroprotective properties and may represent a promising approach for PRKN-PD, with potential broader applications in idiopathic PD and other neurodegenerative diseases.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147365063","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

Virus-mediated gene transfer of soluble amyloid precursor protein-alpha via systemic injection in a mouse model of Alzheimer's disease. 在阿尔茨海默病小鼠模型中通过全身注射介导的可溶性淀粉样蛋白前体蛋白- α的病毒介导基因转移。

IF 4.5 3区医学

Gene Therapy Pub Date : 2026-03-03 DOI: 10.1038/s41434-026-00602-8

Yuanyuan He, Bruce G Mockett, Lucia Schoderboeck, Kirstin O McDonald, Barbara J Logan, Shruthi Sateesh, Owen D Jones, Stephanie M Hughes, Wickliffe C Abraham

{"title":"Virus-mediated gene transfer of soluble amyloid precursor protein-alpha via systemic injection in a mouse model of Alzheimer's disease.","authors":"Yuanyuan He, Bruce G Mockett, Lucia Schoderboeck, Kirstin O McDonald, Barbara J Logan, Shruthi Sateesh, Owen D Jones, Stephanie M Hughes, Wickliffe C Abraham","doi":"10.1038/s41434-026-00602-8","DOIUrl":"https://doi.org/10.1038/s41434-026-00602-8","url":null,"abstract":"Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet effective preventive or therapeutic strategies remain limited. A hallmark of AD pathology is the accumulation of insoluble amyloid-β (Aβ) aggregates, which are targeted by recent antibody-based therapies. Conversely, soluble amyloid precursor protein-alpha (sAPPα), a non-amyloidogenic cleavage product of APP, possesses neuroprotective, neurotrophic, and synaptogenic properties, and the ability to enhance memory. This study evaluated the therapeutic efficacy of adeno-associated virus variant PHP.eB (AAV-PHP.eB) encoding human sAPPα in the APPswe/PS1dE9 transgenic mouse model of AD. Six-month-old female wild-type and transgenic mice received a single intravenous injection via the tail vein. Three months post-injection, brain tissue was harvested for electrophysiological and histological analyses. The treatment significantly increased cortical sAPPα levels and fully restored hippocampal long-term potentiation (LTP) in transgenic mice. Post-mortem analyses revealed a substantial reduction in amyloid plaque burden in both the hippocampus and cortex, with minimal plaque progression from the time of injection. However, no significant changes were observed in astrocytic (GFAP) or microglial (Iba-1) coverage, nor in soluble and insoluble Aβ1-40 or Aβ1-42 levels. These findings suggest that systemic AAV-PHP.eB-mediated sAPPα delivery can ameliorate synaptic dysfunction and aggregated amyloid pathology in AD, highlighting its potential as a therapeutic strategy.","PeriodicalId":12699,"journal":{"name":"Gene Therapy","volume":" ","pages":""},"PeriodicalIF":4.5,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147348190","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