Molecular Therapy-Methods & Clinical Development最新文献_第2页

Anti-TNF-α antisense-oligonucleotide-conjugated PLG nanoparticles protect transplanted islets. 抗tnf -α反义寡核苷酸偶联PLG纳米颗粒保护移植胰岛。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-05-14 eCollection Date: 2025-06-12 DOI: 10.1016/j.omtm.2025.101489

Elizabeth J Bealer, Namit Padgaonkar, Kelly Crumley, Eiji Saito, Zoe Beekman, Alexa DeKorte, Thazha P Prakash, Alexey Revenko, Lonnie D Shea

{"title":"Anti-TNF-α antisense-oligonucleotide-conjugated PLG nanoparticles protect transplanted islets.","authors":"Elizabeth J Bealer, Namit Padgaonkar, Kelly Crumley, Eiji Saito, Zoe Beekman, Alexa DeKorte, Thazha P Prakash, Alexey Revenko, Lonnie D Shea","doi":"10.1016/j.omtm.2025.101489","DOIUrl":"10.1016/j.omtm.2025.101489","url":null,"abstract":"One of the many challenges for islet transplantation as a treatment for type 1 diabetes is inflammation that contributes to islet de-differentiation and death. Innate immune cells such as monocytes and macrophages secrete tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), inducible nitric oxide synthase (iNOS), and IL-6, which directly contribute to islet dysfunction. Attenuation of the early inflammatory response post-transplantation may protect cell survival and subsequent function. Herein, we investigate the development of anti-TNF-α antisense-oligonucleotide-conjugated polylactide-co-glycolide nanoparticles (PLG-aTNF-α NPs) as an anti-inflammatory therapy after stem-cell-derived islet transplantation. PLG-aTNF-α NPs are shelf stable and successfully reduce TNF-α secretion and expression in inflammatory macrophages. Synergy between the aTNF-α antisense oligonucleotide and the polylactide-co-glycolide NPs results in further knockdown of IL-1β, IL-6, iNOS, and IL-12 in vitro indicating PLG-aTNF-α NPs may protect against the inflammatory cascade in vivo. In a diabetic mouse model, stem-cell-derived islets transplanted to the peritoneal fat were protected after treatment with PLG-aTNF-α NPs compared with PLG NPs alone. Tnfα and I l 1β expression was reduced in mice treated with PLG-aTNF-α NPs, indicating inflammation was reduced after transplant. PLG-aTNF-α NPs reduce TNF-α and protect islets, supporting their potential use as a therapeutic in islet transplantation.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 2","pages":"101489"},"PeriodicalIF":4.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12151673/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144267845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Development of circular AAV cargos for targeted seamless insertion with large serine integrases. 具有大型丝氨酸整合酶的靶向无缝插入的圆形AAV货物的开发。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-05-14 eCollection Date: 2025-06-12 DOI: 10.1016/j.omtm.2025.101490

Brett J G Estes, Nisha Gandhi, Jessica R Von Stetina, Dev Paudel, Angela X Nan, Parth Amin, Joshua Rose, Shuai Wu, Kangni Zheng, Yijun Zhang, Jesse C Cochrane, Jonathan D Finn, Jenny Xie

{"title":"Development of circular AAV cargos for targeted seamless insertion with large serine integrases.","authors":"Brett J G Estes, Nisha Gandhi, Jessica R Von Stetina, Dev Paudel, Angela X Nan, Parth Amin, Joshua Rose, Shuai Wu, Kangni Zheng, Yijun Zhang, Jesse C Cochrane, Jonathan D Finn, Jenny Xie","doi":"10.1016/j.omtm.2025.101490","DOIUrl":"10.1016/j.omtm.2025.101490","url":null,"abstract":"Recent advancements in gene insertion have shifted from DNA-repair-dependent mechanisms to more precise approaches, enhancing safety and predictability for editing outcomes. Integrase-mediated programmable genomic integration (I-PGI) utilizes a DNA cargo to insert transgenes in a targeted, unidirectional manner. In vivo, where nuclear delivery of DNA is challenging, adeno-associated virus (AAV) can act as the cargo vector. Although I-PGI does not require DNA double-strand breaks (DSBs) for activity, linear cargo, like AAV, stimulates DNA end-joining activity after integration. To mitigate potential risks from DSBs, we developed two circular AAV cargos capable of seamless gene insertion in non-dividing cells. We first harnessed the orthogonal property of large serine integrases to produce circle-AAV (cAAV) from linear viral genomes in cells. cAAV demonstrated seamless cargo integration in primary human hepatocytes (PHHs) and robust DSB-free insertion structures in vivo. We then investigated the delivery of a packaged circular AAV cargo (AAV.AD), which eliminates the need for enzymatic manipulation in the cell. AAV.AD exhibited functional seamless gene insertion in PHHs and showed cargo efficacy in vivo. Together, these findings provide evidence of DSB-free programmable genomic integration using integrase and AAV cargo, addressing a previously unrecognized challenge in the field.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 2","pages":"101490"},"PeriodicalIF":4.6,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144303583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Enhancing titers of therapeutic lentiviral vectors using PKC agonists. 使用PKC激动剂提高治疗性慢病毒载体的滴度。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-05-07 eCollection Date: 2025-06-12 DOI: 10.1016/j.omtm.2025.101484

Charles Moore-Kelly, Rajesh Reddem, Ben M Alberts, Jordan Wright, Thomas Evans, Anurag Kulkarni, Nicholas G Clarkson, Daniel C Farley, Kyriacos A Mitrophanous, Rui André Saraiva Raposo

{"title":"Enhancing titers of therapeutic lentiviral vectors using PKC agonists.","authors":"Charles Moore-Kelly, Rajesh Reddem, Ben M Alberts, Jordan Wright, Thomas Evans, Anurag Kulkarni, Nicholas G Clarkson, Daniel C Farley, Kyriacos A Mitrophanous, Rui André Saraiva Raposo","doi":"10.1016/j.omtm.2025.101484","DOIUrl":"10.1016/j.omtm.2025.101484","url":null,"abstract":"Lentiviral vector (LV)-based therapies employ the molecular machinery of HIV-1 to stably integrate therapeutic genes into patient cells for long-term disease correction. However, suboptimal expression of LV components in HEK293T-based production systems can limit titers and hinder clinical product development. Here, we identify protein kinase C (PKC) agonists as robust enhancers of LV production. PKC activation resulted in rapid transcription of LV genomic RNA and accelerated vector particle release in a manner that complemented the use of the histone deacetylase (HDAC) inhibitor, sodium butyrate. Stimulation of HEK293T cells strongly upregulated AP-1 transcription factor subunits independently of nuclear factor κB (NF-κB) pathway activation. Application of PKC agonists in LV production resulted in a ∼3-fold improvement in the titer of a chimeric antigen receptor (CAR)-LV. Furthermore, a ∼9-fold increase in titer was achieved when this induction method was combined with co-expression of an LV RNA-targeted U1 snRNA enhancer. Importantly, LV produced using PKC agonists had comparable particle-to-infectivity ratios and preserved T cell transduction efficiency. These findings suggest that incorporating PKC agonists into commercial LV manufacturing could considerably reduce the cost per patient dose of new LV-based gene therapies.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 2","pages":"101484"},"PeriodicalIF":4.6,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12146000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144259414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Exploring human plasma proteomic variations in mucolipidosis type IV. 探讨人血浆蛋白组学在IV型粘脂病中的变化。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-04-24 eCollection Date: 2025-06-12 DOI: 10.1016/j.omtm.2025.101479

Brendan R Tobin, Albert Misko, Victoria Miller-Browne, Madison Sangster, Yulia Grishchuk, Levi B Wood

{"title":"Exploring human plasma proteomic variations in mucolipidosis type IV.","authors":"Brendan R Tobin, Albert Misko, Victoria Miller-Browne, Madison Sangster, Yulia Grishchuk, Levi B Wood","doi":"10.1016/j.omtm.2025.101479","DOIUrl":"10.1016/j.omtm.2025.101479","url":null,"abstract":"Mucolipidosis IV (MLIV) is an autosomal-recessive pediatric disease that leads to motor and cognitive deficits and loss of vision. It is caused by loss of function of the lysosomal channel transient receptor potential mucolipin-1, TRPML1, and is associated with an early brain phenotype consisting of glial reactivity, hypomyelination, and lysosomal abnormalities. Although the field is approaching the first translationally relevant therapy, we currently lack a molecular signature of disease that can be used to detect therapeutic efficacy. Here, we analyzed 7,322 proteins in the plasma proteome from 17 MLIV patients and 37 controls and compared protein profiles with clinical measures of disease severity (motor function, muscle tone, and age). We found a decrease in neuronal proteins and an increase in muscle proteins in MLIV, consistent with neuronal dysfunction and muscle pathology observed in patients. Reduced synaptic proteins (e.g., GABARAP) best correlated with disease severity. Comparing the MLIV plasma proteome to the brain proteome from the MLIV mouse model identified shared alterations in 45 proteins, including upregulated proteins related to lysosomal function (e.g., ACTN2, GLB1) and downregulated proteins related to myelination (e.g., TPPP3, CNTN2). These data indicate that peripheral blood plasma protein signatures mirror changes found in the MLIV brain.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 2","pages":"101479"},"PeriodicalIF":4.6,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12141561/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144250871","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Highly efficient in vivo hematopoietic stem cell transduction using an optimized self-complementary adeno-associated virus. 高效体内造血干细胞转导使用优化的自互补腺相关病毒。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-02-21 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2025.101438

Carsten T Charlesworth, Shota Homma, Anais K Amaya, Carla Dib, Sriram Vaidyanathan, Tze-Kai Tan, Masashi Miyauchi, Yusuke Nakauchi, Fabian P Suchy, Sicong Wang, Kyomi J Igarashi, M Kyle Cromer, Amanda M Dudek, Alvaro Amorin, Agnieszka Czechowicz, Adam C Wilkinson, Hiromitsu Nakauchi

{"title":"Highly efficient in vivo hematopoietic stem cell transduction using an optimized self-complementary adeno-associated virus.","authors":"Carsten T Charlesworth, Shota Homma, Anais K Amaya, Carla Dib, Sriram Vaidyanathan, Tze-Kai Tan, Masashi Miyauchi, Yusuke Nakauchi, Fabian P Suchy, Sicong Wang, Kyomi J Igarashi, M Kyle Cromer, Amanda M Dudek, Alvaro Amorin, Agnieszka Czechowicz, Adam C Wilkinson, Hiromitsu Nakauchi","doi":"10.1016/j.omtm.2025.101438","DOIUrl":"10.1016/j.omtm.2025.101438","url":null,"abstract":"In vivo gene therapy targeting hematopoietic stem cells (HSCs) holds significant therapeutic potential for treating hematological diseases. This study uses adeno-associated virus serotype 6 (AAV6) vectors and Cre recombination to systematically optimize the parameters for effective in vivo HSC transduction. We evaluated various genetic architectures and delivery methods of AAV6, establishing an optimized protocol that achieved functional recombination in more than two-thirds of immunophenotypic HSCs. Our findings highlight that second-strand synthesis is a critical limiting factor for transgene expression in HSCs, leading to significant under-detection of HSC transduction with single-stranded AAV6 vectors. We also demonstrate that HSCs in the bone marrow (BM) are readily accessible to transduction, with neither localized injection nor mobilization of HSCs into the bloodstream, enhancing transduction efficacy. Additionally, we observed a surprising preference for HSC transduction over other BM cells, regardless of the AAV6 delivery route. Together, these findings not only underscore the potential of AAV vectors for in vivo HSC gene therapy but also lay a foundation that can inform the development of both in vivo AAV-based HSC gene therapies and potentially in vivo HSC gene therapies that employ alternative delivery modalities.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101438"},"PeriodicalIF":4.6,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Efficient nonviral integration of large transgenes into human T cells using Cas9-CLIPT. 利用Cas9-CLIPT将大转基因高效地整合到人T细胞中。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-02-18 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2025.101437

Anna Tommasi, Dan Cappabianca, Madison Bugel, Kirstan Gimse, Karl Lund-Peterson, Hum Shrestha, Denis Arutyunov, James A Williams, Seshidhar Reddy Police, Venkata Indurthi, Sage Z Davis, Muhammed Murtaza, Christian M Capitini, Krishanu Saha

{"title":"Efficient nonviral integration of large transgenes into human T cells using Cas9-CLIPT.","authors":"Anna Tommasi, Dan Cappabianca, Madison Bugel, Kirstan Gimse, Karl Lund-Peterson, Hum Shrestha, Denis Arutyunov, James A Williams, Seshidhar Reddy Police, Venkata Indurthi, Sage Z Davis, Muhammed Murtaza, Christian M Capitini, Krishanu Saha","doi":"10.1016/j.omtm.2025.101437","DOIUrl":"10.1016/j.omtm.2025.101437","url":null,"abstract":"CRISPR-Cas9 ribonucleoproteins (RNPs) combined with a nucleic acid template encoding a chimeric antigen receptor (CAR) transgene can edit human cells to produce CAR T cells with precise CAR insertion at a single locus. However, many human cells have adverse innate immune responses to foreign nucleic acids, particularly circular double-stranded DNA (dsDNA). Here, we introduce Cleaved, LInearized with Protein Template (Cas9-CLIPT), a circular plasmid containing a single target sequence for the Cas9 RNP, such that during manufacturing, Cas9-RNP binds and cleaves the plasmid to linearize the dsDNA in vitro. Cas9-RNP remains bound to the linearized template and is delivered to cells to promote precise knock-in via homology-directed repair with Cas9-CLIPT. Cas9-CLIPT Nanoplasmids generate up to 1.7-fold higher rates of precise knock-in relative to linearized dsDNA, reaching efficiencies up to 60% with non-homologous end joining inhibition. Cas9-CLIPT-manufactured GD2 TRAC-CAR T cells are potent against GD2+ neuroblastoma cells and exhibit an enriched stem cell memory phenotype. On several electroporation instruments and approaching clinically relevant yields, we successfully manufactured TRAC-CAR T cells using Cas9-CLIPT plasmids containing large (2-6 kb) transgenes. Cas9-CLIPT strategies have the potential to simplify donor template production and integrate large transgenes, allowing for more efficient nonviral manufacturing of multifunctional, genome-edited immune cell therapies.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101437"},"PeriodicalIF":4.6,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11930092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Why do lipid nanoparticles target the liver? Understanding of biodistribution and liver-specific tropism. 为什么脂质纳米颗粒靶向肝脏？了解生物分布和肝脏特异性趋向性。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-02-15 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2025.101436

Mahboubeh Hosseini-Kharat, Kristen E Bremmell, Clive A Prestidge

{"title":"Why do lipid nanoparticles target the liver? Understanding of biodistribution and liver-specific tropism.","authors":"Mahboubeh Hosseini-Kharat, Kristen E Bremmell, Clive A Prestidge","doi":"10.1016/j.omtm.2025.101436","DOIUrl":"10.1016/j.omtm.2025.101436","url":null,"abstract":"Lipid nanoparticles (LNPs) are now highly effective transporters of nucleic acids to the liver. This liver-specificity is largely due to their association with certain serum proteins, most notably apolipoprotein E (ApoE), which directs them to liver cells by binding to the low-density lipoprotein (LDL) receptors on hepatocytes. The liver's distinct anatomy, with its various specialized cell types, also influences how LNPs are taken up from the circulation, cleared, and how effective they are in delivering treatments. In this review, we consider factors that facilitate LNP's effective liver targeting and explore the latest advances in liver-targeted LNP technologies. Understanding how LNPs are targeted to the liver can help for effective design and optimization of nanoparticle-based therapies. Comprehension of the cellular interaction and biodistribution of LNPs not only leads to better treatments for liver diseases but also delivers insight for directing nanoparticles to other tissues, potentially broadening their range of therapeutic applications.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101436"},"PeriodicalIF":4.6,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659688","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Evaluation of efficacy and safety of AAV8-ΔC4ATP7B gene therapy in a mutant mouse model of Wilson's disease. AAV8-ΔC4ATP7B基因治疗威尔森氏病突变小鼠模型的疗效和安全性评价

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-02-13 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2025.101435

Chunhua Zeng, Yunting Lin, Xinshuo Lu, Shehong Chen, Yan Xia, Kangdi Zhang, Yongxian Shao, Zhihong Guan, Rong Du, Zongcai Liu, Mingqi Zhao, Xiaoling Jiang, Yanna Cai, Taolin Li, Xueying Su, Yaoyong Chen, Xiaoyan Dong, Wen Zhang, Li Liu, Wenhao Zhou

{"title":"Evaluation of efficacy and safety of AAV8-ΔC4ATP7B gene therapy in a mutant mouse model of Wilson's disease.","authors":"Chunhua Zeng, Yunting Lin, Xinshuo Lu, Shehong Chen, Yan Xia, Kangdi Zhang, Yongxian Shao, Zhihong Guan, Rong Du, Zongcai Liu, Mingqi Zhao, Xiaoling Jiang, Yanna Cai, Taolin Li, Xueying Su, Yaoyong Chen, Xiaoyan Dong, Wen Zhang, Li Liu, Wenhao Zhou","doi":"10.1016/j.omtm.2025.101435","DOIUrl":"10.1016/j.omtm.2025.101435","url":null,"abstract":"Wilson's disease (WD) is an autosomal recessive disorder caused by pathogenic variants in the ATP7B gene, resulting in the toxic accumulation of copper (Cu). Impaired Cu homeostasis in WD is characterized by low serum ceruloplasmin, excess hepatic Cu, and elevated urinary Cu. WD often presents with hepatic and/or neurological diseases and is fatal if untreated. Adeno-associated virus (AAV)-mediated gene therapy holds promise for WD, but challenges remain in efficacy and safety. Here, we established an Atp7b R780L knockin (KI) mouse model corresponding to the human ATP7B R778L variant and investigated the therapeutic efficacy and safety of liver-targeted AAV8-mediated ATP7B (AAV8-ΔC4ATP7B) gene therapy in this model. The results demonstrated the Atp7b KI/KI mice recapitulated key features of impaired Cu metabolism in WD but had mild liver disease. Ten-week-old Atp7b KI/KI mice received a single-dose of AAV8-ΔC4ATP7B and were sacrificed at 8 or 30 weeks after treatment. Treated Atp7b KI/KI mice showed normalization of serum ceruloplasmin, reduced hepatic Cu, decreased urinary Cu, and reversed liver histopathology. Serum transaminases had a transient increase at 8 weeks after treatment but returned to normal at 30 weeks after treatment. These data provide evidence for the efficacy and safety of AAV8-ΔC4ATP7B in animals, supporting clinical translation to patients with WD.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101435"},"PeriodicalIF":4.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

A comprehensive study of AAV tropism across C57BL/6 mice, BALB/c mice, and crab-eating macaques. AAV在C57BL/6小鼠、BALB/c小鼠和食蟹猕猴间趋向性的综合研究

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-02-13 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2025.101434

Kailun Fang, Xiali Yang, Yuanhua Liu, Junhui Xia, Ruoxi Wu, Fan Yang, Canbin Feng, Xinyu Liu, Linyu Shi, Guannan Geng, Hui Yang

{"title":"A comprehensive study of AAV tropism across C57BL/6 mice, BALB/c mice, and crab-eating macaques.","authors":"Kailun Fang, Xiali Yang, Yuanhua Liu, Junhui Xia, Ruoxi Wu, Fan Yang, Canbin Feng, Xinyu Liu, Linyu Shi, Guannan Geng, Hui Yang","doi":"10.1016/j.omtm.2025.101434","DOIUrl":"10.1016/j.omtm.2025.101434","url":null,"abstract":"Recombinant adeno-associated viruses (AAVs) have been widely used for gene delivery and gene therapy. However, certain AAV serotypes exhibited distinct transduction patterns among different mouse strains or between mice and non-human primates (NHPs). These variations prompted us to investigate the AAV tropism of 21 capsid variants using barcoded AAV libraries among different tissues in C57BL/6 and BALB/c mice, as well as in crab-eating macaques. Our study unveiled that AAV tropisms varied significantly among different mouse strains and species, particularly in capsid variants such as AAV4, AAV9, PHP.B, and CAP-B10. Notably, AAV4 exhibited liver-detargeting properties in both mice and NHPs, and was remarkably efficient in transducing the lung, glomerulus, and pancreatic islet. These findings furnish crucial insights into the variations of AAV tropism among different mouse strains and species and facilitate the selection of appropriate AAV capsids for target tissues among different mouse strains and in NHPs.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101434"},"PeriodicalIF":4.6,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Selective RNAi silencing of Schwann cell Piezo1 alleviates mechanical hypersensitization following peripheral nerve injury. 选择性RNAi沉默雪旺细胞Piezo1可减轻周围神经损伤后的机械超敏反应。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-02-12 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2025.101433

Brandon Itson-Zoske, Uarda Gani, Alexander Mikesell, Chensheng Qiu, Fan Fan, Cheryl L Stucky, Quinn H Hogan, Seung Min Shin, Hongwei Yu

{"title":"Selective RNAi silencing of Schwann cell Piezo1 alleviates mechanical hypersensitization following peripheral nerve injury.","authors":"Brandon Itson-Zoske, Uarda Gani, Alexander Mikesell, Chensheng Qiu, Fan Fan, Cheryl L Stucky, Quinn H Hogan, Seung Min Shin, Hongwei Yu","doi":"10.1016/j.omtm.2025.101433","DOIUrl":"10.1016/j.omtm.2025.101433","url":null,"abstract":"The present study was designed to investigate the role of Schwann cell (SC) Piezo1 in peripheral nociception. We first developed an AAV vector that has primary SC tropism after delivery into the sciatic (or tibial) nerve. This was achieved by packing AAV-GFP transcribed by a CBA promoter using a capsid AAVolig001 to generate AAVolig001-CBA-GFP. Six weeks after intraneural injection of AAVolig001-CBA-GFP in naive rats, GFP expression was detected selectively in both myelinating SCs (mSCs) and non-myelinating SCs (nmSCs). A dual promoter and bidirectional AAV encoding a U6-driven short hairpin RNA against rat Piezo1 (PZ1shRNA) and CBA-transcribed GFP was packed with capsid olig001 (AAVolig001-PZ1shRNA), and AAV was injected into unilateral sciatic (or tibial) nerve immediately after induction of common peroneal nerve injury (CPNI). Results showed that the development of mechanical hypersensitivity in the CPNI rats injected with AAVolig001-PZ1shRNA was mitigated compared to rats subjected to AAVolig001-scramble. Selective in vivo SC transduction and functional block of Piezo1 channel activity of primary cultured SCs was confirmed. These data demonstrate that (1) AAVolig001 has unique and selective primary tropism to SCs via intraneural delivery, and (2) SC Piezo1 contributes to mechanical hypersensitivity following nerve injury.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101433"},"PeriodicalIF":4.6,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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