Molecular Therapy最新文献

Discovery and preclinical development of a potent epigenic editor targeting PCSK9 to lower LDL cholesterol. 靶向PCSK9降低LDL胆固醇的有效表观遗传编辑器的发现和临床前开发。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-22 DOI: 10.1016/j.ymthe.2025.04.012

Qiang Xiong,Frederic Tremblay,Jennifer Marlowe

引用次数: 0

Small Molecule Inhibition of SUMOylation Increases Expression from AAV Vectors Both During and After Initial Transduction in Mice. 小分子抑制SUMOylation增加AAV载体在小鼠初始转导期间和之后的表达。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-21 DOI: 10.1016/j.ymthe.2025.04.022

Maria C Seleme,Aradhana Kasimsetty,Young Hwang,Carole Lee,Aoife M Roche,Allysen C Henriksen,John K Everett,Frederic D Bushman,Denise E Sabatino

{"title":"Small Molecule Inhibition of SUMOylation Increases Expression from AAV Vectors Both During and After Initial Transduction in Mice.","authors":"Maria C Seleme,Aradhana Kasimsetty,Young Hwang,Carole Lee,Aoife M Roche,Allysen C Henriksen,John K Everett,Frederic D Bushman,Denise E Sabatino","doi":"10.1016/j.ymthe.2025.04.022","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.022","url":null,"abstract":"AAV-based gene therapy has been used to treat thousands of patients, but a limitation can be inefficient transgene expression from AAV vectors. AAV transduction can be affected by the small ubiquitin-like modifier (SUMO) system, in which SUMO proteins are attached to proteins after translation, thereby modulating their function and stability. However, to date, practical modulators of SUMOylation to increase AAV vector transgene expression have not been available. Here we demonstrate that small molecule inhibitors of SUMOylation can boost expression from AAV vectors. Treatment with the SUMOylation inhibitor TAK-981 sharply increased AAV transgene expression in transformed human cells, in primary human cells, and in mice. Increased transgene expression in vitro and in vivo was associated with increased mRNA levels per vector DNA template. Treatment of mice with TAK-981 during AAV delivery increased AAV transgene expression; in addition, TAK-981 could boost transgene expression when introduced at long times after initial AAV vector transduction regardless of whether mice had been exposed to TAK-981 previously. Modulators of SUMOylation are currently in clinical trials in human patients, and thus, may soon represent a viable strategy for boosting AAV transgene expression to improve human gene therapy outcomes.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"7 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Histone deacetylases and their inhibitors in kidney diseases. 肾病中的组蛋白去乙酰化酶及其抑制剂。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-21 DOI: 10.1016/j.ymthe.2025.04.026

Yue Zheng,Tie-Ning Zhang,Peng-Hui Hao,Ni Yang,Yue Du

引用次数: 0

Identification of a robust promoter in mouse and human hepatocytes by in vivo biopanning of a barcoded AAV library. 在小鼠和人肝细胞中通过条形码AAV文库的活体生物筛选鉴定一个健壮的启动子。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-21 DOI: 10.1016/j.ymthe.2025.04.027

Jonas Becker,Claire Domenger,Pervinder Choksi,Chiara Krämer,Conradin Baumgartl,Olena Maiakovska,Jae-Jun Kim,Jonas Weinmann,Georg Huber,Florian Schmidt,Christian Thirion,Oliver J Müller,Holger Willenbring,Dirk Grimm

{"title":"Identification of a robust promoter in mouse and human hepatocytes by in vivo biopanning of a barcoded AAV library.","authors":"Jonas Becker,Claire Domenger,Pervinder Choksi,Chiara Krämer,Conradin Baumgartl,Olena Maiakovska,Jae-Jun Kim,Jonas Weinmann,Georg Huber,Florian Schmidt,Christian Thirion,Oliver J Müller,Holger Willenbring,Dirk Grimm","doi":"10.1016/j.ymthe.2025.04.027","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.027","url":null,"abstract":"Recombinant adeno-associated viruses (AAV) are leading vectors for in vivo human gene therapy. An integral vector element are promoters, which control transgene expression in either a ubiquitous or cell-type-selective manner. Identifying optimal capsid-promoter combinations is challenging, especially when considering on- versus off-target expression. Here, we report a pipeline for in vivo promoter biopanning in AAV building on our AAV capsid barcoding technology and illustrate its potential by screening 53 promoters in 16 murine tissues using an AAV9 vector. Surprisingly, the 2.2 kb human glial fibrillary acidic protein (GFAP) promoter was the top hit in the liver, where it outperformed robust benchmarks such as the human alpha-1-antitrypsin promoter or the clinically used liver-specific promoter 1 (LP1). Analysis of hepatic cell populations revealed preferred GFAP promoter activity in hepatocytes. Notably, the GFAP promoter also surpassed the LP1 and cytomegalovirus (CMV) promoters in human hepatocytes engrafted in an immune-deficient mouse. These findings establish the GFAP promoter as an exciting alternative for research and clinical applications requiring efficient and specific transgene expression in hepatocytes. Our pipeline expands the arsenal of technologies for high-throughput in vivo screening of viral vector components and is compatible with capsid barcoding, facilitating the combinatorial interrogation of complex AAV libraries.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"21 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Clinical Perspective: Advancing hemophilia treatment through gene therapy approaches. 临床展望：通过基因治疗方法推进血友病治疗。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-21 DOI: 10.1016/j.ymthe.2025.04.023

Courtney D Thornburg,Steve W Pipe,Alessio Cantore,Carmen Unzu,Micheala Jones,Wolfgang A Miesbach

{"title":"Clinical Perspective: Advancing hemophilia treatment through gene therapy approaches.","authors":"Courtney D Thornburg,Steve W Pipe,Alessio Cantore,Carmen Unzu,Micheala Jones,Wolfgang A Miesbach","doi":"10.1016/j.ymthe.2025.04.023","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.023","url":null,"abstract":"Hemophilia, a congenital bleeding disorder, can cause arthropathy, impaired mobility, pain, and life-threatening hemorrhage events, significantly impacting quality of life for patients and caregivers. Current therapies, although effective, necessitate costly lifelong treatment, often in specialized settings. However, as a monogenic disorder caused by loss-of-function genetic variants, hemophilia is amenable to gene therapy. In this article, three primary gene therapy approaches at the forefront of clinical development are reviewed. Adeno-associated virus-based gene therapy, having secured approval in the EU, UK, and USA after promising Phase 3 trial results, demonstrates clear superiority over standard-of-care treatment. Lentivirus-based approaches capable of transducing dividing and nondividing cells may improve the durability of treatment and have low susceptibility to pre-existing neutralizing antibodies to viral vectors. Finally, gene editing techniques such as zinc finger nucleases and CRISPR aim to correct genetic defects directly, holding promise as novel, effective, and highly durable therapeutic strategies in adults and children with hemophilia. This review provides a comprehensive summary of the current status of these gene therapy approaches, highlighting advantages, limitations, and potential future developments.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"37 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Gene-based therapies for steatotic liver disease. 脂肪变性肝病的基因治疗

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-19 DOI: 10.1016/j.ymthe.2025.04.024

Viktoriia Iakovleva,Ype P de Jong

{"title":"Gene-based therapies for steatotic liver disease.","authors":"Viktoriia Iakovleva,Ype P de Jong","doi":"10.1016/j.ymthe.2025.04.024","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.024","url":null,"abstract":"Advances in nucleic acid delivery have positioned the liver as a key target for gene therapy, with adeno-associated virus vectors showing long-term effectiveness in treating hemophilia. Steatotic liver disease (SLD), the most common liver condition globally, primarily results from metabolic dysfunction-associated and alcohol-associated liver diseases. In some individuals, SLD progresses from simple steatosis to steatohepatitis, cirrhosis, and eventually hepatocellular carcinoma, driven by a complex interplay of genetic, metabolic, and environmental factors. Genetic variations in various lipid metabolism-related genes, such as patatin-like phospholipase domain-containing protein 3 (PNPLA3), 17β-hydroxysteroid dehydrogenase type 13 (HSD17B13), and mitochondrial amidoxime reducing component 1 (MTARC1), impact the progression of SLD and offer promising therapeutic targets. This review largely focuses on genes identified through clinical association studies, as they are more likely to be effective and safe for therapeutic intervention. While preclinical research continues to deepen our understanding of genetic factors, early-stage clinical trials involving gene-based SLD therapies, including transient antisense and small molecule approaches, are helping prioritize therapeutic targets. Meanwhile, hepatocyte gene editing technologies are advancing rapidly, offering alternatives to transient methods. As such, gene-based therapies show significant potential for preventing the progression of SLD and enhancing long-term liver health.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"11 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Draining the brain: Gene therapy reverses brain edema in mice with the leukodystrophy MLC. 引流脑：基因疗法逆转脑水肿小鼠脑白质营养不良MLC。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-19 DOI: 10.1016/j.ymthe.2025.04.011

Rogier Min,Niek P van Til,Marjo S van der Knaap

引用次数: 0

GRP94 is Indispensable for Definitive Endoderm Specification of Human Induced Pluripotent Stem Cells. GRP94对人类诱导多能干细胞的最终内胚层规范化不可或缺

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-19 DOI: 10.1016/j.ymthe.2025.04.025

Hua Wei,Christiana Kappler,Erica Green,Hanna Jiang,Tiffany Yeung,Hongjun Wang

{"title":"GRP94 is Indispensable for Definitive Endoderm Specification of Human Induced Pluripotent Stem Cells.","authors":"Hua Wei,Christiana Kappler,Erica Green,Hanna Jiang,Tiffany Yeung,Hongjun Wang","doi":"10.1016/j.ymthe.2025.04.025","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.025","url":null,"abstract":"Human induced pluripotent stem cell (hiPSC)-derived insulin-producing β cell therapy shows promise in treating type 1 diabetes (T1D) and potentially type 2 diabetes (T2D). Understanding the genetic factors controlling hiPSC differentiation could optimize this therapy. In this study, we investigated the role of glucose-regulated protein 94 (GRP94) in human β cell development by generating HSP90B1/GRP94 knockout (KO) hiPSCs, re-expressing GRP94 in the mutants and inducing their β cell differentiation. Our results revealed that GRP94 depletion hindered β cell generation by promoting cell death induced by endoplasmic reticulum (ER) stress and other stressors during definitive endoderm (DE) differentiation. Moreover, GRP94 deletion resulted in decreased activation of WNT/β-catenin signaling, which is critical for DE specification. Re-expression of GRP94 in GRP94 KO iPSCs partially reversed DE differentiation deficiency and alleviated cell death. These findings highlight the previously unrecognized indispensable role of GRP94 in human DE formation and consequent β cell development from hiPSCs. GRP94 mitigates ER stress-induced cell death and regulates the WNT/β-catenin signaling pathway, which is both crucial for successful β cell differentiation. These results provide new insights into the molecular mechanisms underlying β cell differentiation from hiPSCs and suggest that targeting GRP94 pathways could enhance the efficiency of hiPSC-derived insulin-producing cell therapies for diabetes treatment.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"24 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Intravitreal adenine base editing of RS1 improves vision in a preclinical mouse model of retinoschisis. 玻璃体内腺嘌呤碱基编辑RS1改善视网膜裂小鼠临床前模型的视力。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-18 DOI: 10.1016/j.ymthe.2025.04.021

Dong Hyun Jo,Hyewon Jang,Chang Sik Cho,Seok Jae Lee,Ji Hwa Heo,Jung Ah Kim,Se Jin Kim,WonHyoung Ryu,Chan-Wook Park,Byeong-Cheol Kang,Heon Yung Gee,Young Hoon Sung,Hyongbum Henry Kim,Jeong Hun Kim

{"title":"Intravitreal adenine base editing of RS1 improves vision in a preclinical mouse model of retinoschisis.","authors":"Dong Hyun Jo,Hyewon Jang,Chang Sik Cho,Seok Jae Lee,Ji Hwa Heo,Jung Ah Kim,Se Jin Kim,WonHyoung Ryu,Chan-Wook Park,Byeong-Cheol Kang,Heon Yung Gee,Young Hoon Sung,Hyongbum Henry Kim,Jeong Hun Kim","doi":"10.1016/j.ymthe.2025.04.021","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.021","url":null,"abstract":"Base editing offers high potential for treating genetic diseases, particularly those with limited treatment options. Retinoschisis, an X-linked retinal disease causing progressive vision loss, currently lacks effective therapies. We identified the c.422G>A (p.Arg141His) variant of the RS1 gene in six male patients with retinoschisis and generated a humanized mouse model harboring this variant, which mimicked the disease phenotype. By testing adenine base editors and single guide RNAs, we identified an optimal combination of high editing efficiency and low bystander editing. Intravitreal injection of adeno-associated viral vectors encoding this adenine base editor achieved approximately 40% editing efficiency in all retinal cells, restored retinal layer integrity, and preserved visual functions in 2-week-old male hemizygous mice. These mice exhibited retinal layer splitting at baseline, further validating the model. This study demonstrates a strategy for identifying effective base editing tools for clinical use through the preclinical evaluation of humanized mouse lines with patient-derived mutations and highlights their applicability in treating genetic diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"25 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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 vivo programming of adult pericytes aids axon regeneration by providing cellular bridges for SCI repair. 成年周细胞的体内编程通过为脊髓损伤修复提供细胞桥来帮助轴突再生。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-18 DOI: 10.1016/j.ymthe.2025.04.020

Wenjing Sun,Elliot Dion,Fabio Laredo,Allyson Okonak,Jesse A Sepeda,Esraa Haykal,Min Zhou,Heithem M El-Hodiri,Andy J Fischer,Jerry Silver,Juan Peng,Andrew Sas,Andrea Tedeschi

{"title":"In vivo programming of adult pericytes aids axon regeneration by providing cellular bridges for SCI repair.","authors":"Wenjing Sun,Elliot Dion,Fabio Laredo,Allyson Okonak,Jesse A Sepeda,Esraa Haykal,Min Zhou,Heithem M El-Hodiri,Andy J Fischer,Jerry Silver,Juan Peng,Andrew Sas,Andrea Tedeschi","doi":"10.1016/j.ymthe.2025.04.020","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.020","url":null,"abstract":"Pericytes are contractile cells of the microcirculation that participate in wound healing after spinal cord injury (SCI). Thus far, the extent to which pericytes cause or contribute to axon growth and regeneration failure after SCI remains controversial. Here, we found that SCI leads to profound changes in vasculature architecture and pericyte coverage. We demonstrated that pericytes constrain sensory axons on their surface, causing detrimental structural and functional changes in adult DRG neurons that contribute to axon regeneration failure after SCI. Perhaps more excitingly, we discovered that in vivo programming of adult pericytes via local administration of platelet-derived growth factor BB (PDGF-BB) effectively promotes axon regeneration and recovery of hindlimb function by contributing to the formation of cellular bridges that span the lesion. Ultrastructural analysis showed that PDGF-BB induced fibronectin fibril alignment and extension, effectively converting adult pericytes into a permissive substrate for axon growth. In addition, PDGF-BB localized delivery positively affects the physical and chemical nature of the lesion environment, thereby creating more favorable conditions for SCI repair. Thus, therapeutic manipulation rather than wholesale ablation of pericytes can be exploited to prime axon regeneration and SCI repair.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"61 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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