Molecular Therapy最新文献_第8页

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

Prenatal treatment of spinal muscular atrophy. 脊髓性肌萎缩症的产前治疗。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-18 DOI: 10.1016/j.ymthe.2025.04.010

Laurent Servais

引用次数: 0

Enhanced CAR-T Function and Mitochondrial Fitness from Earlier Unfractionated Stem Cell Product in Multiple Myeloma. 早期未分离干细胞产品在多发性骨髓瘤中增强CAR-T功能和线粒体适应度。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-18 DOI: 10.1016/j.ymthe.2025.04.019

Ciara L Freeman,Julieta Abraham-Miranda,Meghan Menges,Reginald M Atkins,Jerald Noble,Hien Liu,Salvatore Corallo,Luis A Cuadrado Delgado,Albert J Ribickas,Constanza Savid-Frontera,Gabriel de Avila,Omar A Castaneda Puglianini,Jose Ochoa-Bayona,Doris K Hansen,Melissa Alsina,Rachid Baz,Taiga Nishihori,Kenneth H Shain,Frederick L Locke

{"title":"Enhanced CAR-T Function and Mitochondrial Fitness from Earlier Unfractionated Stem Cell Product in Multiple Myeloma.","authors":"Ciara L Freeman,Julieta Abraham-Miranda,Meghan Menges,Reginald M Atkins,Jerald Noble,Hien Liu,Salvatore Corallo,Luis A Cuadrado Delgado,Albert J Ribickas,Constanza Savid-Frontera,Gabriel de Avila,Omar A Castaneda Puglianini,Jose Ochoa-Bayona,Doris K Hansen,Melissa Alsina,Rachid Baz,Taiga Nishihori,Kenneth H Shain,Frederick L Locke","doi":"10.1016/j.ymthe.2025.04.019","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.019","url":null,"abstract":"Chimeric antigen receptor T-cells (CAR-T) targeting B-Cell Maturation Antigen (BCMA) have changed the treatment landscape for patients with relapsed and refractory multiple myeloma. However, T-cell dysfunction associated with progressive disease and multiple prior lines of therapy (PLOT) raises concerns about the feasibility of consistently manufacturing effective CAR-T cells. We investigated the practicality of utilizing previously cryopreserved mobilized apheresis to generate potent anti-BCMA CAR-T cells. Paired patient samples collected longitudinally from: 1) Mobilized, unfractionated apheresis obtained prior to hematopoietic cell transplantation (mobHCT), and 2) Apheresis obtained for commercial CAR-T manufacture (aphCAR) were directly compared head-to-head. Median time from transplant to commercial CAR-T infusion was 4.2 years (range 2.5-12.5), and prior to CAR-T collection all patients were triple-class exposed. Analysis revealed that mobHCT samples exhibited a higher CD4:CD8 ratio and a greater proportion of naïve T-cells (CCR7+CD45RO-) in both CD4 and CD8 compartments compared to aphCAR samples. CAR-T cells derived from mobHCT samples demonstrated superior expansion during manufacturing, enhanced interleukin-2 secretion, reduced expression of checkpoint inhibitors, improved cytotoxicity through multiple stimulation rounds, and enhanced mitochondrial function. These findings underscore the potential of utilizing cryopreserved mobilized apheresis collected earlier in the disease course to produce potent and metabolically robust CAR-T cells.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"24 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143857351","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

Combinatorial gene therapy for gyrate atrophy of the choroid and retina. 脉络膜和视网膜旋转性萎缩的组合基因治疗。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-14 DOI: 10.1016/j.ymthe.2025.03.063

Anil Chekuri

引用次数: 0

Celebrating 25 years of Molecular Therapy. 庆祝分子疗法问世25周年。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-14 DOI: 10.1016/j.ymthe.2025.03.059

Joseph C Glorioso

引用次数: 0

Response to: Safety and efficacy considerations of HSC-based gene therapy for RAG1-deficient SCID. 基于hsc的基因治疗rag1缺陷SCID的安全性和有效性考虑

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-14 DOI: 10.1016/j.ymthe.2025.03.049

Eugenio Montini,Luigi Naldini,Claire Booth,Donald B Kohn,Alessandro Aiuti

引用次数: 0

Seltoplasmid promotes ulcer healing versus placebo for treating patients with chronic limb-threatening ischemia: HOPE CLTI-2 trial. Seltoplasmid 与安慰剂相比，可促进慢性肢体缺血患者的溃疡愈合：HOPE CLTI-2 试验。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-11 DOI: 10.1016/j.ymthe.2025.04.009

Xiao Di,Changwei Liu,Siqiao Sun,Jinbao Qin,Xueli Guo,Yikuan Chen,Xin Li,Hongkun Zhang,Ming Liu,Liu Yang,Hui Zhao,Shaoying Lu,Jingyong Huang,Yunfeng Zhang,Jun Li,Xiaolei Lin,Kai Yao,Jingdong Tang,Jian Wang,Zhanfeng Gao,Jinjun Wang,Xiaojin Huang,Songshan Xu,Yue Liu,Wei Han,Leng Ni,Wei Ye,Yuehong Zheng,Yuexin Chen,Bao Liu

{"title":"Seltoplasmid promotes ulcer healing versus placebo for treating patients with chronic limb-threatening ischemia: HOPE CLTI-2 trial.","authors":"Xiao Di,Changwei Liu,Siqiao Sun,Jinbao Qin,Xueli Guo,Yikuan Chen,Xin Li,Hongkun Zhang,Ming Liu,Liu Yang,Hui Zhao,Shaoying Lu,Jingyong Huang,Yunfeng Zhang,Jun Li,Xiaolei Lin,Kai Yao,Jingdong Tang,Jian Wang,Zhanfeng Gao,Jinjun Wang,Xiaojin Huang,Songshan Xu,Yue Liu,Wei Han,Leng Ni,Wei Ye,Yuehong Zheng,Yuexin Chen,Bao Liu","doi":"10.1016/j.ymthe.2025.04.009","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.009","url":null,"abstract":"Intramuscular injection of donaperminogene seltoplasmid (recombinant human hepatocyte growth factor plasmids) represents a gene therapy that treat patients with chronic limb-threatening ischemia (CLTI). The HOPE CLTI-2 trial was a Phase 3, multicenter, double-blind, placebo-controlled study aimed to evaluate the efficacy and safety of seltoplasmid in patients with Rutherford class 5 CLTI. This study did not require participants to be ineligible for revascularization, allowing enrollment of patients with CLTI caused by either atherosclerosis (ASO) or Buerger's disease (TAO). The primary endpoint was the complete ulcer healing rate at 6 months. A total of 242 participants (53.3% ASO versus 46.7% TAO) were enrolled, with 161 receiving seltoplasmid and 81 receiving placebo. Complete ulcer healing was achieved in 70 patients in the seltoplasmid group compared to 15 patients in the placebo group, resulting in an adjusted healing rate difference of 26.1% (95% confidence interval [CI]: 15.1-37.0%; P < 0.001). The hazard ratio for healing was 2.31 (95% CI: 1.32-4.05; P = 0.004). The benefits of seltoplasmid on ulcer healing persisted in both TAO and ASO subgroups. Serious adverse events were rare. Our study demonstrated that seltoplasmid significantly improved ulcer healing rates in patients with Rutherford class 5 CLTI compared to placebo.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"108 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831562","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

Low-level shRNA Cytotoxicity Can Contribute to MYC-induced Hepatocellular Carcinoma in Adult Mice. 低水平shRNA细胞毒性可促进myc诱导的成年小鼠肝细胞癌。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-10 DOI: 10.1016/j.ymthe.2025.03.036

Shelly Beer, David I Bellovin, Joyce S Lee, Kimberly Komatsubara, Lora S Wang, Huishan Koh, Kathleen Börner, Theresa A Storm, Corrine R Davis, Mark A Kay, Dean W Felsher, Dirk Grimm

引用次数: 0