Molecular Therapy最新文献_第2页

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

DNA based Immunotherapy for Cancer: in vivo Approaches for Recalcitrant Targets. 基于DNA的癌症免疫治疗：难治性靶点的体内方法。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-04-09 DOI: 10.1016/j.ymthe.2025.04.008

Pratik S Bhojnagarwala,Joshua Jose,Shushu Zhao,David B Weiner

{"title":"DNA based Immunotherapy for Cancer: in vivo Approaches for Recalcitrant Targets.","authors":"Pratik S Bhojnagarwala,Joshua Jose,Shushu Zhao,David B Weiner","doi":"10.1016/j.ymthe.2025.04.008","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.008","url":null,"abstract":"Immunotherapy has revolutionized cancer treatment which complements traditional therapies including surgery, chemotherapy, radiation and targeted therapies. Immunotherapy redirects the patient's immune system against tumors via several immune mediated approaches. Over the past few years, therapeutic immunization, which enable the patient's T cells to better recognize and kill tumors, have been increasingly tested in the clinic with several approaches demonstrating treatment improvements. There has been a renewed interest in cancer vaccines due to advances in tumor-antigen identification, immune response optimization, novel adjuvants, next-generation vaccine delivery platforms and antigen designs. The Covid-19 pandemic accelerated progress in nucleic acid-based vaccine manufacturing, which spurred broader interest in mRNA or plasmid platforms. Enhanced DNA vaccine designs including optimized leader sequences, RNA and codon optimizations, improved formulations and delivery via adaptive electroporation using stereotactic intramuscular/intradermal methods have improved T cell responses to plasmid-delivered tumor-antigens. Additionally, advancements for direct in vivo delivery of DNA-encoded mono/bispecific antibodies offer novel tumor-targeting strategies. This review summarizes recent clinical data for therapeutic cancer vaccines utilizing the DNA platform, including vaccines targeting common tumor-associated and viral antigens and neoantigen vaccines using nucleic acid technologies. We also summarize preclinical data using DNA-launched monoclonal/bispecific antibodies, underscoring their potential as a novel cancer therapy tool.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"13 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822563","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

Recent progress and future challenges in structure-based protein-protein interaction prediction. 基于结构的蛋白-蛋白相互作用预测的最新进展和未来挑战。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-06 DOI: 10.1016/j.ymthe.2025.04.003

Rongqing Yuan, Jing Zhang, Jian Zhou, Qian Cong

引用次数: 0

Gene Regulation Technologies for Gene and Cell Therapy. 基因和细胞治疗中的基因调控技术。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-06 DOI: 10.1016/j.ymthe.2025.04.004

Gabriel L Butterfield, Samuel J Reisman, Nahid Iglesias, Charles A Gersbach

{"title":"Gene Regulation Technologies for Gene and Cell Therapy.","authors":"Gabriel L Butterfield, Samuel J Reisman, Nahid Iglesias, Charles A Gersbach","doi":"10.1016/j.ymthe.2025.04.004","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.004","url":null,"abstract":"Gene therapy stands at the forefront of medical innovation, offering unique potential to treat underlying causes of genetic disorders and broadly enable regenerative medicine. However, unregulated production of therapeutic genes can lead to decreased clinical utility due to various complications. Thus, many technologies for controlled gene expression are under development, including regulated transgenes, modulation of endogenous genes to leverage native biological regulation, mapping and repurposing of transcriptional regulatory networks, and engineered systems that dynamically react to cell state changes. Transformative therapies enabled by advances in tissue-specific promoters, inducible systems, and targeted delivery have already entered clinical testing and demonstrated significantly improved specificity and efficacy. This review highlights next-generation technologies under development to expand the reach of gene therapies by enabling precise modulation of gene expression. These technologies, including epigenome editing, antisense oligonucleotides, RNA editing, transcription factor-mediated reprogramming, and synthetic genetic circuits, have the potential to provide powerful control over cellular functions. Despite these remarkable achievements, challenges remain in optimizing delivery, minimizing off-target effects, and addressing regulatory hurdles. However, the ongoing integration of biological insights with engineering innovations promises to expand the potential for gene therapy, offering hope for treating not only rare genetic disorders but also complex multifactorial diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803844","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 delivery of a SUMO1-derived peptide rescues neuronal degeneration and motor deficits in an rAAV-α-synuclein-A53T mouse model of Parkinson's disease. 在rAAV-α-synuclein-A53T帕金森病小鼠模型中，sumo1衍生肽的基因传递可拯救神经元变性和运动缺陷。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-04-05 DOI: 10.1016/j.ymthe.2025.04.005

Zhaohui Liang, Suresh Kanna Murugappan, Yuxuan Li, Man Nga Lai, Yajing Qi, Yi Wang, Ho Yin Edwin Chan, Marianne M Lee, Michael K Chan

{"title":"Gene delivery of a SUMO1-derived peptide rescues neuronal degeneration and motor deficits in an rAAV-α-synuclein-A53T mouse model of Parkinson's disease.","authors":"Zhaohui Liang, Suresh Kanna Murugappan, Yuxuan Li, Man Nga Lai, Yajing Qi, Yi Wang, Ho Yin Edwin Chan, Marianne M Lee, Michael K Chan","doi":"10.1016/j.ymthe.2025.04.005","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.04.005","url":null,"abstract":"Developing α-synuclein aggregation inhibitors is challenging because its aggregation process involves several microscopic steps and heterogenous intermediates. Previously, we identified a SUMO1-derived peptide, SUMO1(15-55), that exhibits tight binding to monomeric α-synuclein via SUMO-SIM interactions, and effectively blocks the initiation of aggregation and formation of toxic aggregates in vitro. In cellular and Drosophila models, SUMO1(15-55) was efficacious in protecting neuronal cells from α-synuclein-induced neurotoxicity and neuronal degeneration. Given the demonstrated ability of SUMO1(15-55) to sequester α-synuclein monomers thereby blocking oligomers formation, we sought to evaluate whether it could be equally effective against the aggregation-prone familial mutant α-synuclein-A53T. Herein, we show that SUMO1(15-55) selectively binds to monomeric α-synuclein-A53T, inhibits primary nucleation, and prevents the formation of structured protofibrils in vitro, thereby protecting neuronal cells from protofibril-induced cell death. We further demonstrate that larval feeding of a designed His10-SUMO1(15-55) that exhibits enhanced sub-stoichiometric suppression of α-synuclein-A53T aggregation in vitro can ameliorate PD-related symptoms in α-synuclein-A53T transgenic Drosophila models, while its rAAV-mediated gene delivery can relieve the PD-related histological and behavioral deficiencies in an rAAV-α-synuclein-A53T mouse PD model. Our findings suggest that gene delivery of His10-SUMO1(15-55) may serve as a clinical therapy for a spectrum of α-synuclein-aggregation associated synucleinopathies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795762","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