Molecular Therapy最新文献

Tailoring capsid-directed evolution technology for improved AAV-mediated CAR-T generation. 定制囊壳定向进化技术，改进 AAV 介导的 CAR-T 生成。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2024-12-12 DOI: 10.1016/j.ymthe.2024.12.012

Adrian Westhaus, Elena Barba-Sarasua, Yuyan Chen, Kenneth Hsu, Suzanne Scott, Maddison Knight, Florencia Haase, Santiago Mesa Mora, Benjamin C Houghton, Ramon Roca-Pinilla, Predrag Kalajdzic, Geraldine O'Neill, Adrian J Thrasher, Giorgia Santilli, Leszek Lisowski

{"title":"Tailoring capsid-directed evolution technology for improved AAV-mediated CAR-T generation.","authors":"Adrian Westhaus, Elena Barba-Sarasua, Yuyan Chen, Kenneth Hsu, Suzanne Scott, Maddison Knight, Florencia Haase, Santiago Mesa Mora, Benjamin C Houghton, Ramon Roca-Pinilla, Predrag Kalajdzic, Geraldine O'Neill, Adrian J Thrasher, Giorgia Santilli, Leszek Lisowski","doi":"10.1016/j.ymthe.2024.12.012","DOIUrl":"10.1016/j.ymthe.2024.12.012","url":null,"abstract":"Chimeric antigen receptor (CAR) T cell (CAR-T) therapies present options for patients diagnosed with certain leukemias. Recent advances of the technology included a method to integrate the CAR into the T cell receptor alpha constant (TRAC) locus to take advantage of the endogenous promoter and regulatory elements for CAR expression. This method used adeno-associated viral (AAV) vectors based on AAV6 to deliver the donor template encoding the CAR construct. Since the original publication, improvements have been made to this targeted CAR integration technique; however, none of those techniques focused on improving the AAV vector used to deliver the therapeutic cargo. The herein presented study developed a novel AAV capsid directed evolution platform that allows for specifically selecting for novel AAV capsid variants that enable more efficient targeted gene editing-mediated CAR construct integration into the TRAC locus in primary T cells. Using this new platform, we selected several novel AAVs that enable more efficient editing in T cells than AAV6. Two novel capsids, AAV-T1 and AAV-T2, were able to mediate 5-fold improvement for on-target knockin, which resulted in 5-fold reduction of the vector dose to produce highly cytolytic T cells against a brain tumor cell line.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2801-2818"},"PeriodicalIF":12.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142824321","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

Autologous transplantation of mitochondria/rAAV IGF-I platforms in human osteoarthritic articular chondrocytes to treat osteoarthritis. 线粒体/rAAV IGF-I平台在人骨关节炎关节软骨细胞内的自体移植作为治疗人骨关节炎的新概念

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2024-12-30 DOI: 10.1016/j.ymthe.2024.12.047

Gang Zhong, Wei Liu, Jagadeesh K Venkatesan, Dan Wang, Henning Madry, Magali Cucchiarini

{"title":"Autologous transplantation of mitochondria/rAAV IGF-I platforms in human osteoarthritic articular chondrocytes to treat osteoarthritis.","authors":"Gang Zhong, Wei Liu, Jagadeesh K Venkatesan, Dan Wang, Henning Madry, Magali Cucchiarini","doi":"10.1016/j.ymthe.2024.12.047","DOIUrl":"10.1016/j.ymthe.2024.12.047","url":null,"abstract":"Despite various available treatments, highly prevalent osteoarthritis (OA) cannot be cured in patients. In light of evidence showing mitochondria dysfunction during the disease progression, our goal was to develop a novel therapeutic concept based on the transplantation of mitochondria as a platform to deliver recombinant adeno-associated virus (rAAV) gene vectors with potency for OA. For the first time, to our best knowledge, we report the successful creation of a safe mitochondria/rAAV system effectively promoting the overexpression of a candidate insulin-like growth factor I (IGF-I) by administration to autologous human osteoarthritic articular chondrocytes versus control conditions (reporter mitochondria/rAAV lacZ system, rAAV-free system, absence of mitochondria transplantation; up to 8.4-fold difference). The candidate mitochondria/rAAV IGF-I system significantly improved key activities in the transplanted cells (proliferation/survival, extracellular matrix production, mitochondria functions) relative to the control conditions (up to a 9.5-fold difference), including when provided in a pluronic F127 (PF127) hydrogel for reinforced delivery (up to a 5.9-fold difference). Such effects were accompanied by increased levels of cartilage-specific SOX9 and Mfn-1 (mitochondria fusion) and decreased levels of Drp-1 (mitochondria fission) and proinflammatory tumor necrosis factor alpha (TNF-α; up to 4.5-fold difference). This study shows the potential of combining the use of mitochondria with rAAV as a promising approach for human OA.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2900-2912"},"PeriodicalIF":12.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915307","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 development of allogeneic chimeric antigen receptor αβ-T cells. 异体嵌合抗原受体αβ-T细胞的临床研究。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2025-03-27 DOI: 10.1016/j.ymthe.2025.03.040

Christos Georgiadis, Roland Preece, Waseem Qasim

{"title":"Clinical development of allogeneic chimeric antigen receptor αβ-T cells.","authors":"Christos Georgiadis, Roland Preece, Waseem Qasim","doi":"10.1016/j.ymthe.2025.03.040","DOIUrl":"10.1016/j.ymthe.2025.03.040","url":null,"abstract":"Ready-made banks of allogeneic chimeric antigen receptor (CAR) T cells, produced to be available at the time of need, offer the prospect of accessible and cost-effective cellular therapies. Various strategies have been developed to overcome allogeneic barriers, drawing on cell engineering platforms including RNA interference, protein-based restriction, and genome editing, including RNA-guided CRISPR-Cas and base editing tools. Alloreactivity and the risk of graft-versus-host disease from non-matched donor cells have been mitigated by disruption of αβ-T cell receptor expression on the surface of T cells and stringent removal of any residual αβ-T cell populations. In addition, host-mediated rejection has been tackled through a combination of augmented lymphodepletion and cell engineering strategies that have allowed infused cells to evade immune recognition or conferred resistance to lymphodepleting agents to promote persistence and expansion of effector populations. Early-phase studies using off-the-shelf universal donor CAR T cells have been undertaken mainly in the context of blood malignancies, where emerging data of clinical responses have supported wider adoption and further applications. These developments offer the prospect of alternatives to current autologous approaches through the emerging application of genome engineering solutions to improve safety, persistence, and function of universal donor products.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2426-2440"},"PeriodicalIF":12.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743064","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

Lung endothelial transduction in a patient that succumbed to acute respiratory distress syndrome following high-dose rAAV9 gene therapy. 高剂量rAAV9基因治疗致急性呼吸窘迫综合征患者的肺内皮转导

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2025-05-28 DOI: 10.1016/j.ymthe.2025.05.017

Juliette Hordeaux, R Jason Lamontagne, Sushobhana Bandyopadhyay, Peter Bell, James M Wilson, Terence R Flotte

引用次数: 0

The landscape of cell and gene therapy today. 细胞和基因治疗的现状。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2025-05-29 DOI: 10.1016/j.ymthe.2025.05.006

David Barrett, Daniel Digaudio

引用次数: 0

Recent developments in translational imaging of in vivo gene therapy outcomes. 体内基因治疗结果转化成像的最新进展。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2024-12-30 DOI: 10.1016/j.ymthe.2024.12.049

Isabel L Day, Mikayla Tamboline, Gerald S Lipshutz, Shili Xu

{"title":"Recent developments in translational imaging of in vivo gene therapy outcomes.","authors":"Isabel L Day, Mikayla Tamboline, Gerald S Lipshutz, Shili Xu","doi":"10.1016/j.ymthe.2024.12.049","DOIUrl":"10.1016/j.ymthe.2024.12.049","url":null,"abstract":"Gene therapy achieves therapeutic benefits by delivering genetic materials, packaged within a delivery vehicle, to target cells with defective genes. This approach has shown promise in treating various conditions, including cancer, metabolic disorders, and tissue-degenerative diseases. Over the past 5 years, molecular imaging has increasingly supported gene therapy development in both preclinical and clinical studies. High-quality images from positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and computed tomography (CT) enable quantitative and reliable monitoring of gene therapy. Most reported studies have applied imaging biomarkers to non-invasively evaluate the outcomes of gene therapy. This review aims to inform researchers in molecular imaging and gene therapy about the integration of these two disciplines. We highlight recent developments in using imaging biomarkers to monitor the outcome of in vivo gene therapy, where the therapeutic delivery vehicle is administered systemically. In addition, we discuss prospects for further incorporating imaging biomarkers to support the development and application of gene therapy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"2548-2564"},"PeriodicalIF":12.1,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142915323","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

Killing the killers: Natural killer cell therapy targeting glioma stem cells in high-grade glioma. 杀死杀手：针对高级别胶质瘤干细胞的自然杀伤细胞疗法。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2025-03-03 DOI: 10.1016/j.ymthe.2025.02.043

Poorva Poorva, Jensen Mast, Bihui Cao, Mitesh V Shah, Karen E Pollok, Jia Shen

引用次数: 0

Recent advances in therapeutic gene-editing technologies. 治疗性基因编辑技术的最新进展。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2025-03-20 DOI: 10.1016/j.ymthe.2025.03.026

Dongqi Liu, Di Cao, Renzhi Han

引用次数: 0

Mesenchymal stromal cell therapy: Progress to date and future outlook. 间充质间质细胞治疗：迄今为止的进展和未来展望。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2025-02-06 DOI: 10.1016/j.ymthe.2025.02.003

Wen Lu, Julie Allickson

引用次数: 0

The impact of revised regenerative medicine regulations on unapproved gene therapies in Japan. 日本修订再生医学法规对未经批准的基因疗法的影响。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-06-04 Epub Date: 2025-02-25 DOI: 10.1016/j.ymthe.2025.02.018

Yuichiro Ukon, Satoshi Hosoya, Kazuki Morita, Eisuke Minegishi, Jun Sugihara

引用次数: 0