Molecular TherapyPub Date : 2025-09-22DOI: 10.1016/j.ymthe.2025.09.034
Ziyu Chen,Mengfan Wu,Samerender Nagam Hanumantharao,Pratik Koirala,Soheila Ali Akbari Ghavimi,Ashley E Siegel,Chang Liu,Erin Taylor,Justin Broyles,Indranil Sinha,Vicki Rosen,Shailesh Agarwal
{"title":"Adipocyte cell therapy targeting bone morphogenetic protein signaling alleviates fibroadipose tissue deposition in secondary lymphedema.","authors":"Ziyu Chen,Mengfan Wu,Samerender Nagam Hanumantharao,Pratik Koirala,Soheila Ali Akbari Ghavimi,Ashley E Siegel,Chang Liu,Erin Taylor,Justin Broyles,Indranil Sinha,Vicki Rosen,Shailesh Agarwal","doi":"10.1016/j.ymthe.2025.09.034","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.034","url":null,"abstract":"Secondary lymphedema is a chronic disease affecting an isolated limb following lymph node resection for cancer treatment. Management options are limited and onerous, leading to near-universal progression to subcutaneous fibroadipose tissue deposition. Here, we identify bone morphogenetic protein ligands (BMPs) as mediators of fibroadipose tissue deposition through in vitro experiments with human lymphedema fluid and BMP-specific inhibitor. Systemic in vivo delivery of BMP inhibitor reduces fibroadipose tissue deposition in a mouse model of hindlimb secondary lymphedema. Considering systemic delivery may be undesirable for an anatomically-isolated disease, we engineered a cell therapy using purified adipocytes, aiming for clinical translation in a resource- and time- constrained environment requiring only mechanical manipulation. We then devised a strategy for gene delivery into adipocytes and verified the secretion of the recombinant peptide inhibitor of BMP ligands. Upon in vivo delivery of the engineered adipocytes, we verified secretion of the BMP inhibitor and a reduction in fibroadipose tissue deposition in the mice hindlimb. Our findings highlight BMPs as signaling mediators for fibroadipose tissue deposition and provide a blueprint for a cell therapy using genetically-modified adipocytes for local drug delivery. This approach may be in a point-of-care strategy and potentially be amenable to various conditions.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"18 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127083","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}
{"title":"Chimeric Enzymes Enhance Treatment Potential For Globoid Cell Leukodystrophy through Hematopoietic Stem Cell Gene Therapy.","authors":"Federica Cascino,Alessandra Ricca,Ilaria Picciotti,Erika Valeri,Giulia Unali,Veronica Saporito,Marta Freschi,Francesco Morena,Sabata Martino,Anna Kajaste-Rudnitski,Angela Gritti","doi":"10.1016/j.ymthe.2025.09.030","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.030","url":null,"abstract":"Globoid cell leukodystrophy (GLD) is a fatal lysosomal storage disorder caused by a deficiency in the β-galactosylceramidase (GALC) enzyme, leading to severe demyelination and neurodegeneration, and often death before the age of two. Hematopoietic stem/progenitor cell transplantation (HSPC-T) has limited efficacy due to inadequate GALC delivery to the central and peripheral nervous systems (CNS, PNS) and associated risks. In vivo gene therapy (GT) using adeno-associated viral vectors shows promise, but safety concerns persist. This research presents a strategy using lentiviral vector (LV)-mediated ex vivo HSPC-GT with a chimeric GALC enzyme that incorporates peptides from alpha-L-iduronidase (IDUA) and apolipoprotein E II (APO) to enhance expression and blood-brain barrier penetration. The chimeric IDUAsp.GALC.APO enzyme exhibited superior production and secretion compared to native GALC and previous chimeric variants in LV-transduced HSPCs, resulting in improved cross-correction and normalization of GALC activity in GLD neural cells. Proof-of-concept studies demonstrated effective enzyme production, secretion, and cross-correction capability of macrophages from GLD patients. In vivo results showed stable gene marking, sustained enzyme production, and efficient delivery of the chimeric GALC in affected organs, including the CNS and PNS. These findings highlight the potential of HSPC-GT using chimeric GALC enzymes as an innovative therapeutic approach for treating GLD.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"40 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127136","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}
{"title":"A STING agonist potentiates C1 lipidoid-based mRNA cancer vaccine through promoting TNF-α secretion in vivo.","authors":"Hongxia Zhang,Yang Lin,Liying Wang,Lei Cui,Zining Wang,Xinru You,Chunyuan Xie,Huanling Zhang,Yongxiang Liu,Mengyun Li,Xiaojuan Wang,Jun Wu,Xiaojun Xia","doi":"10.1016/j.ymthe.2025.09.032","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.032","url":null,"abstract":"Intracellular delivery of antigen-encoding mRNA-based vaccine has shown great potential in the treatment of cancer and infectious diseases. We previously developed a minimalist cancer nanovaccine using C1 lipidoid nanoparticle with self-adjuvant activity, which markedly improve mRNA delivery and antigen presentation through TLR4 signaling activation. Although C1-mRNA nanovaccine induced strong antitumor efficiency in prophylactic and therapeutic settings, it could not eliminate tumors with low immunogenicity. To further improve the therapeutic efficacy of mRNA vaccine, we screened several innate immune receptor agonists and identified STING agonist as an effective adjuvant for C1-mRNA vaccine, which could effectively promote the production of type I interferon and proinflammatory cytokines including IL-12 and TNF-α in dendritic cells. Such C1-mRNA cancer vaccine adjuvanted with STING agonist effectively promoted antigen presentation in dendritic cells and enhanced T cell activation and exhibited strong antitumor activity on tumor models. Mechanistically, this mRNA vaccine showed improved antitumor efficacy largely depending on STING protein expression in dendritic cells and TNF-α induction in vivo, while type I interferon or IL-12 induction seemed dispensable. Together, by optimizing the antitumor efficacy of C1-mRNA cancer vaccine with STING agonist, this work provides a potential mRNA cancer vaccine platform for treating a wide range of tumor types.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"40 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127163","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}
Molecular TherapyPub Date : 2025-09-20DOI: 10.1016/j.ymthe.2025.09.021
Isaac Gannon,Claire Roddie,Alex Rampotas
{"title":"To c or not to c-KIT?: High toxicity and modest efficacy in CD117-directed CAR T cell therapy.","authors":"Isaac Gannon,Claire Roddie,Alex Rampotas","doi":"10.1016/j.ymthe.2025.09.021","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.021","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"59 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103383","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}
Molecular TherapyPub Date : 2025-09-19DOI: 10.1016/j.ymthe.2025.09.012
Timur O Yarovinsky,Anish V Sharda,John Hwa
{"title":"EROdicating arterial thrombosis with a novel endoplasmic reticulum oxidoreductase 1α inhibitor.","authors":"Timur O Yarovinsky,Anish V Sharda,John Hwa","doi":"10.1016/j.ymthe.2025.09.012","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.012","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"56 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093560","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}