Molecular TherapyPub Date : 2025-10-01Epub Date: 2025-07-16DOI: 10.1016/j.ymthe.2025.07.003
Li Guo, Pascal Duchesneau, Eric D Jong, Evan Sawula, Chengjin Li, Thomas K Waddell, Andras Nagy
{"title":"GDF11-secreting cell transplant efficiently ameliorates age-related pulmonary fibrosis.","authors":"Li Guo, Pascal Duchesneau, Eric D Jong, Evan Sawula, Chengjin Li, Thomas K Waddell, Andras Nagy","doi":"10.1016/j.ymthe.2025.07.003","DOIUrl":"10.1016/j.ymthe.2025.07.003","url":null,"abstract":"<p><p>Here, we present a combination of cell and gene therapy that harnesses the regenerative properties of GDF11 in age-related pulmonary fibrosis. Our genome-edited SafeCell-GDF11 mouse embryonic stem cell line provides controlled proliferation and efficient derivation to lung progenitors while inducibly expressing GDF11. When these cells were transplanted into bleomycin-injured aged mice, they acted as a source of reparative cells, restoring the damaged alveolar epithelium. Furthermore, the transplanted cells acted as an \"in situ factory,\" enabling the production of GDF11 in response to the inducer drug. This approach attenuated age-associated senescence and led to the successful resolution of fibrosis. Our study presents a GDF11-expressing cell-based strategy that demonstrates the feasibility of promoting alveolar regeneration in a mouse model of age-related pulmonary fibrosis. Additionally, this approach offers a versatile tool that can be expanded to incorporate other regenerative and anti-aging factors. This helps overcome limitations such as high production costs and a short half-life of therapeutic factors. One of the strengths of our system is its ability to allow precise regulation of factor expression when needed to address specific aging phenotypes.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"5131-5148"},"PeriodicalIF":12.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144659681","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 : 2025-10-01Epub Date: 2025-08-08DOI: 10.1016/j.ymthe.2025.07.052
J Qi, L Zhang, Y Lu, R Chai
{"title":"Targeting NLRP3/caspase-1/GSDMD to treat inner ear injury from labyrinthine hemorrhage.","authors":"J Qi, L Zhang, Y Lu, R Chai","doi":"10.1016/j.ymthe.2025.07.052","DOIUrl":"10.1016/j.ymthe.2025.07.052","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4684-4685"},"PeriodicalIF":12.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812139","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 : 2025-09-30DOI: 10.1016/j.ymthe.2025.09.047
Jessie L Chiello,Nijamuddin Shaikh,Justine Jacobi,Nicole Gaulin,Gabriel Santos,Christopher Keck,Suzanne M Hess,Brian Lichty,Prashant K Singh,Spencer R Rosario,Scott I Abrams,Emese Zsiros,Mark D Long,A J Robert McGray
{"title":"BiTE-secreting T cells rationally combine with PD-1 blockade and vaccine boosting to reshape antitumor immunity in ovarian cancer.","authors":"Jessie L Chiello,Nijamuddin Shaikh,Justine Jacobi,Nicole Gaulin,Gabriel Santos,Christopher Keck,Suzanne M Hess,Brian Lichty,Prashant K Singh,Spencer R Rosario,Scott I Abrams,Emese Zsiros,Mark D Long,A J Robert McGray","doi":"10.1016/j.ymthe.2025.09.047","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.047","url":null,"abstract":"Despite some clinical success, ovarian cancer (OC) patients rarely achieve durable benefit from current immunotherapies, suggesting a need for strategies that improve OC immune recognition. We previously reported that engineered T cells secreting folate receptor alpha (FRα) targeted bispecific T cell engagers (FR-B T cells) elicit robust antitumor responses in OC, in part by engaging endogenous T cells. Here, we use clinical OC specimens and preclinical OC to evaluate FR-B T cells combined with PD-1 blockade. Assessing the tumor microenvironment during acute and prolonged FR-B T cell + anti-PD-1 responses revealed broad immune cell engagement/reorganization. Early CD8+ T cell-driven responses and myeloid cell influx were followed by accumulation of CXCL13-producing macrophages, activated B cells, and effector memory CD4+ T cells with durable response, hallmarks that were diminished with progressive disease. Resistant OC (characterized by FRα loss and metabolic reprogramming) emerged at disease relapse, suggesting a need to target additional vulnerabilities to extend responses. As FR-B T cells promoted epitope spreading beyond FRα, we employed a booster vaccine to enhance antitumor immunity, improving OC control. Our findings point to rationally combining FR-B T cells with PD-1 blockade in OC and an opportunity to apply personalized cancer vaccines to limit OC relapse.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"3 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194820","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":"Stroma-Targeted Gene Delivery for Efficient Immunogene Therapy against Pancreatic Cancer.","authors":"Hsi-Chien Huang,Yi-Ju Chen,Mei-Wei Lin,Chih-I Huang,Chia-Yueh Hsiung,Sheng Yang,Yi-Yu Ke,Yu-Ting Yen,Hsin-Tzu Hsieh,Yen-Fei Lu,Yun-Chieh Sung,Fu-Fei Hsu,Anthony Yan-Tang Wu,Charles Pin-Kuang Lai,Jane Wang,Min-Yuan Chou,Chung-Pin Li,Shu-Yi Lin,Yunching Chen","doi":"10.1016/j.ymthe.2025.09.043","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.043","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to its aggressive nature and resistance to chemotherapy. Immunotherapies have shown promise in various cancers but are limited in PDAC due to poor drug penetration through dense stroma and systemic toxicities. Herein, we developed a stroma-targeted gene delivery platform for efficient immunogene therapy in PDAC. Using an in vitro-in vivo phage display screening approach, we identified the LQT peptide, which selectively binds to fibronectin 1 (FN1) in pancreatic stellate cells (PSCs), key mediators of PDAC stroma. We then engineered a lipid-dendrimer-CaP (LDCP) nanoparticle functionalized with the LQT peptide for targeted gene delivery of interleukin-2 (IL-2) plasmid DNA (pDNA). This design improves delivery to PSCs, enhances nanoparticle accumulation and penetration in PDAC, and facilitates endosomal escape and effective nuclear entry through its pH-responsive calcium phosphate core and thymine-capped polyamidoamine (PAMAM) dendrimers. The production of IL-2 significantly amplifies CD8 T cell infiltration and activation, counteracting the immunosuppressive microenvironment. When combined with checkpoint inhibitors such as anti-PD-1 antibodies or costimulatory molecules like OX40 ligand (OX40L), this gene therapy strategy leads to substantial suppression of PDAC progression. This stroma-targeted immunogene therapy shows significant promise as a safe and effective approach for PDAC treatment.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"27 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182558","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 : 2025-09-27DOI: 10.1016/j.ymthe.2025.09.045
Chenming Ye,Yongjie Ma,Raunak Shrestha,Jingwen Cai,Yutao Liu,Liu Peng,Jindan Yu,Houjian Cai
{"title":"Extracellular vesicles-mediated delivery of CRISPR machinery silences androgen receptor in castration-resistant prostate cancer cells.","authors":"Chenming Ye,Yongjie Ma,Raunak Shrestha,Jingwen Cai,Yutao Liu,Liu Peng,Jindan Yu,Houjian Cai","doi":"10.1016/j.ymthe.2025.09.045","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.045","url":null,"abstract":"CRISPR-mediated gene editing is a promising technology for treatment of diseases by silencing a driver gene at the genomic DNA level. However, delivery of CRISPR machinery remains challenging for potential therapeutic application. Here, we developed a platform using extracellular vesicles (EVs) as a vehicle to deliver Cas9/single guide RNA (sgRNA) ribonucleoprotein (RNP) complex to silence androgen receptor (AR) gene in prostate cancer (PCa) cells. A genetic modification conferred the N-myristoylation to the Cas9 protein, which enhanced the encapsulation of Cas9/sgRNA RNP into EVs and silenced both ectopic and endogenous AR gene. Interestingly, gene editing efficiency varied across PCa cell lines, associated with different chromatin accessibility at the target site. Functional analyses demonstrated that Cas9/sgRNA RNP (targeting the N-terminal domain of the AR gene) did not change gene-edited AR mRNA levels, but significantly inhibited expression levels of AR downstream genes, thereby attenuating PCa cell proliferation. Importantly, EVs-mediated delivery of the Cas9/sgRNA RNP introduced indels into the AR gene and inhibited proliferation of enzalutamide-resistant PCa cells. This study highlights a therapeutic strategy for treatment of castration-resistant PCa using a programmable EVs-mediated delivery platform.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"27 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182606","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":"Non-neurological, non skeletal outcomes after hematopoietic stem and progenitor cell-gene therapy -OTL-203- for Hurler syndrome.","authors":"Francesca Tucci,M Luz Uria Oficialdegui,Giulia Consiglieri,Matilde Cossutta,Chiara Filisetti,Francesca Fumagalli,Carla Butera,Roberto Santangelo,Michele Colombo,Maria Pia Manitto,Monica Stoppani,Elisabetta Martina,Giulia Danè,Chiara Camesasca,Giulia Risca,Maurizio De Pellegrin,Stefano Scarparo,Marina Sarzana,Cristina Puricelli,Stefania Galimberti,Silvia Darin,Paolo Silvani,Sonia Bonanomi,Serena Gasperini,Luigi Naldini,Bernhard Gentner,Rossella Parini,Mireia Del Toro,Cristina Diaz-de-Heredia,Alessandro Aiuti,Maria Ester Bernardo","doi":"10.1016/j.ymthe.2025.09.042","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.042","url":null,"abstract":"Patients with Mucopolysaccharidosis type I Hurler (MPSIH) experience multisystem clinical manifestations which are only partially addressed by allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study evaluated outcomes from a lentiviral vector (LV)-mediated hematopoietic stem and progenitor cell gene therapy (HSPC-GT) trial (NCT03488394) in 8 MPSIH patients followed up to 4 years post-treatment. Key findings included corneal clouding, hearing loss (HL), carpal tunnel syndrome (CTS) and cardiac evaluations. A retrospective comparison with an external cohort of 9 MPSIH patients undergoing allo-HSCT was performed. All patients are alive at last follow-up, show stable engraftment without graft failure, insertional oncogenesis, or immune responses to the transgene. Notably, at last follow-up 3/8 HSPC-GT patients experienced corneal clouding resolution, while all allo-HSCT patients maintained moderate corneal clouding. 4/8 HSPC-GT patients showed normal hearing function at last follow-up due to improvement (n=3) or stabilization (n=1); 7/9 allo-HSCT patients had mild or moderate HL at baseline, while 2/9 showed moderate HL at last follow-up. No HSPC-GT patients required surgery for CTS developed after HSPC-GT, while 7/9 patients needed such surgery after allo-HSCT. No HSPC-GT patients developed severe cardiomyopathy or valvular disease, while in the HSCT cohort 4/9 patients experienced progression of valvular insufficiency although not requiring valve replacement. Our results indicate a favorable effect of HSPC-GT on MPSIH multisystemic manifestations up to 4-year after treatment; long-term, prospective comparative studies are warranted for definitive conclusions.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"4 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182674","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 : 2025-09-27DOI: 10.1016/j.ymthe.2025.09.044
Lynn J A Ebner, Cornelia Imsand, Duygu Karademir, Florian Peters, Eva Kiessling, Antonia Fottner, Claudia Matter, Diego S Fajardo, Luca Merolla, Gabriele M Wögenstein, Ioanna Tsioti, Larissa P Govers, Frank Blaser, Isabelle Meneau, Sanford L Boye, Shannon E Boye, Christian Grimm, Marijana Samardzija
{"title":"A novel multiplex RNAi therapy simultaneously targets Hif1a and Hif2a to defy retinal degeneration in two models of AMD.","authors":"Lynn J A Ebner, Cornelia Imsand, Duygu Karademir, Florian Peters, Eva Kiessling, Antonia Fottner, Claudia Matter, Diego S Fajardo, Luca Merolla, Gabriele M Wögenstein, Ioanna Tsioti, Larissa P Govers, Frank Blaser, Isabelle Meneau, Sanford L Boye, Shannon E Boye, Christian Grimm, Marijana Samardzija","doi":"10.1016/j.ymthe.2025.09.044","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.044","url":null,"abstract":"<p><p>Age-related tissue changes lead to reduced oxygen delivery to photoreceptors and the retinal pigment epithelium (RPE), and contribute to the pathology of age-related macular degeneration (AMD). The implication of hypoxia-inducible factors (HIFs) in this process makes them good candidates as therapeutic targets for AMD. We developed a multiplex dual-acting therapy utilizing the shRNAmir system, delivered by a single AAV, that reduces mRNA levels of Hif1a in photoreceptors and Hif2a in the RPE. This RNA interference-based strategy demonstrated a strong therapeutic effect, potently preserving photoreceptors and the RPE in two models of pseudo- and true hypoxia up to 61 weeks post-injection. The efficacy of our dual-acting virus proved superior to single-acting viruses targeting only Hif1a in photoreceptors or Hif2a in the RPE. By targeting a common, conserved disease pathway, this gene-agnostic RNAi therapy shows significant potential to protect tissues from chronic hypoxic insults in complex diseases such as AMD.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.0,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145186344","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 : 2025-09-27DOI: 10.1016/j.ymthe.2025.09.041
Boya Peng,Migara Kavishka Jayasinghe,Anh Hong Le,Nhut Minh Tran,Minh T N Le
{"title":"Designing nucleic acid-based therapeutics for cancer treatment: Updates on the state of the art.","authors":"Boya Peng,Migara Kavishka Jayasinghe,Anh Hong Le,Nhut Minh Tran,Minh T N Le","doi":"10.1016/j.ymthe.2025.09.041","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.041","url":null,"abstract":"Like an art, the ability of nucleic acids to be designed and synthesized as a novel treatment modality is limited only by the imagination. Nucleic acids of virtually all sizes and forms can be synthesized on demand, from short antisense oligonucleotides to large mRNAs, to entire chromosomes. Given the genetic basis of cancer, nucleic acid-based therapy is a particularly promising avenue for anti-cancer therapeutic development. This has led to a profusion of studies exploring strategies to utilize nucleic acid-based drugs to treat cancer, with some approaches demonstrating great potential for clinical translation. In this review, we summarize the various nucleic acid-based strategies being developed for cancer therapy. We also provide a comprehensive overview of current efforts to enhance the potency and safety of nucleic acid-based drugs, exploring advances in nucleotide composition, design, and delivery strategies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"74 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145182560","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 : 2025-09-23DOI: 10.1016/j.ymthe.2025.09.031
Eugenio Marco,Patricia Sousa,Tusneem Janoudi,Edouard de Dreuzy,Jack M Heath,Ramya Viswanathan,John A Zuris,Gregory M Gotta,Georgia Giannoukos,Scott Hansen,David K Wood,Mark C Walters,John F Tisdale,Christopher J Wilson,Kai-Hsin Chang
{"title":"Nonclinical evaluation of renizgamglogene autogedtemcel for SCD and TDT.","authors":"Eugenio Marco,Patricia Sousa,Tusneem Janoudi,Edouard de Dreuzy,Jack M Heath,Ramya Viswanathan,John A Zuris,Gregory M Gotta,Georgia Giannoukos,Scott Hansen,David K Wood,Mark C Walters,John F Tisdale,Christopher J Wilson,Kai-Hsin Chang","doi":"10.1016/j.ymthe.2025.09.031","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.031","url":null,"abstract":"Sickle cell disease and transfusion-dependent β-thalassemia can be treated by fetal hemoglobin upregulation. Disruption of the distal BCL11A binding site at the HBG1/2 promoters to induce fetal hemoglobin using either SpCas9 or AsCas12a mimics multiple hereditary persistence of fetal hemoglobin mutations. AsCas12a showed higher editing efficiency, higher specificity, and increased fetal hemoglobin induction potential compared with SpCas9. AsCas12a-edited healthy donor CD34+ cells exhibited long-term, multi-lineage, and polyclonal engraftment in immunocompromised mice. High-level fetal hemoglobin induction was observed in erythroid progeny derived in vivo from edited healthy donor CD34+ cells, and sickle cell disease or transfusion-dependent β-thalassemia donor CD34+ cells in vitro. In erythroid cells from patients with sickle cell disease, gene editing reduced sickling and improved rheological behaviors under deoxygenated conditions. In erythroid cells from patients with β-thalassemia, gene editing ameliorated ineffective erythropoiesis and significantly increased hemoglobin content per cell. A comprehensive off-target editing evaluation in edited CD34+ cells showed AsCas12a to be highly specific, with no off-target editing detected. In summary, editing CD34+ cells at the HBG1/2 promoter distal BCL11A binding site using AsCas12a phenocopied hereditary persistence of fetal hemoglobin mutations, demonstrating its potential as a gene editing approach for the treatment of β-hemoglobinopathies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"17 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134004","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}