Molecular Therapy最新文献

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Selective inhibition of ERO1α with M6766, a novel small-molecule inhibitor, prevents arterial thrombosis and ischemic stroke in mice. 新型小分子抑制剂M6766选择性抑制ERO1α,可预防小鼠动脉血栓形成和缺血性中风。
IF 12.4 1区 医学
Molecular Therapy Pub Date : 2025-07-23 DOI: 10.1016/j.ymthe.2025.07.033
Jinzhi Wang,Jae-Sung Kim,Vishwanath Jha,Gavriel Brown,Jingu Lee,Radka Bokorova,Boram Jin,Muteen Ahmed,Esmeralda Castelblanco,Daniel Johnson,Michael Prinsen,Ma Xenia G Ilagan,Maria S Remedi,Babak Razani,Roland E Dolle,Jaehyung Cho
{"title":"Selective inhibition of ERO1α with M6766, a novel small-molecule inhibitor, prevents arterial thrombosis and ischemic stroke in mice.","authors":"Jinzhi Wang,Jae-Sung Kim,Vishwanath Jha,Gavriel Brown,Jingu Lee,Radka Bokorova,Boram Jin,Muteen Ahmed,Esmeralda Castelblanco,Daniel Johnson,Michael Prinsen,Ma Xenia G Ilagan,Maria S Remedi,Babak Razani,Roland E Dolle,Jaehyung Cho","doi":"10.1016/j.ymthe.2025.07.033","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.033","url":null,"abstract":"Using endoplasmic reticulum oxidoreductase 1α (ERO1α) conditional knockout (CKO) mice, recent studies underscore the crucial role of ERO1α in platelet activation under thrombotic conditions. Through a high-throughput screen of 39,901 compounds, we identify M6766 as a selective inhibitor of ERO1α with an IC50 of 1.4 μM and a KD of 1.1 μM. A docking model and biochemical studies reveal that M6766 binds to the FAD-binding pocket in ERO1α and exhibits >70-fold selectivity over other tested enzymes, except ERO1β, which it inhibits with an IC50 of 7.2 μM. M6766 concentration-dependently inhibits granule secretion, αIIbβ3 integrin activation, Ca2+ mobilization, and platelet aggregation induced by various agonists, but it does not affect agonist-induced production of reactive oxygen species. Pretreatment of ERO1α with M6766 reduces its binding to the Ca2+ sensor stromal interaction molecule 1. To validate whether these inhibitory effects result from inhibition of ERO1α and ERO1β, we generate megakaryocyte-specific Ero1β or Ero1α/β CKO mice. Deletion of platelet Ero1α/β impairs platelet activation and aggregation, whereas deletion of Ero1β has no effect. While EN460 markedly inhibits the function of Ero1α/β-null platelets, M6766 does not, highlighting its specificity. M6766 treatment diminishes platelet accumulation on collagen-coated surfaces under arterial shear conditions. Moreover, intravenous injection of M6766 into mice decreases arterial thrombosis and infarct volume during ischemic stroke without prolonging tail bleeding times. Although eptifibatide, an αIIbβ3 antagonist, effectively blocks arterial thrombosis, it prolongs bleeding times at therapeutic doses. Our findings suggest that ERO1α inhibition is a promising anti-thrombotic strategy with potential advantages over current therapies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"4 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701300","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
Pharmacological Gq targeting prevents asthmatic airway remodeling. 药理Gq靶向预防哮喘气道重塑。
IF 12.4 1区 医学
Molecular Therapy Pub Date : 2025-07-23 DOI: 10.1016/j.ymthe.2025.07.032
Jennifer M Dietrich,Michaela Matthey,Annika Simon,Alexander Seidinger,Cynthia Koziol-White,Reynold A Panettieri,Bernd K Fleischmann,Daniela Wenzel
{"title":"Pharmacological Gq targeting prevents asthmatic airway remodeling.","authors":"Jennifer M Dietrich,Michaela Matthey,Annika Simon,Alexander Seidinger,Cynthia Koziol-White,Reynold A Panettieri,Bernd K Fleischmann,Daniela Wenzel","doi":"10.1016/j.ymthe.2025.07.032","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.032","url":null,"abstract":"Airway remodeling is a critical hallmark of chronic asthma that is very difficult to treat. We have investigated this pathological process and found that local application of the pharmacological Gq inhibitor FR900359 (FR) attenuates the main features of airway remodeling, namely collagen deposition and goblet cell metaplasia in the chronic ovalbumin-induced asthma model in mouse. We have explored the molecular mechanisms underlying the FR action and demonstrate that FR mitigates the growth of human lung fibroblasts in response to pathological stimuli in vitro. Likewise, FR inhibits mucus production and secretion in air-liquid interface cultures of human bronchial epithelial cells and in a human lung mucoepidermoid cell line. Notably, FR blocks mucus secretion in human lung slices from asthmatic patients. Thus, Gq proteins play a critical role in airway remodeling, hence pharmacological inhibition of Gq signaling represents a promising strategy for the treatment of chronic asthma.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"19 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701301","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
Amlodipine as an Immunomodulatory Agent in Cancer Therapy: Enhancing Dendritic Cell Activation in Combination with Tumor-associated Antigen. 氨氯地平作为肿瘤治疗中的免疫调节剂:与肿瘤相关抗原联合增强树突状细胞活化。
IF 12.4 1区 医学
Molecular Therapy Pub Date : 2025-07-23 DOI: 10.1016/j.ymthe.2025.07.030
Zhixuan Wang,Xinxuan Huang,Lifan Duan,Shujie Tian,Chenxi Shi,Yongbin Mou,Heng Dong,Yu Gao,Lixing Weng
{"title":"Amlodipine as an Immunomodulatory Agent in Cancer Therapy: Enhancing Dendritic Cell Activation in Combination with Tumor-associated Antigen.","authors":"Zhixuan Wang,Xinxuan Huang,Lifan Duan,Shujie Tian,Chenxi Shi,Yongbin Mou,Heng Dong,Yu Gao,Lixing Weng","doi":"10.1016/j.ymthe.2025.07.030","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.030","url":null,"abstract":"This study explores the immunomodulatory effects of amlodipine, a widely used antihypertensive, on dendritic cell (DC) maturation and anti-tumor immunity. Using flow cytometry, ELISA, and single-cell RNA sequencing, we found that amlodipine significantly promotes DC maturation, evidenced by increased CD80 and CD86 expression and upregulation of genes like CCL4 and Saa3 related to T cell activation. Furthermore, when amlodipine was administered in conjunction with indocyanine green (ICG) or doxorubicin (DOX) therapy in murine models of 4T1 breast cancer and CT26 colon cancer, we observed a notable activation of CD8+ T cell. This combination therapy also resulted in elevated serum levels of cytokines such as TNF-α, IFN-γ, and IL-12, and the upregulation of CD8+ effector memory T cells indicative of a robust systemic immune activation, which ultimately contributed to the inhibition of tumor growth and a decrease in lung metastasis. Our research elucidates the immunomodulatory role of amlodipine in enhancing DC maturation and anti-tumor immune responses, suggesting a promising avenue for future cancer immunotherapy strategies and warranting further investigation in clinical trials.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"19 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693352","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
Oncolytic HSV and cancer drug interactions: Current clinical status and future directions. 溶瘤性HSV与癌症药物相互作用:临床现状及未来发展方向。
IF 12.4 1区 医学
Molecular Therapy Pub Date : 2025-07-23 DOI: 10.1016/j.ymthe.2025.07.034
Karina Vázquez-Arreguín,Kimberly A Rivera-Caraballo,Divya Ventarapragada,E Antonio Chiocca,Balveen Kaur
{"title":"Oncolytic HSV and cancer drug interactions: Current clinical status and future directions.","authors":"Karina Vázquez-Arreguín,Kimberly A Rivera-Caraballo,Divya Ventarapragada,E Antonio Chiocca,Balveen Kaur","doi":"10.1016/j.ymthe.2025.07.034","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.034","url":null,"abstract":"Oncolytic herpes simplex viruses (oHSVs) are engineered to target and replicate specifically in tumor cells, minimizing damage to normal tissues. This live virus biotherapy entails direct tumor cell killing followed by stimulation of anti-tumor immunity, leading to abscopal effects in untreated lesions. Currently, there are two clinically approved oHSV biotherapeutics: Imlygic, marketed by Amgen for treatment of advanced melanoma in USA and Europe, and Delytact, conditionally approved for recurrent brain tumors in Japan. Lessons learnt from initial testing in patients have led to the development of second-generation viruses designed to improve tumor cytotoxicity and/or anti-tumor immune responses. Preclinical research has also uncovered numerous virus-drug interactions predicted to be synergistic. This has resulted in numerous clinical trials that are currently evaluating these second-generation viruses as single agents or in combination with other anti-neoplastic therapeutics. As of this review, there are more than one hundred clinical trials evaluating their safety and efficacy. Here, we lay out a summary of oHSVs and the rationale behind various virus-drug combinations in clinical trials for patients with different malignancies. We provide a comprehensive review that details the underlying mechanisms of oHSV design and virus-drug interactions that form the basis of their clinical investigation.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"14 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693353","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
Cell-Selective Telomere Damage by Thiopurine-Based Oligonucleotide for Diffuse Large B-cell Lymphoma Immunotherapy. 巯基寡核苷酸对弥漫性大b细胞淋巴瘤细胞选择性端粒损伤的免疫治疗。
IF 12.4 1区 医学
Molecular Therapy Pub Date : 2025-07-23 DOI: 10.1016/j.ymthe.2025.07.029
Chunsong Yu,Elaine Y Kang,Dongfang Wang,Yong Liang,Piotr Swiderski,Ye Feng,Haiqing Li,Timothy Synold,Stephen Forman,Larry Kwak,Marcin Kortylewski
{"title":"Cell-Selective Telomere Damage by Thiopurine-Based Oligonucleotide for Diffuse Large B-cell Lymphoma Immunotherapy.","authors":"Chunsong Yu,Elaine Y Kang,Dongfang Wang,Yong Liang,Piotr Swiderski,Ye Feng,Haiqing Li,Timothy Synold,Stephen Forman,Larry Kwak,Marcin Kortylewski","doi":"10.1016/j.ymthe.2025.07.029","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.029","url":null,"abstract":"Telomerase (TERT) is an enzyme involved in maintaining telomere length in diffuse large B-cell lymphoma (DLBCL). Previous attempts to target TERT+ cancers faced challenges, including the delayed clinical responses and on-target/off-tumor toxicities. Here, we present a DLBCL-targeted oligonucleotide designed to deliver a synthetic TERT substrate, 6-thio-2'-deoxy-guanosine (6tdG), damaging telomeres and triggering apoptosis. In vitro, 6tdG-oligonucleotides (6tdGOs) were selectively cytotoxic to TERT+ DLBCL cells without affecting activated T-cells or non-malignant TERT- cells. Repeated intravenous administration of 6tdGO, but not 6tdG nucleoside, had significant antitumor effects against xenotransplanted human DLBCL models and syngeneic Eμ-myc/15A lymphoma in mice. In immunocompetent mice, treatment with 6tdGO induced systemic, lymphoma-specific and CD8 T-cell-mediated antitumor immune responses. The abscopal effects of 6tdGO were abolished in mice lacking expression of Sting1 or Ifnar1 but not Trl9. These findings suggest that 6tdGO-induced lymphoma cell death triggered STING-mediated type-I IFN signaling, thereby promoting recruitment/activation of CD8 T-cells. Importantly, the repeated 6tdGO treatments were well-tolerated in humanized hCD34/NOG mice. Except for the reduced percentage of human B-cells, 6tdGO did not decrease the numbers of hematopoietic stem cells, myeloid cells, or T-cells. Overall, 6tdGO offers an effective and safer strategy against aggressive TERT+ DLBCL with potential to activate T-cell based antitumor immunity.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"52 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701298","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
Targeted Silencing of Engrailed-1 Reprograms Profibrotic Fibroblast Lineages for Scarless Wound Healing. 靶向沉默镌刻-1重编程纤维化成纤维细胞系用于无疤痕伤口愈合。
IF 12.4 1区 医学
Molecular Therapy Pub Date : 2025-07-23 DOI: 10.1016/j.ymthe.2025.07.031
Xuehan Xu,Luyi Wang,Xinyue Bi,Tingting Cao,Menghua Gao,Buwei Hu,Jiafeng Zhong,Chenlin Ji,Rui Sun,Chengjie Sun,Yanjun Zhao,Qin Zhou,Jianjun Cheng
{"title":"Targeted Silencing of Engrailed-1 Reprograms Profibrotic Fibroblast Lineages for Scarless Wound Healing.","authors":"Xuehan Xu,Luyi Wang,Xinyue Bi,Tingting Cao,Menghua Gao,Buwei Hu,Jiafeng Zhong,Chenlin Ji,Rui Sun,Chengjie Sun,Yanjun Zhao,Qin Zhou,Jianjun Cheng","doi":"10.1016/j.ymthe.2025.07.031","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.031","url":null,"abstract":"Skin wounds typically healed with dysfunctional scarring, a fibrotic process largely driven by Engrailed-1 (En1) lineage-positive fibroblasts (EPFs). However, the potential reversibility of EPFs' profibrotic effects and corresponding therapeutic strategies remain elusive. Here, we develop a nanoscale fibroblast-mimic carrier (FibroMC) for targeted delivery of En1-specific small interfering RNA (siEn1) to fibroblasts, aiming to inhibit En1 expression and reverse their profibrotic effects. FibroMC was constructed by functionalizing Food and Drug Administration (FDA)-approved ionizable lipid nanoparticles with fibroblast cell membrane. With incorporated cell membrane proteins (e.g., integrin β1 and N-cadherin), FibroMC was preferentially taken up by fibroblasts, leading to potent silencing of En1 in all EPF populations both in vitro and in vivo. Consequently, FibroMC treatment significantly inhibited collagen I expression and myofibroblast differentiation. A single dose of topical application of FibroMC to the wound effectively restored collagen architecture, regenerated skin appendages, recover skin mechanical property and ultimately prevented scar formation. Our findings demonstrate that FibroMC-mediated En1 silencing can reverse the profibrotic effect of EPFs, offering a promising therapeutic strategy for scarless wound healing.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"23 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701302","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
APOBEC3 and the mutational signature of lentiviral vectors. APOBEC3与慢病毒载体的突变特征。
IF 12.4 1区 医学
Molecular Therapy Pub Date : 2025-07-18 DOI: 10.1016/j.ymthe.2025.07.001
Eugenio Montini
{"title":"APOBEC3 and the mutational signature of lentiviral vectors.","authors":"Eugenio Montini","doi":"10.1016/j.ymthe.2025.07.001","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.001","url":null,"abstract":"","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"15 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664208","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
AAV-delivered PPT1 provides long-term neurological benefits in CLN1 mice and achieves therapeutic levels in sheep brain. aav递送的PPT1在CLN1小鼠中提供长期的神经学益处,并在绵羊脑中达到治疗水平。
IF 12.4 1区 医学
Molecular Therapy Pub Date : 2025-07-17 DOI: 10.1016/j.ymthe.2025.07.011
Md Suhail Alam,Apeksha Khatiwada,Samantha L Eaton,Daniel M Cohen,John White,Melissa Derby,Drew Peterson,Graciela Rivera-Pena,Mohamad Nayal,Mallory Becker,Heena Beck,Charlie Li,Renee Gentzel,George Atkins,Stephen N Greenhalgh,Simon G Lillico,Rachael Gregson,Eddie Clutton,Fraser Murdoch,James Nixon,Mark Gray,Gerard Thompson,Jodi McBride,Thomas M Wishart,Maria Grazia Biferi,Elizabeth Ramsburg
{"title":"AAV-delivered PPT1 provides long-term neurological benefits in CLN1 mice and achieves therapeutic levels in sheep brain.","authors":"Md Suhail Alam,Apeksha Khatiwada,Samantha L Eaton,Daniel M Cohen,John White,Melissa Derby,Drew Peterson,Graciela Rivera-Pena,Mohamad Nayal,Mallory Becker,Heena Beck,Charlie Li,Renee Gentzel,George Atkins,Stephen N Greenhalgh,Simon G Lillico,Rachael Gregson,Eddie Clutton,Fraser Murdoch,James Nixon,Mark Gray,Gerard Thompson,Jodi McBride,Thomas M Wishart,Maria Grazia Biferi,Elizabeth Ramsburg","doi":"10.1016/j.ymthe.2025.07.011","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.011","url":null,"abstract":"CLN1 disease is a fatal neurodegenerative condition caused by deficiency in Palmitoyl-Protein Thioesterase 1 (PPT1), for which no disease-modifying therapy exists. The disease affects the entire central nervous system (CNS), necessitating widespread delivery of therapeutics to the brain and spinal cord. Adeno-associated virus (AAV)-based PPT1 gene therapy delivered intrathecally has been tested in mouse models but has shown limited efficacy due to inadequate brain bioavailability. Here, to maximize therapeutic benefit, PPT1 was engineered for improved cross-correction capabilities, packaged in Spark100, a neurotropic AAV capsid, and administered through intracerebroventricular route in neonatal Ppt1-/- mice. This achieved sustained expression of PPT1 protein across the CNS, including key disease-relevant structures, for up to 15 months. It resulted in long-term therapeutic benefits, such as extended lifespan, preserved neurobehavioral function, and prevention of neuropathology, making treated Ppt1-/- mice nearly indistinguishable from WT. A translatability study in healthy adult sheep, assessing biodistribution of therapeutic in a large and fully developed brain, showed widespread CNS transduction and PPT1 expression with no adverse effects. These studies demonstrate the potential of this approach for treating CLN1 disease and suggest that a similar platform, using a secreted therapeutic protein, might apply to other neurological disorders with broad CNS deficits.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"12 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664211","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
Therapeutic AASS inhibition by AAV-miRNA rescues glutaric aciduria type I severe phenotype in mice. AAV-miRNA治疗性抑制AASS可挽救小鼠戊二酸尿I型严重表型。
IF 12.4 1区 医学
Molecular Therapy Pub Date : 2025-07-17 DOI: 10.1016/j.ymthe.2025.07.022
Eulàlia Segur-Bailach,Anna Mateu-Bosch,Xavier Bofill-De Ros,Marta Parés,Patricia da Silva Buttkus,Birgit Rathkolb,Valérie Gailus-Durner,Martin Hrabě de Angelis,Pedram Moeini,Gloria Gonzalez-Aseguinolaza,Frederic Tort,Antonia Ribes,Clara D M van Karnebeek,Judit García-Villoria,Cristina Fillat
{"title":"Therapeutic AASS inhibition by AAV-miRNA rescues glutaric aciduria type I severe phenotype in mice.","authors":"Eulàlia Segur-Bailach,Anna Mateu-Bosch,Xavier Bofill-De Ros,Marta Parés,Patricia da Silva Buttkus,Birgit Rathkolb,Valérie Gailus-Durner,Martin Hrabě de Angelis,Pedram Moeini,Gloria Gonzalez-Aseguinolaza,Frederic Tort,Antonia Ribes,Clara D M van Karnebeek,Judit García-Villoria,Cristina Fillat","doi":"10.1016/j.ymthe.2025.07.022","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.022","url":null,"abstract":"Glutaric aciduria type I (GA1) is an inherited disorder caused by the enzymatic defect of glutaryl-CoA dehydrogenase in the lysine degradation pathway, characterized by the accumulation of toxic metabolites in the central nervous system. We reasoned that substrate reduction therapy targeting the alpha-Aminoadipic Semialdehyde Synthase (AASS), the first enzyme in the catabolism of lysine, could provide an attractive therapeutic alternative. We explored to reduce the expression of AASS by an artificial microRNA with AASS target sequences embedded in a miR-16 backbone (miR_AASS). We analyzed several delivery routes and AAV serotypes and evaluated the therapeutic efficacy of a systemic neonatal delivery of AAV9_miR_AASS in the Gcdh-/- mouse model of GA1. We detected dose-dependent miR-AASS expression and AASS inhibition in liver and striatum, the main tissues affected in GA1. Treatment with AAV9_miR_AASS in lysine overload challenged mice reduced the accumulation of neurotoxic metabolites, up to six months post-treatment in the striatum, prevented the neuropathological alterations and improved mouse survival. Our results show that AAV9_miR_AASS supports AASS-lowering as a potential gene therapy strategy for GA1.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"121 2 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664207","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
Preclinical quality, safety, and efficacy of a cGMP iPSC-derived myogenic progenitor product for the treatment of muscular dystrophies. cGMP ipsc衍生肌源性祖细胞产品治疗肌营养不良的临床前质量、安全性和有效性
IF 12.4 1区 医学
Molecular Therapy Pub Date : 2025-07-17 DOI: 10.1016/j.ymthe.2025.07.007
Karim Azzag,Alessandro Magli,James Kiley,Darin Sumstad,Diane Kadidlo,Sarah B Crist,Beverly Norris,Aaron Ahlquist,Laura L Hocum Stone,John Everett,Jill Schappa Faustich,Davis Seelig,Parthasarathy Rangarajan,Hyunkee Kim,Craig Flory,Frederic Bushman,Sabarinathan Ramachandran,Peter B Kang,Robert J Schumacher,John E Wagner,Michael Kyba,Melanie L Graham,David H McKenna,Rita C R Perlingeiro
{"title":"Preclinical quality, safety, and efficacy of a cGMP iPSC-derived myogenic progenitor product for the treatment of muscular dystrophies.","authors":"Karim Azzag,Alessandro Magli,James Kiley,Darin Sumstad,Diane Kadidlo,Sarah B Crist,Beverly Norris,Aaron Ahlquist,Laura L Hocum Stone,John Everett,Jill Schappa Faustich,Davis Seelig,Parthasarathy Rangarajan,Hyunkee Kim,Craig Flory,Frederic Bushman,Sabarinathan Ramachandran,Peter B Kang,Robert J Schumacher,John E Wagner,Michael Kyba,Melanie L Graham,David H McKenna,Rita C R Perlingeiro","doi":"10.1016/j.ymthe.2025.07.007","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.07.007","url":null,"abstract":"Pluripotent stem cell (PSC)-derived therapies are in clinical trials of terminally differentiated or transiently-required cell types, but to date no PSC-derived trial contributing tissue-specific stem cells has been approved, nor any PSC-based skeletal muscle regeneration trial. We describe a process in accordance with current good manufacturing practices (cGMP) to generate large-scale cryopreserved PAX7-induced myogenic progenitors, that reconstitute both fibers and satellite cells, from PSCs. We subjected this clinical-grade cell product, MyoPAXon, to biodistribution, toxicity, and tumorigenicity studies in mice under GLP conditions with no adverse effects, and demonstrate long-term engraftment (> 1 year), and efficacy in dystrophic mice. Transplantation of 37-60 million MyoPAXon cells into immunosuppressed non-human primates showed human contribution to muscle fibers and satellite cells, with no safety concerns. The FDA has recently authorized this fully characterized off-the-shelf cGMP product, for a first-in-human clinical trial in Duchenne MD, representing the first iPSC-derived tissue-specific stem cell therapy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"73 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664210","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
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