Molecular Therapy最新文献_第4页

AAV-Mediated Exon Skipping Therapy for Usher Syndrome, Type 2A. aav介导的外显子跳跃治疗Usher综合征，2A型。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-23 DOI: 10.1016/j.ymthe.2025.09.038

Stephanie A Mauriac,Jiyoon Lee,Jingyuan Zhang,Jiahe Jin,Carl Nist-Lund,Camille T Martin,Cristobal R Von Muhlenbrock,Sydney O'Malley,Mary G Chaves,Margot A Madison,Kate Foster,Shinong Long,Chris Jacobs,Sripriya Ravindra Kumar,Silvia Ramirez,Justin Ichida,Karl R Koehler,Jeffrey R Holt,Gwenaëlle S G Géléoc

{"title":"AAV-Mediated Exon Skipping Therapy for Usher Syndrome, Type 2A.","authors":"Stephanie A Mauriac,Jiyoon Lee,Jingyuan Zhang,Jiahe Jin,Carl Nist-Lund,Camille T Martin,Cristobal R Von Muhlenbrock,Sydney O'Malley,Mary G Chaves,Margot A Madison,Kate Foster,Shinong Long,Chris Jacobs,Sripriya Ravindra Kumar,Silvia Ramirez,Justin Ichida,Karl R Koehler,Jeffrey R Holt,Gwenaëlle S G Géléoc","doi":"10.1016/j.ymthe.2025.09.038","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.038","url":null,"abstract":"Usher syndrome can cause loss of vision, hearing and balance. There are four clinical subtypes, USH1 through 4, which are associated with mutations in genes important for structure, function and survival of photoreceptor cells in the retina and sensory hair cells in the inner ear. Genetic mutations in the USH2A gene, which encodes usherin protein, are the most common cause of Usher syndrome worldwide, with c.2299delG (p.Glu767Serfs*21) being the most frequent pathogenic variant. An investigational antisense oligonucleotide (ASO) for USH2A c.2299delG, QR-421a, designed to bypass the mutation, has already shown promise in Phase 1/2 clinical trials (Dulla et al., 2021). While recently developed chemistry provides longer ASO half-lives, repeated injection of ASOs may be required to provide long-term efficiency. To overcome this limitation, we screened novel USH2A exon 13 skippers and 20 AAV capsids with the goal of developing a vectorized ASO exon skipping strategy. Optimized vectors and skippers were evaluated in inner ear and retinal organoids derived from human stem cell lines bearing the USH2A c.2299delG mutation. The data revealed enhanced skipping of the pathogenic exon, offering an alternative strategy for treatment of USH2A patients using a single local injection which may prevent progression of vision and hearing loss.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"13 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134035","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 delivery of full length SYNGAP1 rescues epileptic and behavioral phenotypes in a mouse model of SYNGAP1-related disorders. 在SYNGAP1相关疾病的小鼠模型中，AAV递送全长SYNGAP1可挽救癫痫和行为表型。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-23 DOI: 10.1016/j.ymthe.2025.09.040

Meagan A Quinlan,Rong Guo,Andrew G Clark,Emily M Luber,Robert J Christian,Refugio A Martinez,Erin L Groce,Jiatai Liu,Yemeserach M Bishaw,Ravi Bhowmik,Elizabeth Liang,Melissa Reding,Kara Ronellenfitch,Vonn Wright,Kathryn M Gudsnuk,Jennifer M Leedy,John K Mich,Bryan B Gore,Tanya L Daigle,Manuel E Lopez,Ed S Lein,Justin K Ichida,Boaz P Levi

{"title":"AAV delivery of full length SYNGAP1 rescues epileptic and behavioral phenotypes in a mouse model of SYNGAP1-related disorders.","authors":"Meagan A Quinlan,Rong Guo,Andrew G Clark,Emily M Luber,Robert J Christian,Refugio A Martinez,Erin L Groce,Jiatai Liu,Yemeserach M Bishaw,Ravi Bhowmik,Elizabeth Liang,Melissa Reding,Kara Ronellenfitch,Vonn Wright,Kathryn M Gudsnuk,Jennifer M Leedy,John K Mich,Bryan B Gore,Tanya L Daigle,Manuel E Lopez,Ed S Lein,Justin K Ichida,Boaz P Levi","doi":"10.1016/j.ymthe.2025.09.040","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.040","url":null,"abstract":"SYNGAP1-related disorders (SRDs) are rare neurodevelopmental conditions characterized by severe neurological symptoms including epilepsy, motor impairment, and cognitive dysfunction. Current treatment options are limited, with patients relying on a cocktail of medications to manage the diverse symptoms, but that do not address the underlying pathology. SRDs are primarily caused by haploinsufficiency of the SYNGAP1 gene, which encodes the synaptic scaffolding and signaling protein, SynGAP. We developed a gene supplementation strategy to deliver broad neuronal expression of human SYNGAP1 via an adeno-associated virus (AAV). Driven by the pan-neuronal SYNAPSIN I promoter, SYNGAP1 delivery alleviated several disease phenotypes in a Syngap1 heterozygous mouse model including epileptiform activity, hyperactivity, and risk-taking behaviors. Notably, AAV-SYNGAP1 administration in juvenile mice, which corresponds to the typical age of diagnosis in humans, rescued behavioral deficits, highlighting its clinical relevance. Our findings provide the first evidence that AAV-mediated gene therapy can restore SYNGAP1 function and reverse key phenotypes, supporting its potential as a transformative therapeutic for SRD patients.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"114 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127080","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

The conserved N-terminal histidine in an engineered peptide mediates sepsis treatment efficacy via dual binding to CD14 and LPS. 工程肽中保守的n端组氨酸通过与CD14和LPS的双重结合介导脓毒症的治疗效果。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-23 DOI: 10.1016/j.ymthe.2025.09.033

Ganna Petruk,Firdaus Samsudin,Manoj Puthia,Jitka Petrlova,Peter J Bond,Artur Schmidtchen

{"title":"The conserved N-terminal histidine in an engineered peptide mediates sepsis treatment efficacy via dual binding to CD14 and LPS.","authors":"Ganna Petruk,Firdaus Samsudin,Manoj Puthia,Jitka Petrlova,Peter J Bond,Artur Schmidtchen","doi":"10.1016/j.ymthe.2025.09.033","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.033","url":null,"abstract":"Sepsis remains a major clinical challenge due to the limited efficacy of existing therapies in controlling excessive inflammation. The engineered stapled peptide sHVF18, derived from an evolutionarily conserved thrombin innate fold, binds both lipopolysaccharide (LPS) and the LPS-binding groove of CD14, enabling dual targeting of bacterial components and host immune signaling. To define structural prerequisites for this dual action, we combined evolutionary analysis, in silico modeling, and experimental methods. Substituting the N-terminal histidine with lysine (K) or arginine (R) improved solubility, reduced aggregation, and enhanced interactions with LPS. However, unexpectedly, K-substitutions impaired CD14 binding, whereas R variants retained weaker affinity, possibly through cation-π interactions. The essential role of the evolutionarily conserved N-terminal histidine for CD14 interactions and therapeutic efficacy was demonstrated using LPS-induced shock and polymicrobial sepsis models. While the K variant exhibited superior efficacy in LPS-induced shock, its disrupted CD14 interactions rendered it ineffective in polymicrobial sepsis. In contrast, sHVF18, by engaging both LPS and CD14, effectively reduced inflammation and improved survival in polymicrobial sepsis. These findings highlight that targeting of both LPS and CD14 is essential for therapeutic efficacy, underscoring multivalency as a key principle for future sHVF18-based sepsis therapeutics.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"14 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145134003","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 therapy and mRNA drugs approach for mitochondrial OXPHOS deficiencies. 线粒体OXPHOS缺陷的基因治疗和mRNA药物研究。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-23 DOI: 10.1016/j.ymthe.2025.09.036

Caterina Garone,Silvia Sabeni,Sara Carli

引用次数: 0

Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration. 应激诱导的内皮细胞线粒体断裂破坏血液-视网膜屏障的完整性，导致神经变性。

IF 12 1区医学

Molecular Therapy Pub Date : 2025-09-23 DOI: 10.1016/j.ymthe.2025.09.037

Jorge L Cueva Vargas, Nicolas Belforte, Isaac A Vidal-Paredes, Florence Dotigny, Christine Vande Velde, Heberto Quintero, Adriana Di Polo

{"title":"Stress-induced mitochondrial fragmentation in endothelial cells disrupts blood-retinal barrier integrity causing neurodegeneration.","authors":"Jorge L Cueva Vargas, Nicolas Belforte, Isaac A Vidal-Paredes, Florence Dotigny, Christine Vande Velde, Heberto Quintero, Adriana Di Polo","doi":"10.1016/j.ymthe.2025.09.037","DOIUrl":"10.1016/j.ymthe.2025.09.037","url":null,"abstract":"<p><p>Increased vascular leakage and endothelial cell (EC) dysfunction are major features of neurodegenerative diseases. Here, we investigated the mechanisms leading to EC dysregulation and asked whether altered mitochondrial dynamics in ECs impinge on vascular barrier integrity and neurodegeneration. We show that ocular hypertension, a major risk factor for developing glaucoma, induced mitochondrial fragmentation in retinal capillary ECs, accompanied by increased oxidative stress and ultrastructural defects. Analysis of EC mitochondrial components revealed overactivation of dynamin-related protein 1 (DRP1), a central regulator of mitochondrial fission, during glaucomatous damage. Pharmacological DRP1 inhibition or EC-specific in vivo gene delivery of a dominant-negative DRP1 mutant was sufficient to rescue mitochondrial volume, reduce vascular leakage, and increase expression of the tight junction claudin-5 (CLDN5). We further demonstrate that EC-targeted CLDN5 gene augmentation restored blood-retinal barrier integrity, promoted neuronal survival, and improved light-evoked visual behaviors in glaucomatous mice. Our findings reveal that preserving mitochondrial homeostasis and EC function are valuable strategies to enhance neuroprotection and improve vision in glaucoma.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.0,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138036","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

Sub-endometrial Injection of Human Embryonic Stem Cells-derived Immunity-and-matrix-regulatory Cells Promotes Endometrial Angiogenesis in Patients with Refractory Moderate-to-Severe Intrauterine Adhesion: An Open-label, Single-arm, Single-center, Phase I Dose-escalation Trial. 子宫内膜下注射人胚胎干细胞来源的免疫和基质调节细胞促进难治性中重度宫内粘连患者子宫内膜血管生成：一项开放标签、单臂、单中心、I期剂量递增试验

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-22 DOI: 10.1016/j.ymthe.2025.09.035

Qiang Li,Zhiqi Liao,Xinyao Hu,Jie Hao,Youhua Lai,Cong Sui,Jiayin Zhou,Zishui Fang,Yao Tian,Yueping Zhou,Jie Li,Tingting Gao,Jiaqi Fan,Fan Nan,Yaxin Guo,Wenjing Liu,Wumei Wei,Yan Deng,Zhongwen Li,Bo Huang,Hanwang Zhang,Guihai Feng,Liu Wang,Wei Li,Qi Zhou,Lei Jin,Jun Wu,Baoyang Hu,Kun Qian

{"title":"Sub-endometrial Injection of Human Embryonic Stem Cells-derived Immunity-and-matrix-regulatory Cells Promotes Endometrial Angiogenesis in Patients with Refractory Moderate-to-Severe Intrauterine Adhesion: An Open-label, Single-arm, Single-center, Phase I Dose-escalation Trial.","authors":"Qiang Li,Zhiqi Liao,Xinyao Hu,Jie Hao,Youhua Lai,Cong Sui,Jiayin Zhou,Zishui Fang,Yao Tian,Yueping Zhou,Jie Li,Tingting Gao,Jiaqi Fan,Fan Nan,Yaxin Guo,Wenjing Liu,Wumei Wei,Yan Deng,Zhongwen Li,Bo Huang,Hanwang Zhang,Guihai Feng,Liu Wang,Wei Li,Qi Zhou,Lei Jin,Jun Wu,Baoyang Hu,Kun Qian","doi":"10.1016/j.ymthe.2025.09.035","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.09.035","url":null,"abstract":"Clinical application of mesenchymal stem cells (MSCs) for endometrial repair has been hampered by variability in cell quality, large-scale production, and uncertainty regarding the optimal delivery route. In this study, we investigated the therapeutic potential of clinical-grade human embryonic stem cell-derived immune and matrix-regulatory cells (IMRCs) for treating refractory moderate-to-severe intrauterine adhesion (IUA). In a rabbit IUA model, sub-endometrial injection of IMRCs significantly reduced fibrosis and enhanced endometrial angiogenesis, outperforming uterine perfusion. Transcriptomic analysis revealed distinct pro-angiogenic gene expression profiles between the two delivery routes. In vitro, IMRCs co-cultured with endometrial stromal cells (ESCs) markedly enhanced angiogenic potential compared to either cell type alone. Protein array analysis of the co-culture supernatant showed elevated levels of angiogenic factors, with functional assays confirming that inhibition of ANGPTL4-a non-canonical pro-angiogenic mediator-impaired angiogenesis. In a first-in-human, single-center, Phase I dose-escalation trial involving 18 patients with refractory IUA, high-dose sub-endometrial IMRC injection promoted angiogenesis, reduced uterine scarring, and improved pregnancy outcomes, with no safety concerns observed over three years of follow-up. These findings highlight the translational promise of IMRCs as a novel therapeutic strategy for endometrial regeneration in severe IUA.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"14 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127079","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

New hope for older SMA patients with next-generation self-complementary AAV gene therapy. 新一代自身互补AAV基因治疗为老年SMA患者带来新希望。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-22 DOI: 10.1016/j.ymthe.2025.09.013

Hiroyuki Nakai,Erika L Finanger,Richard Jude Samulski

引用次数: 0

Adipocyte cell therapy targeting bone morphogenetic protein signaling alleviates fibroadipose tissue deposition in secondary lymphedema. 靶向骨形态发生蛋白信号通路的脂肪细胞治疗减轻继发性淋巴水肿的纤维脂肪组织沉积。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-22 DOI: 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}

引用次数: 0

Chimeric Enzymes Enhance Treatment Potential For Globoid Cell Leukodystrophy through Hematopoietic Stem Cell Gene Therapy. 嵌合酶通过造血干细胞基因治疗增强对白细胞营养不良的治疗潜力。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-22 DOI: 10.1016/j.ymthe.2025.09.030

Federica Cascino,Alessandra Ricca,Ilaria Picciotti,Erika Valeri,Giulia Unali,Veronica Saporito,Marta Freschi,Francesco Morena,Sabata Martino,Anna Kajaste-Rudnitski,Angela Gritti

{"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}

引用次数: 0

Pluripotent stem cell-based therapy toward the clinic for muscular dystrophy. 以多能干细胞为基础的肌萎缩症临床治疗。

IF 12.4 1区医学

Molecular Therapy Pub Date : 2025-09-22 DOI: 10.1016/j.ymthe.2025.09.014

Helena Escobar

引用次数: 0