Molecular Therapy最新文献_第2页

Defining the activity of pro-reparative extracellular vesicles in wound healing based on miRNA payloads and cell type-specific lineage mapping. 根据 miRNA 有效载荷和细胞类型特异性系谱图确定促进伤口愈合的细胞外囊泡的活性。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-09-04 Epub Date: 2024-02-19 DOI: 10.1016/j.ymthe.2024.02.019

Dong Jun Park, Wooil Choi, Sakeef Sayeed, Robert A Dorschner, Joseph Rainaldi, Kayla Ho, Jenny Kezios, John P Nolan, Prashant Mali, Todd Costantini, Brian P Eliceiri

{"title":"Defining the activity of pro-reparative extracellular vesicles in wound healing based on miRNA payloads and cell type-specific lineage mapping.","authors":"Dong Jun Park, Wooil Choi, Sakeef Sayeed, Robert A Dorschner, Joseph Rainaldi, Kayla Ho, Jenny Kezios, John P Nolan, Prashant Mali, Todd Costantini, Brian P Eliceiri","doi":"10.1016/j.ymthe.2024.02.019","DOIUrl":"10.1016/j.ymthe.2024.02.019","url":null,"abstract":"Small extracellular vesicles (EVs) are released by cells and deliver biologically active payloads to coordinate the response of multiple cell types in cutaneous wound healing. Here we used a cutaneous injury model as a donor of pro-reparative EVs to treat recipient diabetic obese mice, a model of impaired wound healing. We established a functional screen for microRNAs (miRNAs) that increased the pro-reparative activity of EVs and identified a down-regulation of miR-425-5p in EVs in vivo and in vitro associated with the regulation of adiponectin. We tested a cell type-specific reporter of a tetraspanin CD9 fusion with GFP to lineage map the release of EVs from macrophages in the wound bed, based on the expression of miR-425-5p in macrophage-derived EVs and the abundance of macrophages in EV donor sites. Analysis of different promoters demonstrated that EV release under the control of a macrophage-specific promoter was most abundant and that these EVs were internalized by dermal fibroblasts. These findings suggested that pro-reparative EVs deliver miRNAs, such as miR-425-5p, that stimulate the expression of adiponectin that has insulin-sensitizing properties. We propose that EVs promote intercellular signaling between cell layers in the skin to resolve inflammation, induce proliferation of basal keratinocytes, and accelerate wound closure.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":null,"pages":null},"PeriodicalIF":12.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139913103","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

Full-length dystrophin gene therapy for Duchenne muscular dystrophy. 治疗杜氏肌营养不良症的全长肌营养蛋白基因疗法。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-09-04 Epub Date: 2024-08-12 DOI: 10.1016/j.ymthe.2024.07.026

Dongsheng Duan

引用次数: 0

Engineering a targeted and safe bone anabolic gene therapy to treat osteoporosis in alveolar bone loss. 设计一种有针对性的、安全的骨同化基因疗法，以治疗牙槽骨缺失的骨质疏松症。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-09-04 Epub Date: 2024-06-26 DOI: 10.1016/j.ymthe.2024.06.036

Chujiao Lin, Yeon-Suk Yang, Hong Ma, Zhihao Chen, Dong Chen, Aijaz Ahmad John, Jun Xie, Guangping Gao, Jae-Hyuck Shim

{"title":"Engineering a targeted and safe bone anabolic gene therapy to treat osteoporosis in alveolar bone loss.","authors":"Chujiao Lin, Yeon-Suk Yang, Hong Ma, Zhihao Chen, Dong Chen, Aijaz Ahmad John, Jun Xie, Guangping Gao, Jae-Hyuck Shim","doi":"10.1016/j.ymthe.2024.06.036","DOIUrl":"10.1016/j.ymthe.2024.06.036","url":null,"abstract":"Alveolar bone loss in elderly populations is highly prevalent and increases the risk of tooth loss, gum disease susceptibility, and facial deformity. Unfortunately, there are very limited treatment options available. Here, we developed a bone-targeted gene therapy that reverses alveolar bone loss in patients with osteoporosis by targeting the adaptor protein Schnurri-3 (SHN3). SHN3 is a promising therapeutic target for alveolar bone regeneration, because SHN3 expression is elevated in the mandible tissues of humans and mice with osteoporosis while deletion of SHN3 in mice greatly increases alveolar bone and tooth dentin mass. We used a bone-targeted recombinant adeno-associated virus (rAAV) carrying an artificial microRNA (miRNA) that silences SHN3 expression to restore alveolar bone loss in mouse models of both postmenopausal and senile osteoporosis by enhancing WNT signaling and osteoblast function. In addition, rAAV-mediated silencing of SHN3 enhanced bone formation and collagen production of human skeletal organoids in xenograft mice. Finally, rAAV expression in the mandible was tightly controlled via liver- and heart-specific miRNA-mediated repression or via a vibration-inducible mechanism. Collectively, our results demonstrate that AAV-based bone anabolic gene therapy is a promising strategy to treat alveolar bone loss in osteoporosis.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":null,"pages":null},"PeriodicalIF":12.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469645","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

Prospects and challenges of tissue-derived extracellular vesicles. 组织源性细胞外囊泡（Ti-EVs）的前景与挑战。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-09-04 Epub Date: 2024-06-22 DOI: 10.1016/j.ymthe.2024.06.025

Justin C Lee, Roslyn M Ray, Tristan A Scott

{"title":"Prospects and challenges of tissue-derived extracellular vesicles.","authors":"Justin C Lee, Roslyn M Ray, Tristan A Scott","doi":"10.1016/j.ymthe.2024.06.025","DOIUrl":"10.1016/j.ymthe.2024.06.025","url":null,"abstract":"Extracellular vesicles (EVs) are considered a vital component of cell-to-cell communication and represent a new frontier in diagnostics and a means to identify pathways for therapeutic intervention. Recently, studies have revealed the importance of tissue-derived EVs (Ti-EVs), which are EVs present in the interstitial spaces between cells, as they better represent the underlying physiology of complex, multicellular tissue microenvironments in biology and disease. EVs are native, lipid bilayer membraned nano-sized particles produced by all cells that are packaged with varied functional biomolecules including proteins, lipids, and nucleic acids. They are implicated in short- and long-range cellular communication and may elicit functional responses in recipient cells. To date, studies have often utilized cultured cells or biological fluids as a source for EVs that do not capture local molecular signatures of the tissue microenvironment. Recent work utilizing Ti-EVs has elucidated novel biomarkers for disease and provided insights into disease mechanisms that may lead to the development of novel therapeutic agents. Still, there are considerable challenges facing current studies. This review explores the vast potential and unique challenges for Ti-EV research and provides considerations for future studies that seek to advance this exciting field.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":null,"pages":null},"PeriodicalIF":12.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141443096","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

BCKDK modification enhances the anticancer efficacy of CAR-T cells by reprogramming branched chain amino acid metabolism. BCKDK修饰通过重编程支链氨基酸代谢增强CAR-T细胞的抗癌功效

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-09-04 Epub Date: 2024-05-11 DOI: 10.1016/j.ymthe.2024.05.017

Quanjun Yang, Xinting Zhu, Ping Huang, Chunyan Li, Leng Han, Yonglong Han, Run Gan, Bo Xin, Yixing Tu, Shumin Zhou, Ting Yuan, Juan Hao, Chunqiong Li, Li Zhang, Lei Shi, Cheng Guo

{"title":"BCKDK modification enhances the anticancer efficacy of CAR-T cells by reprogramming branched chain amino acid metabolism.","authors":"Quanjun Yang, Xinting Zhu, Ping Huang, Chunyan Li, Leng Han, Yonglong Han, Run Gan, Bo Xin, Yixing Tu, Shumin Zhou, Ting Yuan, Juan Hao, Chunqiong Li, Li Zhang, Lei Shi, Cheng Guo","doi":"10.1016/j.ymthe.2024.05.017","DOIUrl":"10.1016/j.ymthe.2024.05.017","url":null,"abstract":"Altered branched chain amino acids (BCAAs), including leucine, isoleucine, and valine, are frequently observed in patients with advanced cancer. We evaluated the efficacy of chimeric antigen receptor (CAR) T cell-mediated cancer cell lysis potential in the immune microenvironment of BCAA supplementation and deletion. BCAA supplementation increased cancer cell killing percentage, while accelerating BCAA catabolism and decreasing BCAA transporter decreased cancer cell lysis efficacy. We thus designed BCKDK engineering CAR T cells for the reprogramming of BCAA metabolism in the tumor microenvironment based on the genotype and phenotype modification. BCKDK overexpression (OE) in CAR-T cells significantly improved cancer cell lysis, while BCKDK knockout (KO) resulted in inferior lysis potential. In an in vivo experiment, BCKDK-OE CAR-T cell treatment significantly prolonged the survival of mice bearing NALM6-GL cancer cells, with the differentiation of central memory cells and an increasing proportion of CAR-T cells in the peripheral circulation. BCKDK-KO CAR-T cell treatment resulted in shorter survival and a decreasing percentage of CAR-T cells in the peripheral circulation. In conclusion, BCKDK-engineered CAR-T cells exert a distinct phenotype for superior anticancer efficiency.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":null,"pages":null},"PeriodicalIF":12.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140908737","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

Osr1-mediated mesothelial transition of liver mesenchymal cells exacerbates fibrotic liver damage. Osr1 介导的肝脏间充质细胞间皮细胞转化加剧了纤维化肝损伤。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-09-04 Epub Date: 2024-02-27 DOI: 10.1016/j.ymthe.2024.02.024

Xinxin Nian, Pengyan Lin, Yunfei Bai, Donglin Yu, Xinyan Yang, Bin Zhou, Jie Gao, Yang Zhao

{"title":"Osr1-mediated mesothelial transition of liver mesenchymal cells exacerbates fibrotic liver damage.","authors":"Xinxin Nian, Pengyan Lin, Yunfei Bai, Donglin Yu, Xinyan Yang, Bin Zhou, Jie Gao, Yang Zhao","doi":"10.1016/j.ymthe.2024.02.024","DOIUrl":"10.1016/j.ymthe.2024.02.024","url":null,"abstract":"In chronic liver diseases, hepatic stellate cells (HSCs) are induced to form the myofibroblasts responsible for scar formation, leading to liver fibrosis and cirrhosis. Here, single-cell RNA sequencing with in vivo lineage tracing in nonalcoholic steatohepatitis (NASH) model mice reveals a subpopulation of HSCs transitioning back to a state resembling their developmental precursors, mesothelial cells (MCs), after liver injury. These damage-associated intermediates between HSCs and MCs (DIHMs) can be traced with a dual recombinase system by labeling Krt19-expressing cells within prelabeled Pdgfrb+ HSCs, and DIHMs highly express inflammation- and fibrosis-associated genes. Cre and Dre-inducible depletion of DIHMs by administering diphtheria toxin reduces liver fibrosis and alleviates liver damage in NASH model mice. Importantly, knockdown of Osr1, a zinc finger transcription factor of the OSR gene family, can block DIHM induction in vitro. Conditional knockout Osr1 in Pdgfrb-expressing mesenchymal cells in NASH model mice can reduce liver fibrosis in vivo. Our study collectively uncovers an injury-induced developmental reversion process wherein HSCs undergo what we call a mesenchymal-to-mesothelial transition, which can be targeted to develop interventions to treat chronic liver diseases.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":null,"pages":null},"PeriodicalIF":12.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139983391","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

Hybrid non-viral and viral delivery strategy achieves potent gene editing in growing livers with reduced viral dosage. 非病毒和病毒混合递送策略在降低病毒剂量的同时，实现了对生长中的肝脏进行强效基因编辑。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-09-04 DOI: 10.1016/j.ymthe.2024.08.021

Fanglin Gong, Bowen Li

引用次数: 0

TIPE2 gene transfer ameliorates aging-associated osteoarthritis in a progeria mouse model by reducing inflammation and cellular senescence. 肿瘤坏死因子α诱导的类 8 蛋白 2 (TIPE2) 基因转移通过减少炎症和细胞衰老，改善了早衰小鼠模型中与衰老相关的骨关节炎。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-09-04 Epub Date: 2024-08-05 DOI: 10.1016/j.ymthe.2024.07.027

Ping Guo, Xueqin Gao, Anna-Laura Nelson, Matthieu Huard, Aiping Lu, William Sealy Hambright, Johnny Huard

{"title":"TIPE2 gene transfer ameliorates aging-associated osteoarthritis in a progeria mouse model by reducing inflammation and cellular senescence.","authors":"Ping Guo, Xueqin Gao, Anna-Laura Nelson, Matthieu Huard, Aiping Lu, William Sealy Hambright, Johnny Huard","doi":"10.1016/j.ymthe.2024.07.027","DOIUrl":"10.1016/j.ymthe.2024.07.027","url":null,"abstract":"Osteoarthritis (OA) pain is often associated with the expression of tumor necrosis factor alpha (TNF-α), suggesting that TNF-α is one of the main contributing factors that cause inflammation, pain, and OA pathology. Thus, inhibition of TNF-α could potentially improve OA symptoms and slow disease progression. Anti-TNF-α treatments with antibodies, however, require multiple treatments and cannot entirely block TNF-α. TNF-α-induced protein 8-like 2 (TIPE2) was found to regulate the immune system's homeostasis and inflammation through different mechanisms from anti-TNF-α therapies. With a single treatment of adeno-associated virus (AAV)-TIPE2 gene delivery in the accelerated aging Zmpste24-/- (Z24-/-) mouse model, we found differences in Safranin O staining intensity within the articular cartilage (AC) region of the knee between TIPE2-treated mice and control mice. The glycosaminoglycan content (orange-red) was degraded in the Z24-/- cartilage while shown to be restored in the TIPE2-treated Z24-/- cartilage. We also observed that chondrocytes in Z24-/- mice exhibited a variety of senescent-associated phenotypes. Treatment with TIPE2 decreased TNF-α-positive cells, β-galactosidase (β-gal) activity, and p16 expression seen in Z24-/- mice. Our study demonstrated that AAV-TIPE2 gene delivery effectively blocked TNF-α-induced inflammation and senescence, resulting in the prevention or delay of knee OA in our accelerated aging Z24-/- mouse model.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":null,"pages":null},"PeriodicalIF":12.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879120","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

Reprogramming tumor immune microenvironment by milbemycin oxime results in pancreatic tumor growth suppression and enhanced anti-PD-1 efficacy. 米尔贝霉素肟重编程肿瘤免疫微环境可抑制胰腺肿瘤生长并增强抗 PD1 的疗效。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-09-04 Epub Date: 2024-08-03 DOI: 10.1016/j.ymthe.2024.07.029

Shreyas Gaikwad, Sanjay K Srivastava

{"title":"Reprogramming tumor immune microenvironment by milbemycin oxime results in pancreatic tumor growth suppression and enhanced anti-PD-1 efficacy.","authors":"Shreyas Gaikwad, Sanjay K Srivastava","doi":"10.1016/j.ymthe.2024.07.029","DOIUrl":"10.1016/j.ymthe.2024.07.029","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) has a survival rate of 12%, and multiple clinical trials testing anti-PD-1 therapies against PDAC have failed, suggesting a need for a novel therapeutic strategy. In this study, we evaluated the potential of milbemycin oxime (MBO), an antiparasitic compound, as an immunomodulatory agent in PDAC. Our results show that MBO inhibited the growth of multiple PDAC cell lines by inducing apoptosis. In vivo studies showed that the oral administration of 5 mg/kg MBO inhibited PDAC tumor growth in both subcutaneous and orthotopic models by 49% and 56%, respectively. Additionally, MBO treatment significantly increased the survival of tumor-bearing mice by 27 days as compared to the control group. Interestingly, tumors from MBO-treated mice had increased infiltration of CD8+ T cells. Notably, depletion of CD8+ T cells significantly reduced the anti-tumor efficacy of MBO in mice. Furthermore, MBO significantly augmented the efficacy of anti-PD-1 therapy, and the combination treatment resulted in a greater proportion of active cytotoxic T cells within the tumor microenvironment. MBO was safe and well tolerated in all our preclinical toxicological studies. Overall, our study provides a new direction for the use of MBO against PDAC and highlights the potential of repurposing MBO for enhancing anti-PD-1 immunotherapy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":null,"pages":null},"PeriodicalIF":12.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889723","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

Biomarkers for gene therapy clinical trials of lysosomal storage disorders. 溶酶体贮积症基因治疗临床试验的生物标志物。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-09-04 Epub Date: 2024-06-06 DOI: 10.1016/j.ymthe.2024.06.003

Alessandro Rossi, Sabrina Malvagia, Giancarlo la Marca, Giancarlo Parenti, Nicola Brunetti-Pierri

引用次数: 0