Molecular Therapy最新文献_第10页

Recent developments in gene therapy for Parkinson's disease. 帕金森病基因疗法的最新进展。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-22 DOI: 10.1016/j.ymthe.2025.03.030

Sandor Szunyogh, Emily Carroll, Richard Wade-Martins

{"title":"Recent developments in gene therapy for Parkinson's disease.","authors":"Sandor Szunyogh, Emily Carroll, Richard Wade-Martins","doi":"10.1016/j.ymthe.2025.03.030","DOIUrl":"10.1016/j.ymthe.2025.03.030","url":null,"abstract":"Parkinson's disease (PD) is a progressive, neurodegenerative disorder for which there is currently no cure. Gene therapy has emerged as a novel approach offering renewed hope for the development of treatments that meaningfully alter the course of the disease. In this review, we explore various gene therapy strategies currently being developed targeting key aspects of PD pathogenesis: the restoration of the dopamine system by delivering genes involved in dopamine biosynthesis, reinforcing the inhibitory signaling pathways through glutamic acid decarboxylase (GAD) delivery to increase GABA production, enhancing neuronal survival and development by introducing various neurotrophic factors, delivery of genes to complement recessive familial PD mutations to correct mitochondrial dysfunction, restoring lysosomal function through delivery of GBA1 to increase glucocerebrosidase (GCase) activity, and reducing α-synuclein levels by reducing or silencing SNCA expression. Despite promising early work, challenges remain in developing safe, effective, and long-lasting gene therapies. Key considerations include optimizing viral vectors for targeted delivery, achieving controlled and sustained gene expression using different promoters, minimizing immune responses, and increasing transgene delivery capacity. Future prospects may involve combinatory strategies targeting multiple pathways, such as multi-gene constructs delivered via high-capacity viral systems.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692719","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

AAT-MSC-EVs: Novel implications for suppressing ferroptosis, fibrosis and pain associated with chronic pancreatitis.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-22 DOI: 10.1016/j.ymthe.2025.03.028

Sara Shoeibi, Wenyu Gou, Tiffany Yeung, Kristi Helke, Erica Green, Charlie Strange, Hongjun Wang

{"title":"AAT-MSC-EVs: Novel implications for suppressing ferroptosis, fibrosis and pain associated with chronic pancreatitis.","authors":"Sara Shoeibi, Wenyu Gou, Tiffany Yeung, Kristi Helke, Erica Green, Charlie Strange, Hongjun Wang","doi":"10.1016/j.ymthe.2025.03.028","DOIUrl":"10.1016/j.ymthe.2025.03.028","url":null,"abstract":"Chronic pancreatitis (CP) is characterized by inflammation, acinar cell death, fibrosis, and persistent pain. We investigated mesenchymal stem/stromal cell (MSC)-derived extracellular vesicles (EVs) for CP treatment. CP was modeled in male mice using bile duct TNBS infusion, and pancreatic tissues from CP patients were also analyzed. EVs from immortalized human MSCs overexpressing alpha-1 antitrypsin (iAAT-MSCs) were tested for their effects on ferroptosis, fibrosis, and pain. CP tissues showed reduced glutathione peroxidase 4 (GPx4) activity (p < 0.05) and iron accumulation, indicating ferroptosis. iMSC and iAAT-MSC-EVs alleviated CP symptoms by suppressing ferroptosis, restoring GPx4 activity, reducing MDA levels, and mitigating fibrosis markers (α-smooth muscle actin, transforming growth factor-β1, matrix metalloproteinase 2). EV treatment also alleviated pain by decreasing macrophage and mast cell infiltration into the pancreas and dorsal root ganglia while reducing pain-related gene expression (TRVP1, TacR1, Necab3). Additionally, iAAT-MSC-EVs were distinct in cytokine signaling, PI3K-Akt pathway activation, and upregulation of miRNAs like miR-9, miR-10a-5p, miR-92a, miR-200, miR-370, and miR-146a. These results suggest ferroptosis as a key mechanism in CP and highlight the therapeutic potential of iAAT-MSC-EVs in addressing ferroptosis, fibrosis, and pain, presenting a promising, cell-free therapeutic strategy for CP.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692709","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

Combined AAV-mediated specific Gjb2 expression restores hearing in DFNB1 mouse models.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-22 DOI: 10.1016/j.ymthe.2025.03.029

Qiuhan Sun, Fangzhi Tan, Liyan Zhang, Yicheng Lu, Hao Wei, Nianci Li, Lulu Jiang, Yinyi Zhou, Tian Chen, Ling Lu, Geng-Lin Li, Jieyu Qi, Shiming Yang, Renjie Chai

{"title":"Combined AAV-mediated specific Gjb2 expression restores hearing in DFNB1 mouse models.","authors":"Qiuhan Sun, Fangzhi Tan, Liyan Zhang, Yicheng Lu, Hao Wei, Nianci Li, Lulu Jiang, Yinyi Zhou, Tian Chen, Ling Lu, Geng-Lin Li, Jieyu Qi, Shiming Yang, Renjie Chai","doi":"10.1016/j.ymthe.2025.03.029","DOIUrl":"10.1016/j.ymthe.2025.03.029","url":null,"abstract":"Pathogenic mutations in the Gjb2 gene, encoding connexin 26, are the leading cause of autosomal recessive hereditary deafness. Gene therapy holds significant promise for treating this. Adeno-associated virus (AAV)-mediated therapeutic gene delivery has been shown to be safe and effective in restoring hearing in both animal models and human patients. However, Gjb2 gene therapy has been hindered by the limited specificity and efficiency of the available AAV vectors. In this study, we screened AAV serotypes and found that co-administration of AAV1 and AAV-ie could effectively target Gjb2-expressing cells. However, the ectopic Gjb2 expression in hair cells induced by these AAVs could cause ototoxicity, which was addressed by employing the specific promoter SCpro. Co-injection of AAV1 and AAV-ie carrying exogenous Gjb2 driven by SCpro effectively restored hearing function in Gjb2-deficient mice. Moreover, the combined AAV system can transduce the cochleae of Bama miniature pigs and AAV administration into the inner ear of cynomolgus monkeys did not impair hearing and showed negligible systemic toxicity, indicating the efficiency and safety of this gene therapy in large animals. Thus, this study provides a strategy for Gjb2 gene therapy and lays a foundation for future clinical applications.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692715","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

ABI and generative biology: A new paradigm for gene therapy, genome engineering, and engineered cell therapy. ABI 和生成生物学：基因治疗、基因组工程和工程细胞疗法的新范例。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-21 DOI: 10.1016/j.ymthe.2025.02.021

Adrian Woolfson

引用次数: 0

A synthetic opsin restores vision in patients with severe retinal degeneration. 一种人工合成的视蛋白能恢复严重视网膜变性患者的视力。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-21 DOI: 10.1016/j.ymthe.2025.03.031

Samarendra K Mohanty, Santosh Mahapatra, Subrata Batabyal, Michael Carlson, Gayatri Kanungo, Ananta Ayyagari, Kissaou Tchedre, Joel A Franco, Michael Singer, Samuel Barone, Sai Chavala, Vinit B Mahajan

{"title":"A synthetic opsin restores vision in patients with severe retinal degeneration.","authors":"Samarendra K Mohanty, Santosh Mahapatra, Subrata Batabyal, Michael Carlson, Gayatri Kanungo, Ananta Ayyagari, Kissaou Tchedre, Joel A Franco, Michael Singer, Samuel Barone, Sai Chavala, Vinit B Mahajan","doi":"10.1016/j.ymthe.2025.03.031","DOIUrl":"https://doi.org/10.1016/j.ymthe.2025.03.031","url":null,"abstract":"Inherited Retinal degenerations are the leading cause of blindness worldwide, and in advanced stages, cell loss makes gene replacement ineffective. Optogenetics offers a therapeutic opportunity to restore vision by photo-sensitizing remaining retinal neurons. However, current opsins are kinetically slow, partially activated in ambient light, unresponsive to different light colors, and target low-resolution retinal cell circuits. To overcome these limits, we engineered a synthopsin made of three selectively mutated non-mammalian proteins to achieve a broadband Multi-Characteristic Opsin. The synthopsin was packaged into an optimized AAV2 gene therapy vector that targets human retinal bipolar cells. In an investigator-initiated, open-label study, four blind retinitis pigmentosa patients with ABCA4 variants received a single intravitreal gene therapy injection. Noninvasive imaging confirmed retinal gene expression via a fluorescent reporter protein. Patients showed improvement in vision, shape discrimination, and mobility through 52 weeks. There were no significant safety issues despite what is likely one of the most synthetic, non-mammalian proteins ever expressed in a human. This is the first report of a gene monotherapy that can restore vision in blind patients in a mutation-independent manner utilizing an optogenetics technology platform.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692708","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

Recent advances in therapeutic gene-editing technologies.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-20 DOI: 10.1016/j.ymthe.2025.03.026

Dongqi Liu, Di Cao, Renzhi Han

引用次数: 0

Genetically engineered macrophages reverse the immunosuppressive tumor microenvironment and improve immunotherapeutic efficacy in TNBC.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-20 DOI: 10.1016/j.ymthe.2025.03.024

Ranran Jiang, Liechi Yang, Xin Liu, Yujun Xu, Lulu Han, Yuxin Chen, Ge Gao, Meng Wang, Tong Su, Huizhong Li, Lin Fang, Nan Sun, Hongwei Du, Junnian Zheng, Gang Wang

{"title":"Genetically engineered macrophages reverse the immunosuppressive tumor microenvironment and improve immunotherapeutic efficacy in TNBC.","authors":"Ranran Jiang, Liechi Yang, Xin Liu, Yujun Xu, Lulu Han, Yuxin Chen, Ge Gao, Meng Wang, Tong Su, Huizhong Li, Lin Fang, Nan Sun, Hongwei Du, Junnian Zheng, Gang Wang","doi":"10.1016/j.ymthe.2025.03.024","DOIUrl":"10.1016/j.ymthe.2025.03.024","url":null,"abstract":"The main challenges in current immunotherapy for triple-negative breast cancer (TNBC) lie in the immunosuppressive tumor microenvironment (TME). Considering tumor-associated macrophages (TAMs) are the most abundant immune cells in the TME, resetting TAMs is a promising strategy for ameliorating the immunosuppressive TME. Here, we developed genetically engineered macrophages (GEMs) with gene-carrying adenoviruses, to maintain the M1-like phenotype and directly deliver the immune regulators interleukin-12 and CXCL9 into local tumors, thereby reversing the immunosuppressive TME. In tumor-bearing mice, GEMs demonstrated targeted enrichment in tumors and successfully reprogramed TAMs to M1-like macrophages. Moreover, GEMs significantly enhanced the accumulation, proliferation, and activation of CD8+ T cells, mature dendritic cells, and natural killer cells within tumors, while diminishing M2-like macrophages, immunosuppressive myeloid-derived suppressor cells, and regulatory T cells. This treatment efficiently suppressed tumor growth. In addition, combination therapy with GEMs and anti-programmed cell death protein 1 further improved interferon-γ+CD8+ T cell percentages and tumor inhibition efficacy in an orthotopic murine TNBC model. Therefore, this study provides a novel strategy for reversing the immunosuppressive TME and improving immunotherapeutic efficacy through live macrophage-mediated gene delivery.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676603","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

Astrocytic BEST1 can serve as a target for functional recovery after ischemic stroke.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-20 DOI: 10.1016/j.ymthe.2025.03.022

Shuai Xiong, Meng Sun, Ying Zhang, Pei-Ran Kong, Lu Gan, Ling Gao, Ke Xu, Hai-Yin Wu, Dong-Ya Zhu, Yu-Hui Lin, Rui Li, Chun-Xia Luo

{"title":"Astrocytic BEST1 can serve as a target for functional recovery after ischemic stroke.","authors":"Shuai Xiong, Meng Sun, Ying Zhang, Pei-Ran Kong, Lu Gan, Ling Gao, Ke Xu, Hai-Yin Wu, Dong-Ya Zhu, Yu-Hui Lin, Rui Li, Chun-Xia Luo","doi":"10.1016/j.ymthe.2025.03.022","DOIUrl":"10.1016/j.ymthe.2025.03.022","url":null,"abstract":"Solid evidence from animal experiments supported the concept of peri-infarct tonic inhibition. Related drug targets have the potential to be translated for clinical stroke treatment. Recently, we reported the contribution of neuronal bestrophin-1 (BEST1)-mediated glutamate release to acute ischemic damage exacerbation in rodents. Now, we found a switch of abnormal BEST1 expression and function from neurons to astrocytes in the peri-infarct cortex following astrocytic activation. Excessive GABA was released through astrocytic BEST1 channel during the subacute phase of stroke, leading to sustained tonic inhibition. Astrocyte-specific knockdown of BEST1 promoted motor functional recovery, depending on reduced tonic inhibition. Moreover, we prepared self-assembled nanoparticles encapsulating siBest1 (SNP-siBest1), which displayed high brain accumulation and long circulation and knocked down astrocytic BEST1 effectively and safely. Systemic treatment with SNP-siBest1 after ischemic stroke showed a therapeutic effect in mice. Therefore, BEST1 is a potential target for stroke therapy from acute to subacute phase, and selective BEST1 blockers beyond nanoparticles are worth developing.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677156","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

Correcting a patient-specific Rhodopsin mutation with adenine base editor in a mouse model.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-20 DOI: 10.1016/j.ymthe.2025.03.021

Xiaoxue He, Tong Yan, Zongming Song, Lue Xiang, Jiayang Xiang, Yeqin Yang, Kaiqun Ren, Jicheng Bu, Xilin Xu, Zhuo Li, Xiaowei Guo, Bin Lin, Qinghua Zhou, Ge Lin, Feng Gu

{"title":"Correcting a patient-specific Rhodopsin mutation with adenine base editor in a mouse model.","authors":"Xiaoxue He, Tong Yan, Zongming Song, Lue Xiang, Jiayang Xiang, Yeqin Yang, Kaiqun Ren, Jicheng Bu, Xilin Xu, Zhuo Li, Xiaowei Guo, Bin Lin, Qinghua Zhou, Ge Lin, Feng Gu","doi":"10.1016/j.ymthe.2025.03.021","DOIUrl":"10.1016/j.ymthe.2025.03.021","url":null,"abstract":"Genome editing offers a great promise to treating human genetic diseases. To assess genome-editing-mediated therapeutic effects in vivo, an animal model is indispensable. The genomic disparities between mice and humans often impede the direct clinical application of genome-editing-mediated treatments using conventional mouse models. Thus, the generation of a mouse model with a humanized genomic segment containing a patient-specific mutation is highly sought after for translational research. In this study, we successfully developed a knockin mouse model for autosomal-dominant retinitis pigmentosa (adRP), designated as hT17M knockin, which incorporates a 75-nucleotide DNA segment with the T17M mutation (Rhodopsin-c.C50T; p.T17M). This model demonstrated significant reductions in electroretinogram amplitudes and exhibited disruptions in retinal structure. Subsequently, we administered an adeno-associated virus vectors carrying an adenine base editor (ABE) and a single-guide RNA specifically targeting the T17M mutation, achieving a peak correction rate of 39.7% at the RNA level and significantly improving retinal function in ABE-injected mice. These findings underscore that the hT17M knockin mouse model recapitulates the clinical features of adRP patients and exhibits therapeutic effects with ABE-mediated treatments. It offers a promising avenue for the development of gene-editing therapies for RP.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676587","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

IFN-γ-mediated suppression of Caspase-7 exacerbates acute lung injury induced by CAR-T cells.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2025-03-20 DOI: 10.1016/j.ymthe.2025.03.023

Rui Hou, Xiaoxue Zhang, Zejun Zhang, Wenyin He, Huan Li, Xu Wang, Xuan Zhao, Sijin Li, Zhangchun Guan, Ying Sun, Dan Liu, Junnian Zheng, Ming Shi

{"title":"IFN-γ-mediated suppression of Caspase-7 exacerbates acute lung injury induced by CAR-T cells.","authors":"Rui Hou, Xiaoxue Zhang, Zejun Zhang, Wenyin He, Huan Li, Xu Wang, Xuan Zhao, Sijin Li, Zhangchun Guan, Ying Sun, Dan Liu, Junnian Zheng, Ming Shi","doi":"10.1016/j.ymthe.2025.03.023","DOIUrl":"10.1016/j.ymthe.2025.03.023","url":null,"abstract":"On-target off-tumor effects precipitate severe adverse reactions in patients, significantly hindering the application of chimeric antigen receptor (CAR) T cells in both hematological and solid tumors. The underlying mechanisms remain elusive due to the absence of suitable preclinical models. To elucidate these mechanisms, a human epidermal growth factor receptor 2 (Her2) transgenic mouse model was developed to investigate CAR-T cell-induced on-target off-tumor effects. CAR-T cells initially migrated to the lungs, targeting alveolar epithelial cells and resulting in interferon-γ (IFN-γ)-dependent acute lung injury. Additionally, a regulatory mechanism involving IFN-γ-induced degradation of caspase-7 mRNA 5' untranslated regions (UTR), which amplifies acute lung injury mediated by CAR-T cells, was identified. Consequently, a strategy was validated to antagonize IFN-γ during CAR-T cell infusion, thereby mitigating acute lung injury without compromising antitumor efficacy. These findings elucidate the mechanisms of CAR-T cell-induced acute lung injury and demonstrate the viability of targeting IFN-γ to prevent this adverse reaction.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676611","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