Molecular Therapy最新文献_第7页

Managing allorejection in off-the-shelf CAR-engineered cell therapies. 管理现成 CAR 工程细胞疗法中的异体排斥反应。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-26 DOI: 10.1016/j.ymthe.2024.11.035

Yan-Ruide Li, Ying Fang, Siyue Niu, Yuning Chen, Zibai Lyu, Lili Yang

{"title":"Managing allorejection in off-the-shelf CAR-engineered cell therapies.","authors":"Yan-Ruide Li, Ying Fang, Siyue Niu, Yuning Chen, Zibai Lyu, Lili Yang","doi":"10.1016/j.ymthe.2024.11.035","DOIUrl":"10.1016/j.ymthe.2024.11.035","url":null,"abstract":"Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has revolutionized the treatment of various diseases, including cancers and autoimmune disorders. However, all US Food and Drug Administration (FDA)-approved CAR-T cell therapies are autologous, and their widespread clinical application is limited by several challenges, such as complex individualized manufacturing, high costs, and the need for patient-specific selection. Allogeneic off-the-shelf CAR-engineered cell therapy offers promising potential due to its immediate availability, consistent quality, potency, and scalability in manufacturing. Nonetheless, significant challenges, including the risks of graft-versus-host disease (GvHD) and host-cell-mediated allorejection, must be addressed. Strategies such as knocking out endogenous T cell receptors (TCRs) or using alternative therapeutic cells with low GvHD risk have shown promise in clinical trials aimed at reducing GvHD. However, mitigating allorejection remains critical for ensuring the long-term sustainability and efficacy of off-the-shelf cell products. In this review, we discuss the immunological basis of allorejection in CAR-engineered therapies and explore various strategies to overcome this challenge. We also highlight key insights from recent clinical trials, particularly related to the sustainability and immunogenicity of allogeneic CAR-engineered cell products, and address manufacturing considerations aimed at minimizing allorejection and optimizing the efficacy of this emerging therapeutic approach.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142730719","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

A novel CD71 Centyrin:Gys1 siRNA conjugate reduces glycogen synthesis and glycogen levels in a mouse model of Pompe disease. 新型 CD71 Centyrin:Gys1 siRNA 靶向和递送平台可减少庞贝氏症小鼠模型中糖原的合成并降低糖原水平。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-26 DOI: 10.1016/j.ymthe.2024.11.033

Bryce D Holt, Samuel J Elliott, Rebecca Meyer, Daniela Reyes, Karyn O'Neil, Zhanna Druzina, Swapnil Kulkarni, Beth L Thurberg, Steven G Nadler, Bartholomew A Pederson

{"title":"A novel CD71 Centyrin:Gys1 siRNA conjugate reduces glycogen synthesis and glycogen levels in a mouse model of Pompe disease.","authors":"Bryce D Holt, Samuel J Elliott, Rebecca Meyer, Daniela Reyes, Karyn O'Neil, Zhanna Druzina, Swapnil Kulkarni, Beth L Thurberg, Steven G Nadler, Bartholomew A Pederson","doi":"10.1016/j.ymthe.2024.11.033","DOIUrl":"10.1016/j.ymthe.2024.11.033","url":null,"abstract":"Pompe disease is caused by acid alpha-glucosidase (GAA) deficiency, resulting in lysosomal glycogen accumulation. This disease is characterized by progressive skeletal muscle weakness, respiratory distress, and in the infantile-onset form, cardiomyopathy. The only approved treatment is enzyme replacement therapy (ERT) with human recombinant GAA. While ERT therapy extends life span, residual symptoms remain, with poor muscle uptake and immunogenicity limiting efficacy. We examined a novel Centyrin protein-short interfering ribonucleic acid (siRNA) conjugate targeting CD71 (transferrin receptor type 1, TfR1) and GYS1, a key enzyme involved in glycogen synthesis. Unlike existing ERTs designed to degrade aberrant glycogen deposits observed in Pompe patients, the CD71 Centyrin:Gys1 siRNA is designed to restore glycogen balance by inhibiting glycogen synthesis. To this end, we administered the CD71 Centyrin:Gys1 siRNA conjugate to the 6neo/6neo Pompe mouse model. Once bound to TfR1, siRNA-conjugated Centyrin is internalized into cells to facilitate gene knockdown. We found that treatment with this conjugate significantly reduced GYS1 protein expression, glycogen synthase enzymatic activity, and glycogen levels in muscle. In addition, impaired treadmill exercise performance of male Pompe mice was improved. These data suggest that Centyrin-mediated delivery of Gys1 siRNA may be an effective next generation therapy for late-onset Pompe disease or, in combination with ERT, for infantile-onset Pompe disease.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739990","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

Flavopiridol restores granulopoiesis in experimental models of severe congenital neutropenia.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-22 DOI: 10.1016/j.ymthe.2024.10.031

Masoud Nasri, Benjamin Dannenmann, Larissa Doll, Betül Findik, Franka Bernhard, Sergey Kandabarau, Maksim Klimiankou, Meinrad Gawaz, Claudia Lengerke, Cornelia Zeidler, Karl Welte, Julia Skokowa

{"title":"Flavopiridol restores granulopoiesis in experimental models of severe congenital neutropenia.","authors":"Masoud Nasri, Benjamin Dannenmann, Larissa Doll, Betül Findik, Franka Bernhard, Sergey Kandabarau, Maksim Klimiankou, Meinrad Gawaz, Claudia Lengerke, Cornelia Zeidler, Karl Welte, Julia Skokowa","doi":"10.1016/j.ymthe.2024.10.031","DOIUrl":"https://doi.org/10.1016/j.ymthe.2024.10.031","url":null,"abstract":"Severe congenital neutropenia (CN) patients require life-long treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF), but some show no response. We sought to establish a therapy for CN that targets signaling pathways causing maturation arrest of granulocytic progenitors. We developed an isogenic induced pluripotent stem cell (iPSC) in vitro model of CN associated with ELANE mutations (ELANE-CN) and performed an in silico drug repurposing analysis of the transcriptomics of iPSC-generated hematopoietic stem and progenitor cells. We identified flavopiridol, a Food and Drug Administration (FDA)-approved pan-cyclin-dependent kinase inhibitor, as a potential therapeutic. Treatment with low-dose flavopiridol rescued defective granulopoiesis in primary CD34+ cells of CN patients with different inherited gene mutations in vitro and in two zebrafish CN models in vivo without any toxic effects and leading to functional granulocytes. Flavopiridol also restored granulopoiesis caused by diminished CEBPA expression, a known defective signaling molecule in CN. Thus, we described for the first time a potential therapy for CN with flavopiridol that could be potentially used to treat patients with different types of neutropenia.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142800978","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

Thank you to our 2024 reviewers. 感谢我们的 2024 评论员。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-22 DOI: 10.1016/j.ymthe.2024.11.014

引用次数: 0

Dorsal root ganglion toxicity after AAV intra-CSF delivery of a RNAi expression construct into non-human primates and mice. 向非人灵长类动物和小鼠体内输送 AAV-CSF RNAi 表达构建物后的背根神经节毒性。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-19 DOI: 10.1016/j.ymthe.2024.11.029

Zachary C E Hawley, Ingrid D Pardo, Shaolong Cao, Maria I Zavodszky, Fergal Casey, Kyle Ferber, Yi Luo, Sam Hana, Shukkwan K Chen, Jessica Doherty, Raquel Costa, Patrick Cullen, Yuqing Liu, Thomas M Carlile, Twinkle Chowdhury, Benjamin Doyle, Pete Clarner, Kevin Mangaudis, Edward Guilmette, Shawn Bourque, David Koske, Murali V P Nadella, Patrick Trapa, Michael L Hawes, Denitza Raitcheva, Shih-Ching Lo

{"title":"Dorsal root ganglion toxicity after AAV intra-CSF delivery of a RNAi expression construct into non-human primates and mice.","authors":"Zachary C E Hawley, Ingrid D Pardo, Shaolong Cao, Maria I Zavodszky, Fergal Casey, Kyle Ferber, Yi Luo, Sam Hana, Shukkwan K Chen, Jessica Doherty, Raquel Costa, Patrick Cullen, Yuqing Liu, Thomas M Carlile, Twinkle Chowdhury, Benjamin Doyle, Pete Clarner, Kevin Mangaudis, Edward Guilmette, Shawn Bourque, David Koske, Murali V P Nadella, Patrick Trapa, Michael L Hawes, Denitza Raitcheva, Shih-Ching Lo","doi":"10.1016/j.ymthe.2024.11.029","DOIUrl":"10.1016/j.ymthe.2024.11.029","url":null,"abstract":"Dorsal root ganglion (DRG) toxicity has been consistently reported as a potential safety concern after delivery of adeno-associated viruses (AAVs) containing gene-replacement vectors but has yet to be reported for RNAi-based vectors. Here, we report DRG toxicity after AAV intra-CSF delivery of an RNAi expression construct-artificial microRNA targeting superoxide dismutase 1 (SOD1)-in non-human primates (NHPs) and provide evidence that this can be recapitulated within mice. Histopathology evaluation showed that NHPs and mice develop DRG toxicity after AAV delivery, including DRG neuron degeneration and necrosis and nerve-fiber degeneration that were associated with increases in cerebrospinal fluid (CSF) and serum phosphorylated neurofilament heavy chain (pNF-H). RNA-sequencing analysis of DRGs showed that dysregulated pathways were preserved between NHPs and mice, including increases in innate/adaptive immune responses and decreases in mitochondrial- and neuronal-related genes, following AAV treatment. Finally, endogenous miR-21-5p was upregulated in DRGs of AAV-treated NHPs and mice. Increases in miR-21-5p were also identified within the CSF of NHPs, which significantly correlated with pNF-H, implicating miR-21-5p as a potential biomarker of DRG toxicity in conjunction with other molecular analytes. This work highlights the importance of assessing safety concerns related to DRG toxicity when developing RNAi-based AAV vectors for therapeutic purposes.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676021","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

CRISPR targeting of mmu-miR-21a through a single adeno-associated virus vector prolongs survival of glioblastoma-bearing mice. 通过单一腺相关病毒载体对mmu-miR-21a进行CRISPR靶向可延长胶质母细胞瘤小鼠的存活时间。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-19 DOI: 10.1016/j.ymthe.2024.11.023

Lisa Nieland, Anne B Vrijmoet, Isabelle W Jetten, David Rufino-Ramos, Alexandra J E M de Reus, Koen Breyne, Benjamin P Kleinstiver, Casey A Maguire, Marike L D Broekman, Xandra O Breakefield, Erik R Abels

{"title":"CRISPR targeting of mmu-miR-21a through a single adeno-associated virus vector prolongs survival of glioblastoma-bearing mice.","authors":"Lisa Nieland, Anne B Vrijmoet, Isabelle W Jetten, David Rufino-Ramos, Alexandra J E M de Reus, Koen Breyne, Benjamin P Kleinstiver, Casey A Maguire, Marike L D Broekman, Xandra O Breakefield, Erik R Abels","doi":"10.1016/j.ymthe.2024.11.023","DOIUrl":"10.1016/j.ymthe.2024.11.023","url":null,"abstract":"Glioblastoma (GB), the most aggressive tumor of the central nervous system (CNS), has poor patient outcomes with limited effective treatments available. MicroRNA-21 (miR-21(a)) is a known oncogene, abundantly expressed in many cancer types. miR-21(a) promotes GB progression, and lack of miR-21(a) reduces the tumorigenic potential. Here, we propose a single adeno-associated virus (AAV) vector strategy targeting mmu-miR-21a using the Staphylococcus aureus Cas9 ortholog (SaCas9) guided by a single-guide RNA (sgRNA). Our results demonstrate that AAV8 is a well-suited AAV serotype to express SaCas9-KKH/sgRNA at the tumor site in an orthotopic GB model. The SaCas9-KKH induced a genomic deletion, resulting in lowered mmu-miR-21a levels in the brain, leading to reduced tumor growth and improved overall survival. In this study, we demonstrated that disruption of genomic mmu-miR-21a with a single AAV vector influenced glioma development, resulting in beneficial anti-tumor outcomes in GB-bearing mice.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676017","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

Neuroplasticity therapy using glia-like cells derived from human mesenchymal stem cells for the recovery of cerebral infarction sequelae. 利用从人类间充质干细胞中提取的胶质样细胞进行神经可塑性强化治疗，以恢复脑梗塞后遗症。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-19 DOI: 10.1016/j.ymthe.2024.11.022

Eun Ji Lee, Min-Ju Lee, Ye Jin Ryu, Sang-Hyeon Nam, Rokhyun Kim, Sehyeon Song, Kyunghyuk Park, Young Jun Park, Jong-Il Kim, Seong-Ho Koh, Mi-Sook Chang

{"title":"Neuroplasticity therapy using glia-like cells derived from human mesenchymal stem cells for the recovery of cerebral infarction sequelae.","authors":"Eun Ji Lee, Min-Ju Lee, Ye Jin Ryu, Sang-Hyeon Nam, Rokhyun Kim, Sehyeon Song, Kyunghyuk Park, Young Jun Park, Jong-Il Kim, Seong-Ho Koh, Mi-Sook Chang","doi":"10.1016/j.ymthe.2024.11.022","DOIUrl":"10.1016/j.ymthe.2024.11.022","url":null,"abstract":"Despite a dramatic increase in ischemic stroke incidence worldwide, effective therapies for attenuating sequelae of cerebral infarction are lacking. This study investigates the use of human mesenchymal stem cells (hMSCs) induced toward glia-like cells (ghMSCs) to ameliorate chronic sequelae resulting from cerebral infarction. Transcriptome analysis demonstrated that ghMSCs exhibited astrocytic characteristics, and assessments conducted ex vivo using organotypic brain slice cultures demonstrated that ghMSCs exhibited superior neuroregenerative and neuroprotective activity against ischemic damage compared to hMSCs. The observed beneficial effects of ghMSCs were diminished by pre-treatment with a CXCR2 antagonist, indicating a direct role for CXCR2 signaling. Studies conducted in rats subjected to cerebral infarction demonstrated that ghMSCs restored neurobehavioral functions and reduced chronic brain infarction in a dose-dependent manner when transplanted at the subacute-to-chronic phase. These beneficial impacts were also inhibited by a CXCR2 antagonist. Molecular analyses confirmed that increased neuroplasticity contributed to ghMSCs' neuroregenerative effects. These data indicate that ghMSCs hold promise for treating refractory sequelae resulting from cerebral infarction by enhancing neuroplasticity and identify CXCR2 signaling as an important mediator of ghMSCs' mechanism of action.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676182","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

Targeting PD-1⁺ T cells with small-format immunocytokines enhances IL-12 antitumor activity. 用小格式免疫细胞因子靶向 PD-1+ T 细胞可增强 IL-12 的抗肿瘤活性。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-19 DOI: 10.1016/j.ymthe.2024.11.027

Noelia Silva-Pilipich, Uxue Beloki, Patricia Apaolaza, Ana Igea, Laura Salaberry, Laura Prats-Mari, Eric Rovira, Marina Ondiviela, Marta Gorraiz, Juan José Lasarte, Lucía Vanrell, Cristian Smerdou

{"title":"Targeting PD-1+ T cells with small-format immunocytokines enhances IL-12 antitumor activity.","authors":"Noelia Silva-Pilipich, Uxue Beloki, Patricia Apaolaza, Ana Igea, Laura Salaberry, Laura Prats-Mari, Eric Rovira, Marina Ondiviela, Marta Gorraiz, Juan José Lasarte, Lucía Vanrell, Cristian Smerdou","doi":"10.1016/j.ymthe.2024.11.027","DOIUrl":"10.1016/j.ymthe.2024.11.027","url":null,"abstract":"Immunostimulatory cytokines and immune checkpoint inhibitors hold promise as cancer therapeutics; however, their use is often limited by reduced efficacy and significant toxicity. In this study, we developed small-format immunocytokines (ICKs) based on interleukin-12 (IL-12) and blocking nanobodies (Nbs) targeting mouse and human programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1). Both PD-1- and PD-L1-targeted ICKs demonstrated similar in vitro performance, significantly increasing IL-12 tethering to immune cells and enhancing T cell cytotoxic activity compared with IL-12 alone. The antitumor efficacy of ICKs was evaluated by intratumoral delivery using self-amplifying RNA-based vectors or as recombinant proteins in mice. Despite effective PD-L1-mediated tumor anchoring and promising in vitro results, IL-12 antitumor activity was significantly enhanced only when specific targeting to intratumoral T cells was achieved via anti-PD-1 Nb. This effect was also observed when the PD-1 specific ICK was delivered by electroporation of a DNA/RNA layered vector. Our findings suggest that targeting the appropriate type of cell within the tumor microenvironment could outperform tumor-anchoring strategies in the context of IL-12 therapy. Human versions of these ICKs were also developed, which showed to be active in human immune cells, opening an opportunity for clinical translation.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676191","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

Lipid nanoparticle delivery of TALEN mRNA targeting LPA causes gene disruption and plasma lipoprotein(a) reduction in transgenic mice. 以 LPA 为靶标的 TALEN mRNA 的脂质纳米颗粒递送会导致基因中断和转基因小鼠血浆脂蛋白（a）减少。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-19 DOI: 10.1016/j.ymthe.2024.11.020

Daniel A Garcia, Abigail F Pierre, Linda Quirino, Grishma Acharya, Aishwarya Vasudevan, Yihua Pei, Emily Chung, Jason Y H Chang, Samuel Lee, Michael Endow, Kristen Kuakini, Michael Bresnahan, Maria Chumpitaz, Kumar Rajappan, Suezanne Parker, Pad Chivukula, Stefen A Boehme, Ramon Diaz-Trelles

{"title":"Lipid nanoparticle delivery of TALEN mRNA targeting LPA causes gene disruption and plasma lipoprotein(a) reduction in transgenic mice.","authors":"Daniel A Garcia, Abigail F Pierre, Linda Quirino, Grishma Acharya, Aishwarya Vasudevan, Yihua Pei, Emily Chung, Jason Y H Chang, Samuel Lee, Michael Endow, Kristen Kuakini, Michael Bresnahan, Maria Chumpitaz, Kumar Rajappan, Suezanne Parker, Pad Chivukula, Stefen A Boehme, Ramon Diaz-Trelles","doi":"10.1016/j.ymthe.2024.11.020","DOIUrl":"10.1016/j.ymthe.2024.11.020","url":null,"abstract":"Lipoprotein(a), or Lp(a), is encoded by the LPA gene and is a causal genetic risk factor for cardiovascular disease. Individuals with high Lp(a) are at risk for cardiovascular morbidity and are refractory to standard lipid-lowering agents. Lp(a)-lowering therapies currently in clinical development require repetitive dosing, while a gene editing approach presents an opportunity for a single-dose treatment. In this study, mRNAs encoding transcription activator-like effector nucleases (TALENs) were designed to target human LPA for gene disruption and permanent Lp(a) reduction. TALEN mRNAs were screened in vitro and found to cause on-target gene editing and target protein reduction with minimal off-target editing. TALEN mRNAs were then encapsulated with LUNAR, a proprietary lipid nanoparticle (LNP), and administered to transgenic mice that expressed a human LPA transgene. A single dose of TALEN mRNA-LNPs reduced plasma Lp(a) levels in mice by over 80%, which was sustained for at least 5 weeks. Moreover, both standard and long-read next-generation sequencing confirmed the presence of gene-inactivating deletions at LPA transgene loci. Overall, this study serves as a proof-of-concept for using TALEN-mediated gene editing to disrupt LPA in vivo, paving the way for the development of a feasible gene editing therapy for patients with high Lp(a).","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676022","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

Long-read RNA sequencing: A transformative technology for exploring transcriptome complexity in human diseases. 长读 RNA 测序：探索人类疾病转录组复杂性的变革性技术。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-19 DOI: 10.1016/j.ymthe.2024.11.025

Isabelle Heifetz Ament, Nicole DeBruyne, Feng Wang, Lan Lin

引用次数: 0