Molecular therapy : the journal of the American Society of Gene Therapy最新文献_第4页

Anti-NKG2C/IL-15/anti-CD33 killer engager directs primary and iPSC-derived NKG2C⁺ NK cells to target myeloid leukemia. Anti-NKG2C/IL-15/anti-CD33杀手接合物指导原代和ipsc衍生的NKG2C+ NK细胞靶向髓性白血病。

IF 12.4

Molecular therapy : the journal of the American Society of Gene Therapy Pub Date : 2021-12-01 Epub Date: 2021-06-24 DOI: 10.1016/j.ymthe.2021.06.018

Emily Chiu, Martin Felices, Frank Cichocki, Zachary Davis, Hongbo Wang, Katie Tuninga, Daniel A Vallera, Tom Lee, Ryan Bjordahl, Karl Johan Malmberg, Bahram Valamehr, Jeffrey S Miller

{"title":"Anti-NKG2C/IL-15/anti-CD33 killer engager directs primary and iPSC-derived NKG2C+ NK cells to target myeloid leukemia.","authors":"Emily Chiu, Martin Felices, Frank Cichocki, Zachary Davis, Hongbo Wang, Katie Tuninga, Daniel A Vallera, Tom Lee, Ryan Bjordahl, Karl Johan Malmberg, Bahram Valamehr, Jeffrey S Miller","doi":"10.1016/j.ymthe.2021.06.018","DOIUrl":"https://doi.org/10.1016/j.ymthe.2021.06.018","url":null,"abstract":"Natural killer (NK) cells mediate the cytolysis of transformed cells and are currently used as an adoptive cellular therapy to treat cancer. Infection with human cytomegalovirus has been shown to expand a subset of \"adaptive\" NK cells expressing the activation receptor NKG2C that have preferred functional attributes distinct from conventional NK cells. Because NKG2C delivers a strong activating signal to NK cells, we hypothesized that NKG2C could specifically trigger NK-cell-mediated antitumor responses. To elicit a tumor-directed response from NKG2C+ NK cells, we created an anti-NKG2C/IL-15/anti-CD33 killer engager called NKG2C-KE that directs NKG2C+ cells to target CD33+ cells and tumor-associated antigen expressed by acute myelogenous leukemia cells. The NKG2C-KE induced specific degranulation, interferon-γ production, and proliferation of NKG2C-expressing NK cells from patients who reactivated cytomegalovirus after allogeneic transplantation. The NKG2C-KE was also tested in a more homogeneous system using induced pluripotent stem cell (iPSC)-derived NK (iNK) cells that have been engineered to express NKG2C at high levels. The NKG2C-KE triggered iNK-cell-mediated cytotoxicity against CD33+ cells and primary AML blasts. The NKG2C-KE-specific interaction with adaptive NK and NKG2C+ iNK cells represents a new immunotherapeutic paradigm that uniquely engages highly active NK cells to induce cytotoxicity against AML through redirected targeting.","PeriodicalId":519519,"journal":{"name":"Molecular therapy : the journal of the American Society of Gene Therapy","volume":" ","pages":"3410-3421"},"PeriodicalIF":12.4,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ymthe.2021.06.018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39110863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 11

Mesenchymal stromal cell delivery of oncolytic immunotherapy improves CAR-T cell antitumor activity. 间充质间质细胞传递溶瘤免疫疗法提高CAR-T细胞抗肿瘤活性。

IF 12.4

Molecular therapy : the journal of the American Society of Gene Therapy Pub Date : 2021-12-01 Epub Date: 2021-10-27 DOI: 10.1016/j.ymthe.2021.10.007

Mary K McKenna, Alexander Englisch, Benjamin Brenner, Tyler Smith, Valentina Hoyos, Masataka Suzuki, Malcolm K Brenner

引用次数: 3

circRNA_0025202 Regulates Tamoxifen Sensitivity and Tumor Progression via Regulating the miR-182-5p/FOXO3a Axis in Breast Cancer. circRNA_0025202通过调节乳腺癌中miR-182-5p/FOXO3a轴调控他莫昔芬敏感性和肿瘤进展。

IF 12.4

Molecular therapy : the journal of the American Society of Gene Therapy Pub Date : 2021-12-01 Epub Date: 2021-11-12 DOI: 10.1016/j.ymthe.2021.11.002

Yuting Sang, Bing Chen, Xiaojin Song, Yaming Li, Yiran Liang, Dianwen Han, Ning Zhang, Hanwen Zhang, Ying Liu, Tong Chen, Chen Li, Lijuan Wang, Wenjing Zhao, Qifeng Yang

引用次数: 46

Gene therapy for ALS: A review. ALS的基因治疗:综述。

IF 12.4

Molecular therapy : the journal of the American Society of Gene Therapy Pub Date : 2021-12-01 Epub Date: 2021-04-09 DOI: 10.1016/j.ymthe.2021.04.008

Defne A Amado, Beverly L Davidson

{"title":"Gene therapy for ALS: A review.","authors":"Defne A Amado, Beverly L Davidson","doi":"10.1016/j.ymthe.2021.04.008","DOIUrl":"https://doi.org/10.1016/j.ymthe.2021.04.008","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) has historically posed unique challenges for gene-therapy-based approaches, due to a paucity of therapeutic targets as well as the difficulty of accessing both the brain and spinal cord. Recent advances in our understanding of disease mechanism and ALS genetics, however, have combined with tremendous strides in CNS targeting, gene delivery, and gene editing and knockdown techniques to open new horizons of therapeutic possibility. Gene therapy clinical trials are currently underway for ALS patients with SOD1 mutations, C9orf72 hexanucleotide repeat expansions, ATXN2 trinucleotide expansions, and FUS mutations, as well as sporadic disease without known genetic cause. In this review, we provide an in-depth exploration of the state of ALS-directed gene therapy, including antisense oligonucleotides, RNA interference, CRISPR, adeno-associated virus (AAV)-mediated trophic support, and antibody-based methods. We discuss how each of these approaches has been implemented across known genetic causes as well as sporadic ALS, reviewing preclinical studies as well as completed and ongoing human clinical trials. We highlight the transformative potential of these evolving technologies as the gene therapy field advances toward a true disease-modifying treatment for this devastating illness.","PeriodicalId":519519,"journal":{"name":"Molecular therapy : the journal of the American Society of Gene Therapy","volume":" ","pages":"3345-3358"},"PeriodicalIF":12.4,"publicationDate":"2021-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ymthe.2021.04.008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25588486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 79

The genome-editing decade. 基因组编辑的十年。

IF 12.4

Molecular therapy : the journal of the American Society of Gene Therapy Pub Date : 2021-11-03 Epub Date: 2021-10-26 DOI: 10.1016/j.ymthe.2021.10.016

Paula M Cannon, Hans-Peter Kiem

引用次数: 1

In vivo confusion over in vivo conversion. 对体内转化的体内混淆。

IF 12.4

Molecular therapy : the journal of the American Society of Gene Therapy Pub Date : 2021-11-03 Epub Date: 2021-10-25 DOI: 10.1016/j.ymthe.2021.10.017

Gong Chen

引用次数: 12

Scratching the surface of RGD-directed AAV capsid engineering. rgd定向AAV衣壳工程的初步研究。

IF 12.4

Molecular therapy : the journal of the American Society of Gene Therapy Pub Date : 2021-11-03 Epub Date: 2021-10-26 DOI: 10.1016/j.ymthe.2021.10.020

Sergei Zolotukhin, Prasad D Trivedi, Manuela Corti, Barry J Byrne

引用次数: 4

Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNPs. 利用工程化CD4+细胞归巢mRNA-LNPs高效靶向CD4+ T细胞和基因重组。

IF 12.4

Molecular therapy : the journal of the American Society of Gene Therapy Pub Date : 2021-11-03 Epub Date: 2021-06-04 DOI: 10.1016/j.ymthe.2021.06.004

István Tombácz, Dorottya Laczkó, Hamna Shahnawaz, Hiromi Muramatsu, Ambika Natesan, Amir Yadegari, Tyler E Papp, Mohamad-Gabriel Alameh, Vladimir Shuvaev, Barbara L Mui, Ying K Tam, Vladimir Muzykantov, Norbert Pardi, Drew Weissman, Hamideh Parhiz

{"title":"Highly efficient CD4+ T cell targeting and genetic recombination using engineered CD4+ cell-homing mRNA-LNPs.","authors":"István Tombácz, Dorottya Laczkó, Hamna Shahnawaz, Hiromi Muramatsu, Ambika Natesan, Amir Yadegari, Tyler E Papp, Mohamad-Gabriel Alameh, Vladimir Shuvaev, Barbara L Mui, Ying K Tam, Vladimir Muzykantov, Norbert Pardi, Drew Weissman, Hamideh Parhiz","doi":"10.1016/j.ymthe.2021.06.004","DOIUrl":"https://doi.org/10.1016/j.ymthe.2021.06.004","url":null,"abstract":"Nucleoside-modified messenger RNA (mRNA)-lipid nanoparticles (LNPs) are the basis for the first two EUA (Emergency Use Authorization) COVID-19 vaccines. The use of nucleoside-modified mRNA as a pharmacological agent opens immense opportunities for therapeutic, prophylactic and diagnostic molecular interventions. In particular, mRNA-based drugs may specifically modulate immune cells, such as T lymphocytes, for immunotherapy of oncologic, infectious and other conditions. The key challenge, however, is that T cells are notoriously resistant to transfection by exogenous mRNA. Here, we report that conjugating CD4 antibody to LNPs enables specific targeting and mRNA interventions to CD4+ cells, including T cells. After systemic injection in mice, CD4-targeted radiolabeled mRNA-LNPs accumulated in spleen, providing ∼30-fold higher signal of reporter mRNA in T cells isolated from spleen as compared with non-targeted mRNA-LNPs. Intravenous injection of CD4-targeted LNPs loaded with Cre recombinase-encoding mRNA provided specific dose-dependent loxP-mediated genetic recombination, resulting in reporter gene expression in about 60% and 40% of CD4+ T cells in spleen and lymph nodes, respectively. T cell phenotyping showed uniform transfection of T cell subpopulations, with no variability in uptake of CD4-targeted mRNA-LNPs in naive, central memory, and effector cells. The specific and efficient targeting and transfection of mRNA to T cells established in this study provides a platform technology for immunotherapy of devastating conditions and HIV cure.","PeriodicalId":519519,"journal":{"name":"Molecular therapy : the journal of the American Society of Gene Therapy","volume":" ","pages":"3293-3304"},"PeriodicalIF":12.4,"publicationDate":"2021-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ymthe.2021.06.004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39064560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 61

Targeting RNA editing of antizyme inhibitor 1: A potential oligonucleotide-based antisense therapy for cancer. 靶向RNA编辑的抗酶抑制剂1:一种潜在的基于寡核苷酸的癌症反义治疗方法。

IF 12.4

Molecular therapy : the journal of the American Society of Gene Therapy Pub Date : 2021-11-03 Epub Date: 2021-05-08 DOI: 10.1016/j.ymthe.2021.05.008

Daryl Jin Tai Tay, Yangyang Song, Boya Peng, Tan Boon Toh, Lissa Hooi, Desiree-Faye Kaixin Toh, HuiQi Hong, Sze Jing Tang, Jian Han, Wei Liang Gan, Tim Hon Man Chan, Manchugondanahalli S Krishna, Kiran M Patil, Manikantha Maraswami, Teck Peng Loh, Yock Young Dan, Lei Zhou, Glenn Kunnath Bonney, Pierce Kah-Hoe Chow, Gang Chen, Edward Kai-Hua Chow, Minh T N Le, Leilei Chen

{"title":"Targeting RNA editing of antizyme inhibitor 1: A potential oligonucleotide-based antisense therapy for cancer.","authors":"Daryl Jin Tai Tay, Yangyang Song, Boya Peng, Tan Boon Toh, Lissa Hooi, Desiree-Faye Kaixin Toh, HuiQi Hong, Sze Jing Tang, Jian Han, Wei Liang Gan, Tim Hon Man Chan, Manchugondanahalli S Krishna, Kiran M Patil, Manikantha Maraswami, Teck Peng Loh, Yock Young Dan, Lei Zhou, Glenn Kunnath Bonney, Pierce Kah-Hoe Chow, Gang Chen, Edward Kai-Hua Chow, Minh T N Le, Leilei Chen","doi":"10.1016/j.ymthe.2021.05.008","DOIUrl":"https://doi.org/10.1016/j.ymthe.2021.05.008","url":null,"abstract":"Dysregulated adenosine-to-inosine (A-to-I) RNA editing is implicated in various cancers. However, no available RNA editing inhibitors have so far been developed to inhibit cancer-associated RNA editing events. Here, we decipher the RNA secondary structure of antizyme inhibitor 1 (AZIN1), one of the best-studied A-to-I editing targets in cancer, by locating its editing site complementary sequence (ECS) at the 3' end of exon 12. Chemically modified antisense oligonucleotides (ASOs) that target the editing region of AZIN1 caused a substantial exon 11 skipping, whereas ECS-targeting ASOs effectively abolished AZIN1 editing without affecting splicing and translation. We demonstrate that complete 2'-O-methyl (2'-O-Me) sugar ring modification in combination with partial phosphorothioate (PS) backbone modification may be an optimal chemistry for editing inhibition. ASO3.2, which targets the ECS, specifically inhibits cancer cell viability in vitro and tumor incidence and growth in xenograft models. Our results demonstrate that this AZIN1-targeting, ASO-based therapeutics may be applicable to a wide range of tumor types.","PeriodicalId":519519,"journal":{"name":"Molecular therapy : the journal of the American Society of Gene Therapy","volume":" ","pages":"3258-3273"},"PeriodicalIF":12.4,"publicationDate":"2021-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ymthe.2021.05.008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38889187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

ZFN-mediated in vivo gene editing in hepatocytes leads to supraphysiologic α-Gal A activity and effective substrate reduction in Fabry mice. zfn介导的肝细胞内基因编辑导致Fabry小鼠的超生理α-Gal A活性和有效底物减少。

IF 12.4

Molecular therapy : the journal of the American Society of Gene Therapy Pub Date : 2021-11-03 Epub Date: 2021-03-26 DOI: 10.1016/j.ymthe.2021.03.018

Silvere Pagant, Marshall W Huston, Luciana Moreira, Lin Gan, Susan St Martin, Scott Sproul, Michael C Holmes, Kathleen Meyer, Thomas Wechsler, Robert J Desnick, Makiko Yasuda

{"title":"ZFN-mediated in vivo gene editing in hepatocytes leads to supraphysiologic α-Gal A activity and effective substrate reduction in Fabry mice.","authors":"Silvere Pagant, Marshall W Huston, Luciana Moreira, Lin Gan, Susan St Martin, Scott Sproul, Michael C Holmes, Kathleen Meyer, Thomas Wechsler, Robert J Desnick, Makiko Yasuda","doi":"10.1016/j.ymthe.2021.03.018","DOIUrl":"https://doi.org/10.1016/j.ymthe.2021.03.018","url":null,"abstract":"Fabry disease, a lysosomal storage disorder resulting from the deficient activity of α-galactosidase A (α-Gal A), is characterized by cardiac, renal, and/or cerebrovascular disease due to progressive accumulation of the enzyme's substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). We report here the preclinical evaluation of liver-targeted in vivo genome editing using zinc-finger nuclease (ZFN) technology to insert the human α-galactosidase A (hGLA) cDNA into the albumin \"safe harbor\" locus of Fabry mice, thereby generating an albumin-α-Gal A fusion protein. The mature α-Gal A protein is secreted into the circulation for subsequent mannose-6-phosphate receptor-mediated tissue uptake. Donor vector optimization studies showed that replacing the hGLA cDNA signal peptide sequence with that of human iduronate 2-sulfatase (IDS) achieved higher transgene expression. Intravenous adeno-associated virus (AAV) 2/8-mediated co-delivery of the IDS-hGLA donor and ZFNs targeting the albumin locus resulted in continuous, supraphysiological plasma and tissue α-Gal A activities, which essentially normalized Gb3 and Lyso-Gb3 levels in key tissues of pathology. Notably, this was achieved with <10% of hepatocytes being edited to express hGLA, occurring mostly via non-homologous end joining (NHEJ) rather than homology-directed repair (HDR). These studies indicate that ZFN-mediated in vivo genome editing has the potential to be an effective one-time therapy for Fabry disease.","PeriodicalId":519519,"journal":{"name":"Molecular therapy : the journal of the American Society of Gene Therapy","volume":" ","pages":"3230-3242"},"PeriodicalIF":12.4,"publicationDate":"2021-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ymthe.2021.03.018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25525893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7