Molecular Therapy最新文献_第3页

Exploring methyl-verse: dynamic interplay of epigenome and m6A epitranscriptome.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-09 DOI: 10.1016/j.ymthe.2024.12.003

Katerina-Marina Pilala, Konstantina Panoutsopoulou, Maria-Alexandra Papadimitriou, Konstantinos Soureas, Andreas Scorilas, Margaritis Avgeris

{"title":"Exploring methyl-verse: dynamic interplay of epigenome and m6A epitranscriptome.","authors":"Katerina-Marina Pilala, Konstantina Panoutsopoulou, Maria-Alexandra Papadimitriou, Konstantinos Soureas, Andreas Scorilas, Margaritis Avgeris","doi":"10.1016/j.ymthe.2024.12.003","DOIUrl":"https://doi.org/10.1016/j.ymthe.2024.12.003","url":null,"abstract":"The orchestration of dynamic epigenetic and epitranscriptomic modifications is pivotal for the fine-tuning of gene expression. However, they are traditionally being examined independently. Recent compelling studies have disclosed an interesting communication and interplay between m6A RNA methylation (m6A epitranscriptome) and epigenetic modifications, enabling the formation of feedback circuits and cooperative networks. Intriguingly, the interaction between m6A and DNA methylation machinery, coupled with the crosstalk between m6A RNA and histone modifications shapes the transcriptional profile and translational efficiency. Moreover, m6A modifications interact also with non-coding RNAs, modulating their stability, abundance, and regulatory functions. In the light of those findings, m6A imprinting acts as a versatile checkpoint, linking epigenetic and epitranscriptomic layers towards a multilayer and time-dependent control of gene expression and cellular homeostasis. The scope of the present review is to decipher the m6A-coordinated circuits with DNA imprinting, chromatin architecture and non-coding RNAs networks in normal physiology and carcinogenesis. Ultimately, we summarize the development of innovative CRISPR/dCas engineering platforms fused with m6A catalytic components (m6A writers or erasers) to achieve transcript-specific editing of m6A epitranscriptome that can pave new insights in modern RNA therapeutics.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":12.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142807856","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

R-loops facilitate AAV-mediated nuclease-free gene targeting. R 环促进了 AAV 介导的无核酸酶基因靶向。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-11-13 DOI: 10.1016/j.ymthe.2024.10.030

Bryan Hu, Roland W Herzog, Dongsheng Duan

引用次数: 0

Harnessing gene therapy for liver metabolic dysfunction: An innovative approach to MASH treatment. 利用基因疗法治疗肝脏代谢功能障碍：治疗 MASH 的创新方法。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-11-15 DOI: 10.1016/j.ymthe.2024.11.002

Carmen Unzu, Maite G Fernández-Barrena

引用次数: 0

ANGPTL4-mediated inflammation: A new mechanism of disease and therapeutic approach for rheumatoid arthritis. ANGPTL4 介导的炎症：类风湿性关节炎的新发病机制和治疗方法。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-11-17 DOI: 10.1016/j.ymthe.2024.11.001

Ivan Duran

引用次数: 0

Improving efficacy of in vivo therapy of sickle cell disease by hijacking natural biology of hematopoietic stem cells. 通过劫持造血干细胞的自然生物学特性，提高镰状细胞病体内疗法的疗效。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-11-21 DOI: 10.1016/j.ymthe.2024.11.007

Jia Yao, Dmitry M Shayakhmetov

引用次数: 0

Quantifying and mitigating motor phenotypes induced by antisense oligonucleotides in the central nervous system. 量化和减轻反义寡核苷酸在中枢神经系统中诱导的运动表型

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI: 10.1016/j.ymthe.2024.10.024

Michael P Moazami, Julia M Rembetsy-Brown, Samantha L Sarli, Holly R McEachern, Feng Wang, Masahiro Ohara, Atish Wagh, Karen Kelly, Pranathi Meda Krishnamurthy, Alexandra Weiss, Miklos Marosfoi, Robert M King, Mona Motwani, Heather Gray-Edwards, Katherine A Fitzgerald, Robert H Brown, Jonathan K Watts

{"title":"Quantifying and mitigating motor phenotypes induced by antisense oligonucleotides in the central nervous system.","authors":"Michael P Moazami, Julia M Rembetsy-Brown, Samantha L Sarli, Holly R McEachern, Feng Wang, Masahiro Ohara, Atish Wagh, Karen Kelly, Pranathi Meda Krishnamurthy, Alexandra Weiss, Miklos Marosfoi, Robert M King, Mona Motwani, Heather Gray-Edwards, Katherine A Fitzgerald, Robert H Brown, Jonathan K Watts","doi":"10.1016/j.ymthe.2024.10.024","DOIUrl":"10.1016/j.ymthe.2024.10.024","url":null,"abstract":"Antisense oligonucleotides (ASOs) are emerging as a promising class of therapeutics for neurological diseases. When injected directly into cerebrospinal fluid, ASOs distribute broadly across brain regions and exert long-lasting therapeutic effects. However, many phosphorothioate (PS)-modified gapmer ASOs show transient motor phenotypes when injected into the cerebrospinal fluid, ranging from reduced motor activity to ataxia or acute seizure-like phenotypes. Using a behavioral scoring assay customized to reflect the timing and nature of these effects, we show that both sugar and phosphate modifications influence acute motor phenotypes. Among sugar analogs, DNA induces the strongest motor phenotypes while 2'-substituted RNA modifications improve the tolerability of PS ASOs. Reducing the PS content of gapmer ASOs, which contain a stretch of PS-DNA, improves their toxicity profile, but in some cases also reduces efficacy or duration of effect. We show that this acute toxicity is not mediated by major nucleic acid sensing immune pathways. Formulating ASOs with divalent ions before injection and avoiding phosphate-based buffers modestly improved tolerability through mechanisms at least partially distinct from reduced PS content. Overall, our work identifies and quantifies an understudied aspect of oligonucleotide toxicology in the CNS, explores its mechanism, and presents platform-level medicinal chemistry and formulation approaches that improve tolerability of this class of compounds.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4401-4417"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142504555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bone-protective effects of neutralizing angiopoietin-like protein 4 monoclonal antibody in rheumatoid arthritis. 中和血管生成素样蛋白 4 单克隆抗体对类风湿性关节炎患者骨骼的保护作用。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-04 DOI: 10.1016/j.ymthe.2024.09.031

Liqing Ke, Qifei He, Jing Qu, Xiyue Wang, Kaibo Li, Xun Gong, Lan Li, Jiake Xu, Qiuliyang Yu, Hao Yu, Xuefei Lin, Jian Li, Nguan Soon Tan, Wei Sun, Liang Li, Peng Zhang, Wenxiang Cheng

{"title":"Bone-protective effects of neutralizing angiopoietin-like protein 4 monoclonal antibody in rheumatoid arthritis.","authors":"Liqing Ke, Qifei He, Jing Qu, Xiyue Wang, Kaibo Li, Xun Gong, Lan Li, Jiake Xu, Qiuliyang Yu, Hao Yu, Xuefei Lin, Jian Li, Nguan Soon Tan, Wei Sun, Liang Li, Peng Zhang, Wenxiang Cheng","doi":"10.1016/j.ymthe.2024.09.031","DOIUrl":"10.1016/j.ymthe.2024.09.031","url":null,"abstract":"Despite recent advances, rheumatoid arthritis (RA) patients remain refractory to therapy. Dysregulated overproduction of angiopoietin-like protein 4 (ANGPTL4) is thought to contribute to the disease development. ANGPTL4 was initially identified as a regulator of lipid metabolism, which is hydrolyzed to N-terminal and C-terminal (cANGPTL4) fragments in vivo. cANGPTL4 is involved in several non-lipid-related processes, including angiogenesis and inflammation. This study revealed that the level of ANGPTL4 was markedly elevated in the sera and synovial tissues from patients with RA versus controls. The administration of a neutralizing antibody against cANGPTL4 (anti-cANGPTL4 Ab) resulted in the inhibition of inflammatory processes and bone loss in animal models of collagen-induced arthritis and adjuvant-induced arthritis (AIA). Transcriptomic and proteomic profiling of synovial tissues from an AIA model indicated that the anti-cANGPTL4 Ab inhibited fibroblast-like synoviocyte (FLS) immigration and inflammatory-induced osteoclastogenesis. Mechanistically, the anti-cANGPTL4 Ab has been shown to inhibit TNF-α-induced inflammatory cascades in RA-FLS through the sirtuin 1/nuclear factor-κB signaling pathway. Moreover, the anti-cANGPTL4 Ab was found to block FLS invasion- and immigration-induced osteoclast activation. Collectively, these findings identify ANGPTL4 as a prospective biomarker for the diagnosis of RA, and targeting cANGPTL4 should represent a potential therapeutic strategy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4497-4513"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Liver-directed AAV gene therapy normalizes disease symptoms and provides cross-correction in a model of lysosomal acid lipase deficiency. 肝脏定向 AAV 基因疗法可使溶酶体酸性脂肪酶缺乏症小鼠模型的疾病症状正常化并提供交叉校正。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI: 10.1016/j.ymthe.2024.10.022

Patricia Lam, Deborah A Zygmunt, Anna Ashbrook, Cong Yan, Hong Du, Paul T Martin

{"title":"Liver-directed AAV gene therapy normalizes disease symptoms and provides cross-correction in a model of lysosomal acid lipase deficiency.","authors":"Patricia Lam, Deborah A Zygmunt, Anna Ashbrook, Cong Yan, Hong Du, Paul T Martin","doi":"10.1016/j.ymthe.2024.10.022","DOIUrl":"10.1016/j.ymthe.2024.10.022","url":null,"abstract":"Lysosomal acid lipase deficiency (LAL-D) is caused by mutations in the LIPA gene, which encodes the lysosomal enzyme that hydrolyzes triglycerides and cholesteryl esters to free fatty acids and free cholesterol. The objective of this study was to develop a curative single-treatment therapy for LAL-D using adeno-associated virus (AAV). Treatment at both early (1-2 days) and late (8-week) timepoints with rscAAVrh74.LP1.LIPA, a liver-directed AAV gene therapy, normalized many disease measures in Lipa-/- mice when measured at 24 weeks of age, including hepatosplenomegaly, serum transaminase activity, organ triglyceride and cholesterol levels, and biomarkers of liver inflammation and fibrosis. For most measures, liver-directed therapy was superior to therapy utilizing a constitutive tissue expression approach. rscAAVrh74.LP1.LIPA treatment elevated LAL enzyme activity above wild-type levels in all tissues tested, including liver, spleen, intestine, muscle, and brain, and treatment elicited minimal serum antibody responses to transgenic protein. AAV treatment at 8 weeks of age with 1 × 1013 vg/kg extended survival significantly, with all AAV-treated mice surviving beyond the maximal lifespan of untreated Lipa-/- mice. These results show that this liver-directed LIPA gene therapy has the potential to be a transformative treatment for LAL-D.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4272-4284"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of artificial transcription factors and their applications in cell reprograming, genetic screen, and disease treatment. 人工转录因子：技术开发及在细胞重编程、基因筛选和疾病治疗中的应用。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI: 10.1016/j.ymthe.2024.10.029

Yetong Sang, Lingjie Xu, Zehua Bao

{"title":"Development of artificial transcription factors and their applications in cell reprograming, genetic screen, and disease treatment.","authors":"Yetong Sang, Lingjie Xu, Zehua Bao","doi":"10.1016/j.ymthe.2024.10.029","DOIUrl":"10.1016/j.ymthe.2024.10.029","url":null,"abstract":"Gene dysregulations are associated with many human diseases, such as cancers and hereditary diseases. Artificial transcription factors (ATFs) are synthetic molecular tools to regulate the expression of disease-associated genes, which is of great significance in basic biological research and biomedical applications. Recent advances in the engineering of ATFs for regulating endogenous gene expression provide an expanded set of tools for understanding and treating diseases. However, the potential immunogenicity, large size, inefficient delivery, and off-target effects persist as obstacles for ATFs to be developed into therapeutics. Moreover, the activation of an endogenous gene following ATF activity lacks durability. In this review, we first describe the functional components of ATFs, including DNA-binding domains, transcriptional effector domains, and control switches. We then highlight examples of applications of ATFs, including cell reprogramming and differentiation, pathogenic gene screening, and disease treatment. Finally, we analyze and summarize major challenges for the clinical translation of ATFs and propose potential strategies to improve these useful molecular tools.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4208-4234"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546494","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AAV-mediated genome editing is influenced by the formation of R-loops. AAV 介导的基因组编辑受 R 环形成的影响。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-05 DOI: 10.1016/j.ymthe.2024.09.035

Francesco Puzzo, Magdalena P Crossley, Aranyak Goswami, Feijie Zhang, Katja Pekrun, Jada L Garzon, Karlene A Cimprich, Mark A Kay

{"title":"AAV-mediated genome editing is influenced by the formation of R-loops.","authors":"Francesco Puzzo, Magdalena P Crossley, Aranyak Goswami, Feijie Zhang, Katja Pekrun, Jada L Garzon, Karlene A Cimprich, Mark A Kay","doi":"10.1016/j.ymthe.2024.09.035","DOIUrl":"10.1016/j.ymthe.2024.09.035","url":null,"abstract":"Recombinant adeno-associated viral vectors (rAAV) hold an intrinsic ability to stimulate homologous recombination (AAV-HR) and are the most used in clinical settings for in vivo gene therapy. However, rAAVs also integrate throughout the genome. Here, we describe DNA-RNA immunoprecipitation sequencing (DRIP-seq) in murine HEPA1-6 hepatoma cells and whole murine liver to establish the similarities and differences in genomic R-loop formation in a transformed cell line and intact tissue. We show enhanced AAV-HR in mice upon genetic and pharmacological upregulation of R-loops. Selecting the highly expressed Albumin gene as a model locus for genome editing in both in vitro and in vivo experiments showed that the R-loop prone 3' end of Albumin was efficiently edited by AAV-HR, whereas the upstream R-loop-deficient region did not result in detectable vector integration. In addition, we found a positive correlation between previously reported off-target rAAV integration sites and R-loop enriched genomic regions. Thus, we conclude that high levels of R-loops, present in highly transcribed genes, may promote rAAV vector genome integration. These findings may shed light on potential mechanisms for improving the safety and efficacy of genome editing by modulating R-loops and may enhance our ability to predict regions most susceptible to off-target insertional mutagenesis by rAAV vectors.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4256-4271"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0