Molecular Therapy最新文献_第4页

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

Promoting readthrough of nonsense mutations in CF mouse model: Biodistribution and efficacy of NV848 in rescuing CFTR protein expression. 促进囊性纤维化小鼠模型中无义突变的转化通路：评估 NV848 1,2,4-恶二唑化合物在挽救 CFTR 蛋白表达方面的生物分布和疗效。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI: 10.1016/j.ymthe.2024.10.028

Ignazio Fiduccia, Federica Corrao, Maria Grazia Zizzo, Riccardo Perriera, Francesco Genovese, Emanuele Vitale, Davide Ricci, Raffaella Melfi, Marco Tutone, Andrea Pace, Laura Lentini, Ivana Pibiri

{"title":"Promoting readthrough of nonsense mutations in CF mouse model: Biodistribution and efficacy of NV848 in rescuing CFTR protein expression.","authors":"Ignazio Fiduccia, Federica Corrao, Maria Grazia Zizzo, Riccardo Perriera, Francesco Genovese, Emanuele Vitale, Davide Ricci, Raffaella Melfi, Marco Tutone, Andrea Pace, Laura Lentini, Ivana Pibiri","doi":"10.1016/j.ymthe.2024.10.028","DOIUrl":"10.1016/j.ymthe.2024.10.028","url":null,"abstract":"Nonsense mutations, often resulting from single-nucleotide substitutions, produce mRNA harboring a premature termination codon (PTC), which causes the premature termination of protein synthesis. This produces truncated and non-functional proteins, which cause different genetic diseases, including cystic fibrosis (CF). This work aims to investigate the ability of NV848 (N-(5-methyl-1,2,4-oxadiazol-3-yl)acetamide), a translational readthrough-inducing drug (TRID), to rescue CF transmembrane conductance regulator (CFTR) protein expression in a murine model characterized by the G542X nonsense mutation in the CFTR gene. In vitro experiments assessed the drug's stability in human hepatic metabolism, and in vivo investigations on wild-type mice allowed us to clarify the distribution of the drug to the target organs. Moreover, its efficacy in recovering the CFTR protein after chronic treatment was assessed in G542X homozygous mice. Our results provide valuable insights into the biodistribution and therapeutic attributes of NV848, representing a promising therapeutic tool for enhanced clinical outcomes in individuals affected by CF with nonsense mutations.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4514-4523"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638873/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546496","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

Enhanced mucosal SARS-CoV-2 immunity after heterologous intramuscular mRNA prime/intranasal protein boost vaccination with a combination adjuvant. 使用复合佐剂进行异源肌肉注射 mRNA 原体/鼻内蛋白增强疫苗接种后，增强了针对 SARS-CoV-2 的粘膜抗体和 T 细胞反应。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI: 10.1016/j.ymthe.2024.10.016

Gabriel Laghlali, Matthew J Wiest, Dilara Karadag, Prajakta Warang, Jessica J O'Konek, Lauren A Chang, Seok-Chan Park, Vivian Yan, Mohammad Farazuddin, Katarzyna W Janczak, Adolfo García-Sastre, James R Baker, Pamela T Wong, Michael Schotsaert

{"title":"Enhanced mucosal SARS-CoV-2 immunity after heterologous intramuscular mRNA prime/intranasal protein boost vaccination with a combination adjuvant.","authors":"Gabriel Laghlali, Matthew J Wiest, Dilara Karadag, Prajakta Warang, Jessica J O'Konek, Lauren A Chang, Seok-Chan Park, Vivian Yan, Mohammad Farazuddin, Katarzyna W Janczak, Adolfo García-Sastre, James R Baker, Pamela T Wong, Michael Schotsaert","doi":"10.1016/j.ymthe.2024.10.016","DOIUrl":"10.1016/j.ymthe.2024.10.016","url":null,"abstract":"Current COVID-19 mRNA vaccines delivered intramuscularly (IM) induce effective systemic immunity, but with suboptimal immunity at mucosal sites, limiting their ability to impart sterilizing immunity. There is strong interest in rerouting immune responses induced in the periphery by parenteral vaccination to the portal entry site of respiratory viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), by mucosal vaccination. We previously demonstrated the combination adjuvant, NE/IVT, consisting of a nanoemulsion (NE) and an RNA-based RIG-I agonist (IVT) induces potent systemic and mucosal immune responses in protein-based SARS-CoV-2 vaccines administered intranasally (IN). Herein, we demonstrate priming IM with mRNA followed by heterologous IN boosting with NE/IVT adjuvanted recombinant antigen induces strong mucosal and systemic antibody responses and enhances antigen-specific T cell responses in mucosa-draining lymph nodes compared to IM/IM and IN/IN prime/boost regimens. While all regimens induced cross-neutralizing antibodies against divergent variants and sterilizing immunity in the lungs of challenged mice, mucosal vaccination, either as homologous prime/boost or heterologous IN boost after IM mRNA prime, was required to impart sterilizing immunity in the upper respiratory tract. Our data demonstrate the benefit of hybrid regimens whereby strong immune responses primed via IM vaccination are rerouted by IN vaccination to mucosal sites to provide optimal protection against SARS-CoV-2.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4448-4466"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569271","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

N6-Methyladenosine modification activates the serine synthesis pathway to mediate therapeutic resistance in liver cancer. N6-甲基腺苷（m6A）修饰激活丝氨酸合成途径，介导肝癌的耐药性。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-26 DOI: 10.1016/j.ymthe.2024.10.025

For-Fan Chan, Kenneth Kin-Leung Kwan, Do-Hyun Seoung, Don Wai-Ching Chin, Irene Oi-Lin Ng, Carmen Chak-Lui Wong, Chun-Ming Wong

{"title":"N6-Methyladenosine modification activates the serine synthesis pathway to mediate therapeutic resistance in liver cancer.","authors":"For-Fan Chan, Kenneth Kin-Leung Kwan, Do-Hyun Seoung, Don Wai-Ching Chin, Irene Oi-Lin Ng, Carmen Chak-Lui Wong, Chun-Ming Wong","doi":"10.1016/j.ymthe.2024.10.025","DOIUrl":"10.1016/j.ymthe.2024.10.025","url":null,"abstract":"Metabolic adaptation serves as a significant driving force for cancer growth and poses a substantial obstacle for cancer therapies. Herein, we unraveled the role of m6A-mediated serine synthesis pathway (SSP) regulation in both hepatocellular carcinoma (HCC) development and therapeutic resistance. We demonstrated that treatment of highly specific m6A inhibitor (STM2457) effectively inhibited HCC cell line growth and suppressed spontaneous HCC formation in mice driven by liver-specific Tp53 knockout and Myc overexpression. Using GLORI-seq, we delineated a single-base-resolution m6A landscape in human HCC cell lines. Interestingly, we identified three core enzymes in the SSP (PHGDH, PSAT1, and PSPH) as novel targets of METTL3-mediated m6A modification. In these SSP genes, m6A modification recruited m6A reader IGF2BP3 to stabilize their mRNA transcripts, thereby enhancing their mRNA and protein expression in HCC cells. Most importantly, our GLORI-seq data revealed that sorafenib-resistant HCC cells elevated m6A modification in SSP genes to promote protein expression and antioxidant production. STM2457 treatment attenuated the serine synthesis pathway, induced oxidative stress, and sensitized HCC cells to sorafenib and lenvatinib treatments. In conclusion, our findings suggest that targeting m6A could be a potential therapeutic strategy for HCC treatment.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4435-4447"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638877/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569293","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

Not all carbs are bad for the kidney. 并非所有碳水化合物都对肾脏有害。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-11-19 DOI: 10.1016/j.ymthe.2024.11.006

G Luca Gusella

引用次数: 0

Dual CRALBP isoforms unveiled: iPSC-derived retinal modeling and AAV2/5-RLBP1 gene transfer raise considerations for effective therapy. 揭示双重 CRALBP 同工酶：iPSC 衍生视网膜模型和 AAV2/5-RLBP1 基因转移为有效治疗提供了考虑因素。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-09 DOI: 10.1016/j.ymthe.2024.10.004

Krishna Damodar, Gregor Dubois, Laurent Guillou, Daria Mamaeva, Marie Pequignot, Nejla Erkilic, Carla Sanjurjo-Soriano, Hassan Boukhaddaoui, Florence Bernex, Béatrice Bocquet, Jérôme Vialaret, Yvan Arsenijevic, T Michael Redmond, Christopher Hirtz, Isabelle Meunier, Philippe Brabet, Vasiliki Kalatzis

{"title":"Dual CRALBP isoforms unveiled: iPSC-derived retinal modeling and AAV2/5-RLBP1 gene transfer raise considerations for effective therapy.","authors":"Krishna Damodar, Gregor Dubois, Laurent Guillou, Daria Mamaeva, Marie Pequignot, Nejla Erkilic, Carla Sanjurjo-Soriano, Hassan Boukhaddaoui, Florence Bernex, Béatrice Bocquet, Jérôme Vialaret, Yvan Arsenijevic, T Michael Redmond, Christopher Hirtz, Isabelle Meunier, Philippe Brabet, Vasiliki Kalatzis","doi":"10.1016/j.ymthe.2024.10.004","DOIUrl":"10.1016/j.ymthe.2024.10.004","url":null,"abstract":"Inherited retinal diseases (IRDs) are characterized by progressive vision loss. There are over 270 causative IRD genes, and variants within the same gene can cause clinically distinct disorders. One example is RLBP1, which encodes CRALBP. CRALBP is an essential protein in the rod and cone visual cycles that take place primarily in the retinal pigment epithelium (RPE) but also in Müller cells of the neuroretina. RLBP1 variants lead to three clinical subtypes: Bothnia dystrophy, retinitis punctata albescens, and Newfoundland rod-cone dystrophy. We modeled RLBP1-IRD subtypes using patient-specific induced pluripotent stem cell (iPSC)-derived RPE and identified pathophysiological markers that served as pertinent therapeutic read-outs. We developed an AAV2/5-mediated gene-supplementation strategy and performed a proof-of-concept study in the human models, which was validated in vivo in an Rlbp1-/- murine model. Most importantly, we identified a previously unsuspected smaller CRALBP isoform that is naturally and differentially expressed both in the human and murine retina. This previously unidentified isoform is produced from an alternative methionine initiation site. This work provides further insights into CRALBP expression and RLBP1-associated pathophysiology and raises important considerations for successful gene-supplementation therapy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4319-4336"},"PeriodicalIF":12.1,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11638835/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391978","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