Molecular Therapy最新文献_第10页

Gene therapy trial lights the way for patients with Leber congenital amaurosis 1. 基因治疗试验为莱伯先天性无脑症患者指明了方向 1.

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-10-26 DOI: 10.1016/j.ymthe.2024.10.014

Ying Kai Chan

引用次数: 0

Novel treatment for PXE: Recombinant ENPP1 enzyme therapy. PXE 的新疗法：重组 ENPP1 酶疗法。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-09-27 DOI: 10.1016/j.ymthe.2024.09.028

Ida Joely Jacobs, Dora Obiri-Yeboah, Paul R Stabach, Demetrios T Braddock, Qiaoli Li

{"title":"Novel treatment for PXE: Recombinant ENPP1 enzyme therapy.","authors":"Ida Joely Jacobs, Dora Obiri-Yeboah, Paul R Stabach, Demetrios T Braddock, Qiaoli Li","doi":"10.1016/j.ymthe.2024.09.028","DOIUrl":"10.1016/j.ymthe.2024.09.028","url":null,"abstract":"Pseudoxanthoma elasticum (PXE) is a genetic multisystem ectopic calcification disorder caused by inactivating mutations in the ABCC6 gene encoding ABCC6, a hepatic efflux transporter. ABCC6-mediated ATP secretion by the liver is the main source of a potent endogenous calcification inhibitor, plasma inorganic pyrophosphate (PPi); the deficiency of plasma PPi underpins PXE. Recent studies demonstrated that INZ-701, a recombinant human ENPP1 that generates PPi and is now in clinical trials, restored plasma PPi levels and prevented ectopic calcification in the muzzle skin of Abcc6-/-mice. This study examined the pharmacokinetics, pharmacodynamics, and potency of a new ENPP1-Fc isoform, BL-1118, in Abcc6-/- mice. When Abcc6-/- mice received a single subcutaneous injection of BL-1118 at 0.25, 0.5, or 1 mg/kg, they had dose-dependent elevations in plasma ENPP1 enzyme activity and PPi levels, with an enzyme half-life of approximately 100 h. When Abcc6-/- mice were injected weekly from 5 to 15 weeks of age, BL-1118 dose-dependently increased steady-state plasma ENPP1 activity and PPi levels and significantly reduced ectopic calcification in the muzzle skin and kidneys. These results suggest that BL-1118 is a promising second generation enzyme therapy for PXE, the first generation of which is currently in clinical testing.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3815-3820"},"PeriodicalIF":12.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573614/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350559","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

Unveiling the relevance of immune checkpoints for innate and adaptive response to hepatocellular carcinoma using improved model of humanized mice. 利用改进的人源化小鼠模型，揭示免疫检查点与肝细胞癌的先天性和适应性反应的相关性。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-10-29 DOI: 10.1016/j.ymthe.2024.10.007

Angel Porgador

引用次数: 0

Transcriptional orchestration of EMT: Unraveling novel molecular targets in pulmonary fibrosis. EMT 的转录协调：揭示肺纤维化中的新型分子靶标。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-10-28 DOI: 10.1016/j.ymthe.2024.10.012

Sylwia Bobis-Wozowicz, Milena Paw

引用次数: 0

Urinary Extracellular Vesicles Carrying Klotho Improve the Recovery of Renal Function in an Acute Tubular Injury Model. 携带 Klotho 的尿液细胞外小泡能改善急性肾小管损伤模型中肾功能的恢复。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-09-17 DOI: 10.1016/j.ymthe.2024.09.018

Cristina Grange, Elli Papadimitriou, Veronica Dimuccio, Cecilia Pastorino, Jordi Molina, Ryan O'Kelly, Laura J Niedernhofer, Paul D Robbins, Giovanni Camussi, Benedetta Bussolati

引用次数: 0

On RNA-programmable gene modulation as a versatile set of principles targeting muscular dystrophies. 将 RNA 可编程基因调控作为针对肌肉萎缩症的一套通用原则。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-08-22 DOI: 10.1016/j.ymthe.2024.08.016

Sabrina Capelletti, Sofía C García Soto, Manuel A F V Gonçalves

{"title":"On RNA-programmable gene modulation as a versatile set of principles targeting muscular dystrophies.","authors":"Sabrina Capelletti, Sofía C García Soto, Manuel A F V Gonçalves","doi":"10.1016/j.ymthe.2024.08.016","DOIUrl":"10.1016/j.ymthe.2024.08.016","url":null,"abstract":"The repurposing of RNA-programmable CRISPR systems from genome editing into epigenome editing tools is gaining pace, including in research and development efforts directed at tackling human disorders. This momentum stems from the increasing knowledge regarding the epigenetic factors and networks underlying cell physiology and disease etiology and from the growing realization that genome editing principles involving chromosomal breaks generated by programmable nucleases are prone to unpredictable genetic changes and outcomes. Hence, engineered CRISPR systems are serving as versatile DNA-targeting scaffolds for heterologous and synthetic effector domains that, via locally recruiting transcription factors and chromatin remodeling complexes, seek interfering with loss-of-function and gain-of-function processes underlying recessive and dominant disorders, respectively. Here, after providing an overview about epigenetic drugs and CRISPR-Cas-based activation and interference platforms, we cover the testing of these platforms in the context of molecular therapies for muscular dystrophies. Finally, we examine attributes, obstacles, and deployment opportunities for CRISPR-based epigenetic modulating technologies.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3793-3807"},"PeriodicalIF":12.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018091","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

Expanding CAR-engineered cell therapies into autoimmune diseases. 将 CAR 工程细胞疗法推广到自身免疫性疾病领域。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-10-28 DOI: 10.1016/j.ymthe.2024.10.011

Shon Green

引用次数: 0

Prevention of prostate cancer metastasis by a CRISPR-delivering nanoplatform for interleukin-30 genome editing. 通过CRISPR递送纳米平台进行白细胞介素-30基因组编辑，预防前列腺癌转移。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-09-07 DOI: 10.1016/j.ymthe.2024.09.011

Cristiano Fieni, Stefania Livia Ciummo, Carlo Sorrentino, Simona Marchetti, Simone Vespa, Paola Lanuti, Lavinia Vittoria Lotti, Emma Di Carlo

{"title":"Prevention of prostate cancer metastasis by a CRISPR-delivering nanoplatform for interleukin-30 genome editing.","authors":"Cristiano Fieni, Stefania Livia Ciummo, Carlo Sorrentino, Simona Marchetti, Simone Vespa, Paola Lanuti, Lavinia Vittoria Lotti, Emma Di Carlo","doi":"10.1016/j.ymthe.2024.09.011","DOIUrl":"10.1016/j.ymthe.2024.09.011","url":null,"abstract":"Prostate cancer (PC) is a leading cause of cancer-related deaths in men worldwide. Interleukin-30 (IL-30) is a PC progression driver, and its suppression would be strategic for fighting metastatic disease. Biocompatible lipid nanoparticles (NPs) were loaded with CRISPR-Cas9gRNA to delete the human IL30 (hIL30) gene and functionalized with anti-PSCA-Abs (Cas9hIL30-PSCA NPs). Efficiency of the NPs in targeting IL-30 and the metastatic potential of PC cells was examined in vivo in xenograft models of lung metastasis, and in vitro by using two organ-on-chip (2-OC)-containing 3D spheroids of IL30+ PC-endothelial cell co-cultures in circuit with either lung-mimicking spheroids or bone marrow (BM)-niche-mimicking scaffolds. Cas9hIL30-PSCA NPs demonstrated circulation stability, genome editing efficiency, without off-target effects and organ toxicity. Intravenous injection of three doses/13 days, or five doses/20 days, of NPs in mice bearing circulating PC cells and tumor microemboli substantially hindered lung metastasization. Cas9hIL30-PSCA NPs inhibited PC cell proliferation and expression of IL-30 and metastasis drivers, such as CXCR2, CXCR4, IGF1, L1CAM, METAP2, MMP2, and TNFSF10, whereas CDH1 was upregulated. PC-Lung and PC-BM 2-OCs revealed that Cas9hIL30-PSCA NPs suppressed PC cell release of CXCL2/GROβ, which was associated with intra-metastatic myeloid cell infiltrates, and of DKK1, OPG, and IL-6, which boosted endothelial network formation and cancer cell migration. Development of a patient-tailored nanoplatform for selective CRISPR-mediated IL-30 gene deletion is a clinically valuable tool against PC progression.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3932-3954"},"PeriodicalIF":12.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573607/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146005","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

Case study of CD19 CAR T therapy in a subject with immune-mediate necrotizing myopathy treated in the RESET-Myositis phase I/II trial. 在 RESET-Myositis™ I/II 期试验中对一名免疫性中度坏死性肌病患者进行 CD19 引导嵌合抗原受体 T 细胞疗法的病例研究。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-09-07 DOI: 10.1016/j.ymthe.2024.09.009

Jenell Volkov, Daniel Nunez, Tahseen Mozaffar, Jason Stadanlick, Mallorie Werner, Zachary Vorndran, Alexandra Ellis, Jazmean Williams, Justin Cicarelli, Quynh Lam, Thomas Furmanak, Chris Schmitt, Fatemeh Hadi-Nezhad, Daniel Thompson, Claire Miller, Courtney Little, David Chang, Samik Basu

{"title":"Case study of CD19 CAR T therapy in a subject with immune-mediate necrotizing myopathy treated in the RESET-Myositis phase I/II trial.","authors":"Jenell Volkov, Daniel Nunez, Tahseen Mozaffar, Jason Stadanlick, Mallorie Werner, Zachary Vorndran, Alexandra Ellis, Jazmean Williams, Justin Cicarelli, Quynh Lam, Thomas Furmanak, Chris Schmitt, Fatemeh Hadi-Nezhad, Daniel Thompson, Claire Miller, Courtney Little, David Chang, Samik Basu","doi":"10.1016/j.ymthe.2024.09.009","DOIUrl":"10.1016/j.ymthe.2024.09.009","url":null,"abstract":"Under compassionate use, chimeric antigen receptor (CAR) T cells have elicited durable remissions in patients with refractory idiopathic inflammatory myopathies (IIMs). Here, we report on the safety, efficacy, and correlative data of the first subject with the immune-mediated necrotizing myopathy (IMNM) subtype of IIM who received a fully human, 4-1BBz anti-CD19-CAR T cell therapy (CABA-201) in the RESET-Myositis phase I/II trial (NCT06154252). CABA-201 was well-tolerated following infusion. Notably, no evidence of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome was observed. Creatine kinase levels decreased, and muscular strength improved post-infusion. Peripheral B cells were depleted rapidly following infusion, and the subject achieved peripheral B cell aplasia by day 15 post-infusion. Peripheral B cells returned at 2 months post-infusion and were almost entirely transitional. Autoantibodies to SRP-9, SRP-72, SRP-54, and Ro-52, decreased relative to baseline, whereas antibodies associated with pathogens and vaccinations remained stable. The infusion product consisted of predominantly CD4+ effector memory T cells and exhibited in vitro cytolytic activity. Post-infusion, CABA-201 expansion peaked at day 15 and was preceded by a serum IFN-γ peak on day 8 with peaks in serum IL-12p40 and IP-10 on day 15. These data detail the safety, efficacy, and pharmacodynamics of CABA-201 in the first IMNM subject.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"3821-3828"},"PeriodicalIF":12.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142154630","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

Anti-amyloid treatment is broadly effective in neuronopathic mucopolysaccharidoses and synergizes with gene therapy in MPS-IIIA. 抗淀粉样蛋白治疗对神经病理黏多醣症具有广泛的疗效，并能与 MPS-IIIA 基因疗法协同增效。

IF 12.1 1区医学

Molecular Therapy Pub Date : 2024-11-06 Epub Date: 2024-09-28 DOI: 10.1016/j.ymthe.2024.09.030

Marianna Giaccio, Antonio Monaco, Laura Galiano, Andrea Parente, Luigi Borzacchiello, Riccardo Rubino, Frank-Gerrit Klärner, Dennis Killa, Claudia Perna, Pasquale Piccolo, Marcello Marotta, Xuefang Pan, Marie Khijniak, Ibrar Siddique, Thomas Schrader, Alexey V Pshezhetsky, Nicolina Cristina Sorrentino, Gal Bitan, Alessandro Fraldi

{"title":"Anti-amyloid treatment is broadly effective in neuronopathic mucopolysaccharidoses and synergizes with gene therapy in MPS-IIIA.","authors":"Marianna Giaccio, Antonio Monaco, Laura Galiano, Andrea Parente, Luigi Borzacchiello, Riccardo Rubino, Frank-Gerrit Klärner, Dennis Killa, Claudia Perna, Pasquale Piccolo, Marcello Marotta, Xuefang Pan, Marie Khijniak, Ibrar Siddique, Thomas Schrader, Alexey V Pshezhetsky, Nicolina Cristina Sorrentino, Gal Bitan, Alessandro Fraldi","doi":"10.1016/j.ymthe.2024.09.030","DOIUrl":"10.1016/j.ymthe.2024.09.030","url":null,"abstract":"Mucopolysaccharidoses (MPSs) are childhood diseases caused by inherited deficiencies in glycosaminoglycan degradation. Most MPSs involve neurodegeneration, which to date is untreatable. Currently, most therapeutic strategies aim at correcting the primary genetic defect. Among these strategies, gene therapy has shown great potential, although its clinical application is challenging. We have shown previously in an MPS-IIIA mouse model that the molecular tweezer (MT) CLR01, a potent, broad-spectrum anti-amyloid small molecule, inhibits secondary amyloid storage, facilitates amyloid clearance, and protects against neurodegeneration. Here, we demonstrate that combining CLR01 with adeno-associated virus (AAV)-mediated gene therapy, targeting both the primary and secondary pathologic storage in MPS-IIIA mice, results in a synergistic effect that improves multiple therapeutic outcomes compared to each monotherapy. Moreover, we demonstrate that CLR01 is effective therapeutically in mouse models of other forms of neuronopathic MPS, MPS-I, and MPS-IIIC. These strongly support developing MTs as an effective treatment option for neuronopathic MPSs, both on their own and in combination with gene therapy, to improve therapeutic efficacy and translation into clinical application.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":"4108-4121"},"PeriodicalIF":12.1,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11573617/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142350557","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