Molecular Therapy-Methods & Clinical Development最新文献_第3页

Cathepsin B inhibition blocks amyloidogenesis in the mouse models of neurological lysosomal diseases MPS IIIC and sialidosis. 组织蛋白酶B抑制抑制神经溶酶体疾病MPS IIIC和唾液中毒小鼠模型的淀粉样蛋白形成。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-02-11 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2025.101432

Gustavo M Viana, Xuefang Pan, Shuxian Fan, TianMeng Xu, Alexandra Wyatt, Alexey V Pshezhetsky

{"title":"Cathepsin B inhibition blocks amyloidogenesis in the mouse models of neurological lysosomal diseases MPS IIIC and sialidosis.","authors":"Gustavo M Viana, Xuefang Pan, Shuxian Fan, TianMeng Xu, Alexandra Wyatt, Alexey V Pshezhetsky","doi":"10.1016/j.omtm.2025.101432","DOIUrl":"https://doi.org/10.1016/j.omtm.2025.101432","url":null,"abstract":"Neuronal accumulation of amyloid aggregates is a hallmark of brain pathology in neurological lysosomal storage diseases (LSDs), including mucopolysaccharidoses (MPS); however, the molecular mechanism underlying this pathology has not been understood. We demonstrate that elevated lysosomal cathepsin B (CTSB) levels and CTSB leakage to the cytoplasm triggers amyloidogenesis in two neurological LSDs. CTSB levels were elevated 3- to 5-fold in the cortices of mouse models of MPS IIIC (Hgsnat-Geo and Hgsnat P304L ) and sialidosis (Neu1 ΔEx3 ), as well as in cortical samples of MPS I, IIIA, IIIC, and IIID patients. CTSB was found in the cytoplasm of pyramidal layer IV-V cortical neurons containing thioflavin-S+, β-amyloid+ aggregates consistent with a pro-senile phenotype. In contrast, CTSB-deficient MPS IIIC (Hgsnat P304L /Ctsb -/- ) mice as well as Hgsnat P304L and Neu1 ΔEx3 mice chronically treated with irreversible brain-penetrable CTSB inhibitor E64 showed a drastic reduction in neuronal thioflavin-S+/APP+ deposits. Neurons of Hgsnat P304L /Ctsb -/- mice and E64-treated Hgsnat P304L mice also showed reduced levels of P62+, LC3+ puncta, GM2 ganglioside, and misfolded subunit C of mitochondrial ATP synthase, consistent with restored autophagy. E64 treatment also rescued hyperactivity and reduced anxiety in Hgsnat P304L mice, implying that CTSB may become a novel pharmacological target for MPS III and similar LSDs.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101432"},"PeriodicalIF":4.6,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910108/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Nonclinical study of ixo-vec gene therapy for nAMD supports efficacy for a human dose of 6E10 vg/eye and staggered dosing of fellow eyes. ioxo -vec基因治疗nAMD的非临床研究支持6E10 vg/眼的人剂量和其他眼睛交错给药的疗效。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-02-10 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2025.101430

Kris Poulsen, Kelly Hanna, Julio Nieves, Ngoc Nguyen, Pallavi Sharma, Ruslan Grishanin, Romu Corbau, Szilárd Kiss

{"title":"Nonclinical study of ixo-vec gene therapy for nAMD supports efficacy for a human dose of 6E10 vg/eye and staggered dosing of fellow eyes.","authors":"Kris Poulsen, Kelly Hanna, Julio Nieves, Ngoc Nguyen, Pallavi Sharma, Ruslan Grishanin, Romu Corbau, Szilárd Kiss","doi":"10.1016/j.omtm.2025.101430","DOIUrl":"https://doi.org/10.1016/j.omtm.2025.101430","url":null,"abstract":"Ixoberogene soroparvovec (ixo-vec), formerly ADVM-022, is an adeno-associated virus (AAV) gene therapy using the AAV.7m8 capsid for intravitreal delivery (IVT) to transduce retinal tissue and produce sustained intraocular aflibercept for treating neovascular age-related macular degeneration (nAMD). Non-clinical studies show that aflibercept production by ixo-vec is less than dose proportional, while intraocular inflammation (IOI) increases with dose, suggesting that lower doses could yield effective aflibercept levels with reduced IOI risk. Our evaluation confirmed that doses as low as 3E10 vg (vector genome)/eye (6E10 vg/eye human equivalent) maintained effective aflibercept production. The concept behind ADVM-022 is supported by clinical studies OPTIC (NCT03748784) and LUNA (NCT05536973), where a single IVT administration eliminated or significantly reduced the need for additional anti-VEGF injections in patients. Moreover, LUNA confirmed the clinical efficacy of a 6E10-vg/eye dose, demonstrating robust and sustained aflibercept levels. Additionally, we evaluated staggered dosing in contralateral eyes to treat asynchronous disease development. Staggered dosing, administered 2 months apart, did not exacerbate IOI, and both eyes maintained therapeutic aflibercept levels. These findings support the tolerability and efficacy of staggered dosing, indicating the potential for bilaterally relevant aflibercept levels with ixo-vec, due to immune response confinement to the dosed eye.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101430"},"PeriodicalIF":4.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Deciphering key parameters enhancing lentiviral vector producer cells yields: Vector components copy number and expression. 解密提高慢病毒载体生产细胞产量的关键参数：载体成分的拷贝数和表达量

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-02-10 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2025.101431

Ana S Formas-Oliveira, Mariana Valentim Ferreira, Ana Sofia Coroadinha

{"title":"Deciphering key parameters enhancing lentiviral vector producer cells yields: Vector components copy number and expression.","authors":"Ana S Formas-Oliveira, Mariana Valentim Ferreira, Ana Sofia Coroadinha","doi":"10.1016/j.omtm.2025.101431","DOIUrl":"10.1016/j.omtm.2025.101431","url":null,"abstract":"The use of lentiviral vectors (LVs) in gene therapy is expanding, demanding high-quality viral preparations. Producer cell lines for LV production offer robust manufacturing platforms. However, their development is still progressing and more knowledge on the impact of vector components expression levels on vector yields and quality is essential. This work studies the impact of vector cassette expression and stability on vector titer and quality, identifying key parameters in cell line development. Ten heterogeneous LV stable producer clones established through random cassette integration were characterized. The gag-pol and rev cassettes, expressed under the control of constitutive promoters, showed robust expression generating titers of 109 physical particles (P.P.s)/mL. However, Pol and reverse transcriptase expressions were shown to be better indicators of potential functional titers. Envelope and transfer vector expression levels were key to attaining high functional particles yields. The stability analysis of two top clones and their trans-complementation with each genetic cassette further supported this conclusion. The producer LV clones expressed constitutively the 4070A envelope, but the overexpression of the VSV-G envelope increased 30-fold the titer supporting the envelope as key determinant in LV quality. This work further elucidates bottlenecks in LV producer cell line development providing insights for their optimization.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101431"},"PeriodicalIF":4.6,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11925171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Characterization of VSV-GP morphology by cryo-EM imaging and SEC-MALS. 通过低温电子显微镜成像和 SEC-MALS 分析 VSV-GP 的形态特征。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-02-06 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2025.101429

Dongyue Xin, Leela Kurien, Katherine Briggs, Adrian Schimek, Richard Dambra, Daniel Hochdorfer, Tanja A Arnouk, Marija Brgles, Saurabh Gautam, Dominik Hotter, Johannes Solzin, Thomas Kriehuber, Joseph Ashour, Adam Vigil, Michael Hawley, Xiaorong He

{"title":"Characterization of VSV-GP morphology by cryo-EM imaging and SEC-MALS.","authors":"Dongyue Xin, Leela Kurien, Katherine Briggs, Adrian Schimek, Richard Dambra, Daniel Hochdorfer, Tanja A Arnouk, Marija Brgles, Saurabh Gautam, Dominik Hotter, Johannes Solzin, Thomas Kriehuber, Joseph Ashour, Adam Vigil, Michael Hawley, Xiaorong He","doi":"10.1016/j.omtm.2025.101429","DOIUrl":"10.1016/j.omtm.2025.101429","url":null,"abstract":"Vesicular stomatitis virus expressing the glycoprotein of the lymphocytic choriomeningitis virus (VSV-GP) is a promising platform for oncolytic viruses and cancer vaccines. In this work, cryoelectron microscopy (cryo-EM) imaging was employed to directly visualize VSV-GP particles. Several different subpopulations of virus particle morphology were observed. Definition and fraction counting of subpopulations enabled quantitative comparison of subpopulation profiles between several VSV-GP samples. In developing an orthogonal method with higher throughput, we showed that the morphological profile of the VSV-GP particles can be characterized by size exclusion chromatography coupled with a multi-angle light scattering detector (SEC-MALS) based on a novel shape-based separation mechanism. Together, the two complementary techniques enable the analysis of morphological profile for VSV-GP and potentially other non-spherical viruses or nanoparticles.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101429"},"PeriodicalIF":4.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143625974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Magnetic bead-sensitized optoporation coupled with antibodies-based activation for mRNA CAR-T cell manufacturing. 磁珠增敏光学修饰结合抗体激活mRNA CAR-T细胞制造。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-02-04 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2025.101428

Noelia Maldonado-Pérez, Marie-Agnès Doucey, Dzhangar Dzhumashev, Darel Martínez Bedoya, Luis Castillo Cantero, Caroline Boudousquie, Yann Pierson, Luc Henry, Valérie Dutoit, Denis Migliorini

{"title":"Magnetic bead-sensitized optoporation coupled with antibodies-based activation for mRNA CAR-T cell manufacturing.","authors":"Noelia Maldonado-Pérez, Marie-Agnès Doucey, Dzhangar Dzhumashev, Darel Martínez Bedoya, Luis Castillo Cantero, Caroline Boudousquie, Yann Pierson, Luc Henry, Valérie Dutoit, Denis Migliorini","doi":"10.1016/j.omtm.2025.101428","DOIUrl":"https://doi.org/10.1016/j.omtm.2025.101428","url":null,"abstract":"Immunotherapy is facing a revolution with the advent of immune cell engineering. Chimeric antigen receptor (CAR)-T cell therapy has shown unprecedented efficacy in B cell malignancies and is now being evaluated in other disease areas. Viral transduction is the most common method for immune cell genetic engineering, but presents important limitations, such as high reagent costs and regulatory concerns due to mutagenesis risk. One prevailing non-viral gene delivery strategy relies on the electroporation of non-integrating RNA. However, most modern electroporation technologies also require high reagent costs and rely on the use of proprietary software and transfection buffers. Nanoparticle-sensitized optoporation represents an alternative method for transient permeabilization of cells. Here, we introduce magnetic bead-sensitized optoporation, in which commercially available superparamagnetic beads coupled with anti-human CD3 and CD28 antibodies are used as photosensitizers for efficient genetic cargo delivery into human primary T cells and other immune cells. We show that magnetic bead-sensitized optoporation of human T cells generates functional mRNA-based CAR-T cells without affecting T cell product memory phenotype or activation potential. Importantly, optoporated T cells exhibited a greater proliferation capacity relative to electroporated T cells. In conclusion, our findings suggest that magnetic bead-sensitized optoporation holds promise as mRNA delivery strategy for immune cell therapy.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101428"},"PeriodicalIF":4.6,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143651894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Preclinical development of TAK-754, a high-performance AAV8-based vector expressing coagulation factor VIII. TAK-754的临床前开发，一种高性能的基于aav8表达凝血因子VIII的载体。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-01-28 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2025.101424

Johannes Lengler, Markus Weiller, Franziska Horling, Josef Mayrhofer, Maria Schuster, Falko G Falkner, Irene Gil-Farina, Matthias Klugmann, Friedrich Scheiflinger, Werner Hoellriegl, Hanspeter Rottensteiner

{"title":"Preclinical development of TAK-754, a high-performance AAV8-based vector expressing coagulation factor VIII.","authors":"Johannes Lengler, Markus Weiller, Franziska Horling, Josef Mayrhofer, Maria Schuster, Falko G Falkner, Irene Gil-Farina, Matthias Klugmann, Friedrich Scheiflinger, Werner Hoellriegl, Hanspeter Rottensteiner","doi":"10.1016/j.omtm.2025.101424","DOIUrl":"10.1016/j.omtm.2025.101424","url":null,"abstract":"This report concerns the preclinical development of TAK-754, an AAV8-based human factor VIII (FVIII) vector designed to deliver a codon-optimized and CpG-depleted B domain-deleted F8 transgene under the control of a liver-specific promoter for gene therapy in patients with hemophilia A. A dose-dependent increase in plasma FVIII activity was detected in FVIII knockout mice at a dose of 1.0 × 1012 TAK-754 capsid particles (CP)/kg or higher. This increase was shown to be in accordance with a dose-dependent decrease in blood loss in a hemostatic efficacy assay. TAK-754 (3.1 × 1012 CP/kg) mediated long-term and stable FVIII expression in immunologically tolerant transgenic human FVIII mice. Toxicology and biodistribution assessments with a single administration of TAK-754 ranging between 1.9 × 1012 and 5.0 × 1013 CP/kg were conducted in male C57BL/6J mice. The highest TAK-754 dose occurred without TAK-754-related adverse clinical signs. Biodistribution profiling showed predominant detection in the liver with a low occurrence of vector DNA in other tissues. Integration site analysis revealed minimal vector integration, with no observations of clonal outgrowth or preferred integrations in genes previously implicated in hepatocellular carcinoma formation within the observation period. These preclinical studies demonstrate a good safety and efficacy profile for TAK-754.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101424"},"PeriodicalIF":4.6,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11929063/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694398","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Validation of a quantitative cell-based relative potency assay for LUXTURNA. LUXTURNA定量细胞相对效价法的验证。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-01-25 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2025.101423

Katherine A High, Dave Le Blond, Karen Doucette, Dezhong Liu, Rafal Farjo, Irena Ignatova, George Buchlis, Daniel Chung, Linda B Couto

{"title":"Validation of a quantitative cell-based relative potency assay for LUXTURNA.","authors":"Katherine A High, Dave Le Blond, Karen Doucette, Dezhong Liu, Rafal Farjo, Irena Ignatova, George Buchlis, Daniel Chung, Linda B Couto","doi":"10.1016/j.omtm.2025.101423","DOIUrl":"10.1016/j.omtm.2025.101423","url":null,"abstract":"Voretigene neparvovec-rzyl (Luxturna) is an AAV2 vector (AAV2-hRPE65v2) that expresses a cDNA encoding the human retinal pigment epithelium-specific 65 kDa protein (RPE65). It has been approved for the treatment of visual deficits associated with biallelic mutations in human RPE65 in the US, European Union (EU), and multiple other countries. To achieve regulatory approval, it was necessary to validate an assay demonstrating its biological activity or potency. The assay measures AAV2-hRPE65v2 transduction in HEK293 cells and the subsequent biological activity of the vector-encoded RPE65 protein in cell lysates. RPE65 converts all-trans-retinol to 11-cis-retinol, which is quantified using liquid chromatography with tandem mass spectrometry (LC-MS/MS). The assay was validated for seven characteristics, namely system and sample suitability, specificity, linearity, precision, relative accuracy, range, and robustness. The validated assay can be used to confirm the relative potency levels of different lots of Luxturna in the range of 50%-150% of a reference standard (defined as 100% potent). This represents the first report of validation studies supporting an in vitro cell-based relative potency assay for an AAV vector, which was used to evaluate lot-to-lot consistency, stability, and comparability following manufacturing changes and to successfully launch Luxturna, the first gene therapy approved in the US for a genetic disease.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101423"},"PeriodicalIF":4.6,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Immune-driven gene expression loss following intramuscular AAV delivery to non-human primates is only transient. 非人灵长类动物肌肉注射AAV后，免疫驱动的基因表达丢失只是短暂的。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-01-19 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2025.101409

Malo Journou, Marie Devaux, Nicolas Jaulin, Virginie Pichard, Mercedes Segovia, Aurélie Moreau, Johanne Le Duff, Maria Cristina Cuturi, Mickaël Guilbaud, Oumeya Adjali

{"title":"Immune-driven gene expression loss following intramuscular AAV delivery to non-human primates is only transient.","authors":"Malo Journou, Marie Devaux, Nicolas Jaulin, Virginie Pichard, Mercedes Segovia, Aurélie Moreau, Johanne Le Duff, Maria Cristina Cuturi, Mickaël Guilbaud, Oumeya Adjali","doi":"10.1016/j.omtm.2025.101409","DOIUrl":"10.1016/j.omtm.2025.101409","url":null,"abstract":"Recombinant adeno-associated virus (rAAV) vectors stand out as highly promising for in vivo gene transfer, particularly in targeting the skeletal muscle for treating muscular genetic diseases or secreting therapeutic factors. Despite the simplicity and efficacy of the established intramuscular (IM) route, it has been often associated with an immune-induced rapid loss of transgene expression, in particular in large animal models, and generally considered irreversible as a consequence of a cytotoxic elimination of transduced cells. Here, we report in a non-human primate model that transgene expression loss after IM delivery of an rAAV1 expressing an immunogenic protein is only transient, with the re-expression of the transgene lasting up to 5 years post-injection. We show that the recovery of transgene expression is due to persisting viral genomes in the injected muscles despite the detection of peripheral anti-transgene cellular immunity. Persisting genomes were observed in the presence of infiltrated mononuclear CD8 and CD4 T lymphocytes, among which we were able to detect FoxP3+ regulatory cells. This is to our knowledge the first report of a transient immune-mediated loss of gene expression in a large animal model after rAAV delivery that should shed new light on the issue of rAAV vector immunogenicity.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101409"},"PeriodicalIF":4.6,"publicationDate":"2025-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Antibodies to recombinant human alpha-L-iduronidase prevent disease correction in cortical bone in MPS I mice. 重组人α - l -伊杜糖醛酸酶抗体预防MPSⅰ型小鼠皮质骨疾病纠正。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2025-01-02 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2024.101405

Sarah C Hurt, Steven Q Le, Shih-Hsin Kan, Quang D Bui, Michael D Brodt, Patricia I Dickson

{"title":"Antibodies to recombinant human alpha-L-iduronidase prevent disease correction in cortical bone in MPS I mice.","authors":"Sarah C Hurt, Steven Q Le, Shih-Hsin Kan, Quang D Bui, Michael D Brodt, Patricia I Dickson","doi":"10.1016/j.omtm.2024.101405","DOIUrl":"10.1016/j.omtm.2024.101405","url":null,"abstract":"Mucopolysaccharidosis I (MPS I) is a lysosomal storage disorder caused by deficiency of the enzyme α-l-iduronidase (IDUA). Failure of enzyme replacement therapy (ERT) to treat skeletal disease may be due to development of anti-IDUA antibodies, found previously to alter tissue distribution of ERT in animal models. To test this hypothesis, immunocompromised (non-obese diabetic [NOD]-severe combined immunodeficiency [SCID]) MPS I mice were treated with weekly ERT from birth (ERT alone). Some mice also received weekly injections of rabbit immunoglobulin G (IgG) against IDUA (immunized rabbit immune globulin [IRIG]) concomitant with ERT, imitating antibodies developed in patients (ERT+IRIG). Mice treated with ERT+IRIG showed lower IDUA activity and higher disease burden than mice treated with ERT alone in most tissues. Femora were harvested at 20 weeks for ex vivo microcomputed tomography (μCT). Femoral cortical bone thickness and cortical bone area in MPS I mice were greater than in unaffected mice. Mice treated with ERT alone had values that were statistically indistinguishable from carrier mice, while mice that received ERT+IRIG had no significant differences compared to vehicle-treated MPS I mice. The data suggests that immune-modulatory or immune-suppressive therapy to prevent or reduce the humoral immune response against ERT may improve treatment of skeletal disease due to MPS I.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101405"},"PeriodicalIF":4.6,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11928967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143694360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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

Reducing off-target expression of mRNA therapeutics and vaccines in the liver with microRNA binding sites. 利用 microRNA 结合位点减少 mRNA 疗法和疫苗在肝脏中的脱靶表达。

IF 4.6 2区医学

Molecular Therapy-Methods & Clinical Development Pub Date : 2024-12-19 eCollection Date: 2025-03-13 DOI: 10.1016/j.omtm.2024.101402

Brian J Parrett, Satoko Yamaoka, Michael A Barry

{"title":"Reducing off-target expression of mRNA therapeutics and vaccines in the liver with microRNA binding sites.","authors":"Brian J Parrett, Satoko Yamaoka, Michael A Barry","doi":"10.1016/j.omtm.2024.101402","DOIUrl":"10.1016/j.omtm.2024.101402","url":null,"abstract":"Lipid nanoparticles (LNPs) are often liver tropic, presenting challenges for LNP-delivered mRNA therapeutics intended for other tissues, as off-target expression in the liver may increase side effects and modulate immune responses. To avoid off-target expression in the liver, miR-122 binding sites have been used by others in viral and non-viral therapeutics. Here, we use a luciferase reporter system to compare different copy numbers and insertion locations of miR-122 binding sequences to restrict liver expression. We inserted one to five miR-122 binding sites into the 5' or 3' untranslated regions (UTRs) of luciferase mRNAs and tested them in LNPs in vitro and in vivo via systemic intravenous and local intramuscular injections in mice. Our results showed no significant differences in de-targeting efficacy between mRNAs harboring one or multiple miR-122 binding sites or between those with 5' or 3' UTR placements. To test the impact of miR-122 binding sites on antibody response to a mRNA vaccine, Ebola virus matrix protein VP40 mRNAs were modified with or without miR-122 binding sites and injected in mice intramuscularly. This work reinforces the utility of miR-122 binding sites while providing a comparison of these sites to aid the future development of LNP-mRNA therapies for non-hepatic tissues.","PeriodicalId":54333,"journal":{"name":"Molecular Therapy-Methods & Clinical Development","volume":"33 1","pages":"101402"},"PeriodicalIF":4.6,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758401/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143048574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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