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Journals Molecular Therapy. Methods & C...

Molecular Therapy. Methods & Clinical Development

https://read.qxmd.com/read/38883976/genetic-alteration-of-sj293ts-cells-and-modification-of-serum-free-media-enhances-lentiviral-vector-production
#1
JOURNAL ARTICLE
Matthew Bauler, Francesca Ferrara, Brandon Lowe, Jordan A Beard, Chris Wincek, Matthew M Wielgosz, Jeoungeun J Park, Na Shang, Saikat Nandy, Cai Li, Deanna M Langfitt, Sheng Zhou, Robert E Throm
Successful cell and gene therapy clinical trials have resulted in the US Food and Drug Administration and European Medicines Agency approving their use for treatment of patients with certain types of cancers and monogenetic diseases. These novel therapies, which rely heavily on lentiviral vectors to deliver therapeutic transgenes to patient cells, have driven additional investigations, increasing demand for both pre-clinical and current Good Manufacturing Practices-grade viral vectors. To better support novel studies by improving current production methods, we report the development of a genetically modified HEK293T-based cell line that is null for expression of both Protein Kinase R and Beta-2 microglobulin and grows in suspension using serum-free media, SJ293TS-DPB...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38883975/preclinical-specificity-activity-of-a-fully-human-41bb-expressing-anti-cd19-cart-therapy-for-treatment-resistant-autoimmune-disease
#2
JOURNAL ARTICLE
Binghao J Peng, Andrea Alvarado, Hangameh Cassim, Soprina Guarneri, Steven Wong, Jonathan Willis, Julia SantaMaria, Ashley Martynchuk, Victoria Stratton, Darshil Patel, Chien-Chung Chen, Yan Li, Gwendolyn K Binder, Rebecca Dryer-Minnerly, Jinmin Lee, Samik Basu
Over 4% of the global population is estimated to live with autoimmune disease, necessitating immunosuppressive treatment that is often chronic, not curative, and carries associated risks. B cells have emerged as key players in disease pathogenesis, as evidenced by partial responsiveness to B cell depletion by antibody-based therapies. However, these treatments often have transient effects due to incomplete depletion of tissue-resident B cells. Chimeric antigen receptor (CAR) T cells targeting B cells have demonstrated efficacy in refractory systemic lupus erythematosus...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38872830/identifying-mage-a4-positive-tumors-for-tcr-t%C3%A2-cell-therapies-in-hla-a%C3%A2-02-eligible-patients
#3
JOURNAL ARTICLE
Tianjiao Wang, Jean-Marc Navenot, Stavros Rafail, Cynthia Kurtis, Mark Carroll, Marian Van Kerckhoven, Sofie Van Rossom, Kelly Schats, Konstantinos Avraam, Robyn Broad, Karen Howe, Ashley Liddle, Amber Clayton, Ruoxi Wang, Laura Quinn, Joseph P Sanderson, Cheryl McAlpine, Carly Carozza, Eric Pimpinella, Susan Hsu, Francine Brophy, Erica Elefant, Paige Bayer, Dennis Williams, Marcus O Butler, Jeffrey M Clarke, Justin F Gainor, Ramaswamy Govindan, Victor Moreno, Melissa Johnson, Janet Tu, David S Hong, George R Blumenschein
T cell receptor (TCR) T cell therapies target tumor antigens in a human leukocyte antigen (HLA)-restricted manner. Biomarker-defined therapies require validation of assays suitable for determination of patient eligibility. For clinical trials evaluating TCR T cell therapies targeting melanoma-associated antigen A4 (MAGE-A4), screening in studies NCT02636855 and NCT04044768 assesses patient eligibility based on: (1) high-resolution HLA typing and (2) tumor MAGE-A4 testing via an immunohistochemical assay in HLA-eligible patients...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38868441/adeno-associated-virus-perfusion-enhanced-expression-a-commercially-scalable-high-titer-high-quality-producer-cell-line-process
#4
JOURNAL ARTICLE
Wei Xue, Cameron Fulco, Sha Sha, Nick Alden, Jan Panteli, Patrick Hossler, James Warren
With safety and efficacy demonstrated over hundreds of clinical trials in the last 30 years, along with at least six recent global marketing authorizations achieved since 2017, recombinant adeno-associated viruses (rAAVs) have been established as the leading therapeutic gene transfer vector for rare, monogenic diseases. Significant advances in manufacturing technology have been made in the last few decades to address challenges with GMP production of rAAV products, although yield, cost, scalability, and quality remain a challenge...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38846336/biomanufacturing-in-gene-and-cell-therapy
#5
EDITORIAL
Daniel Stone, Xiuyang Wang, Mohamed Abou-El-Enein
No abstract text is available yet for this article.
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38827250/prenatal-aav9-gfp-administration-in-fetal-lambs-results-in-transduction-of-female-germ-cells-and-maternal-exposure-to-virus
#6
JOURNAL ARTICLE
Beltran Borges, Antonia Varthaliti, Marisa Schwab, Maria T Clarke, Christopher Pivetti, Nalin Gupta, Cathryn R Cadwell, Ghiabe Guibinga, Shirley Phillips, Tony Del Rio, Fatih Ozsolak, Denise Imai-Leonard, Lingling Kong, Diana J Laird, Akos Herzeg, Charlotte J Sumner, Tippi C MacKenzie
Prenatal somatic cell gene therapy (PSCGT) could potentially treat severe, early-onset genetic disorders such as spinal muscular atrophy (SMA) or muscular dystrophy. Given the approval of adeno-associated virus serotype 9 (AAV9) vectors in infants with SMA by the U.S. Food and Drug Administration, we tested the safety and biodistribution of AAV9-GFP (clinical-grade and dose) in fetal lambs to understand safety and efficacy after umbilical vein or intracranial injection on embryonic day 75 (E75) . Umbilical vein injection led to widespread biodistribution of vector genomes in all examined lamb tissues and in maternal uteruses at harvest (E96 or E140; term = E150)...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38827249/quasi-perfusion-studies-for-intensified-lentiviral-vector-production-using-a-continuous-stable-producer-cell-line
#7
JOURNAL ARTICLE
Dale J Stibbs, Pedro Silva Couto, Yasuhiro Takeuchi, Qasim A Rafiq, Nigel B Jackson, Andrea C M E Rayat
Quasi-perfusion culture was employed to intensify lentiviral vector (LV) manufacturing using a continuous stable producer cell line in an 8-day process. Initial studies aimed to identify a scalable seeding density, with 3, 4, and 5 × 104 cells cm-2 providing similar specific productivities of infectious LV. Seeding at 3 × 104 cells cm-2 was selected, and the quasi-perfusion was modulated to minimize inhibitory metabolite accumulation and vector exposure at 37°C. Similar specific productivities of infectious LV and physical LV were achieved at 1, 2, and 3 vessel volumes per day (VVD), with 1 VVD selected to minimize downstream processing volumes...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38779337/nanodysferlins-support-membrane-repair-and-binding-to-trim72-mg53-but-do-not-localize-to-t-tubules-or-stabilize-ca-2-signaling
#8
JOURNAL ARTICLE
Joaquin Muriel, Valeriy Lukyanenko, Thomas A Kwiatkowski, Yi Li, Sayak Bhattacharya, Kassidy K Banford, Daniel Garman, Hannah R Bulgart, Roger B Sutton, Noah Weisleder, Robert J Bloch
Mutations in the DYSF gene, encoding the protein dysferlin, lead to several forms of muscular dystrophy. In healthy skeletal muscle, dysferlin concentrates in the transverse tubules and is involved in repairing the sarcolemma and stabilizing Ca2+ signaling after membrane disruption. The DYSF gene encodes 7-8 C2 domains, several Fer and Dysf domains, and a C-terminal transmembrane sequence. Because its coding sequence is too large to package in adeno-associated virus, the full-length sequence is not amenable to current gene delivery methods...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38779336/sirna-mediated-reduction-of-a-circulating-protein-in-swine-using-lipid-nanoparticles
#9
JOURNAL ARTICLE
Massimo F Cau, Francesca Ferraresso, Monica Seadler, Katherine Badior, Youjie Zhang, Laura M Ketelboeter, Geoffrey G Rodriguez, Taylor Chen, Matteo Ferraresso, Amanda Wietrzny, Madelaine Robertson, Amber Haugen, Pieter R Cullis, Marc de Moya, Mitchell Dyer, Christian J Kastrup
Genetic manipulation of animal models is a fundamental research tool in biology and medicine but is challenging in large animals. In rodents, models can be readily developed by knocking out genes in embryonic stem cells or by knocking down genes through in vivo delivery of nucleic acids. Swine are a preferred animal model for studying the cardiovascular and immune systems, but there are limited strategies for genetic manipulation. Lipid nanoparticles (LNPs) efficiently deliver small interfering RNA (siRNA) to knock down circulating proteins, but swine are sensitive to LNP-induced complement activation-related pseudoallergy (CARPA)...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38774583/an-hplc-sec-based-rapid-quantification-method-for-vesicular-stomatitis-virus-particles-to-facilitate-process-development
#10
JOURNAL ARTICLE
Adrian Schimek, Judy K M Ng, Ioannes Basbas, Fabian Martin, Dongyue Xin, David Saleh, Jürgen Hubbuch
Virus particle (VP) quantification plays a pivotal role in the development of production processes of VPs for virus-based therapies. The yield based on total VP count serves as a process performance indicator for evaluating process efficiency and consistency. Here, a label-free particle quantification method for enveloped VPs was developed, with potential applications in oncolytic virotherapy, vaccine development, and gene therapy. The method comprises size-exclusion chromatography (SEC) separation using high-performance liquid chromatography (HPLC) instruments...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38774582/glycosylation-of-recombinant-adeno-associated-virus-serotype-6
#11
JOURNAL ARTICLE
Yuki Yamaguchi, Kentaro Ishii, Sachiko Koizumi, Hiroaki Sakaue, Takahiro Maruno, Mitsuko Fukuhara, Risa Shibuya, Yasuo Tsunaka, Aoba Matsushita, Karin Bandoh, Tetsuo Torisu, Chie Murata-Kishimoto, Azusa Tomioka, Saho Mizukado, Hiroyuki Kaji, Yuji Kashiwakura, Tsukasa Ohmori, Atsushi Kuno, Susumu Uchiyama
Glycosylation of biopharmaceuticals can affect their safety and efficacy. Glycans can occur on recombinant adeno-associated viruses (rAAVs) that are used for gene therapy; however, the types of glycans that attach to rAAVs are controversial. Here, we conducted lectin microarray analyses on six rAAV serotype 6 (rAAV6) preparations that were produced differently. We demonstrate that O- glycans considered to be attached to rAAV6 were recognized by Agaricus bisporus agglutinin (ABA) and that N- glycans were detected in rAAV6 purified without affinity chromatography...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38770107/bioengineering-extracellular-vesicle-cargo-for-optimal-therapeutic-efficiency
#12
REVIEW
Charlotte A René, Robin J Parks
Extracellular vesicles (EVs) have the innate ability to carry proteins, lipids, and nucleic acids between cells, and thus these vesicles have gained much attention as potential therapeutic delivery vehicles. Many strategies have been explored to enhance the loading of specific cargoes of interest into EVs, which could result in the delivery of more therapeutic to recipient cells, thus enhancing therapeutic efficacy. In this review, we discuss the natural biogenesis of EVs, the mechanism by which proteins and nucleic acids are selected for inclusion in EVs, and novel methods that have been employed to enhance loading of specific cargoes into EVs...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38764780/development-and-testing-of-a-versatile-genome-editing-application-reporter-v-gear-system
#13
JOURNAL ARTICLE
Evan W Kleinboehl, Kanut Laoharawee, Walker S Lahr, Jacob D Jensen, Joseph J Peterson, Jason B Bell, Beau R Webber, Branden S Moriarity
CRISPR-Cas9 and novel cas fusion proteins leveraging specific DNA targeting ability combined with deaminases or reverse transcriptases have revolutionized genome editing. However, their efficacy heavily relies upon protein variants, targeting single guide RNAs, and surrounding DNA sequence context within the targeted loci. This necessitates the need for efficient and rapid screening methods to evaluate these editing reagents and designs. Existing plasmid-based reporters lack flexibility, being fixed to specific DNA sequences, hindering direct comparisons between various editing approaches...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38745896/erratum-gene-replacement-therapy-in-a-schwannoma-mouse-model-of-neurofibromatosis-type-2
#14
Shilpa Prabhakar, Roberta L Beauchamp, Pike See Cheah, Akiko Yoshinaga, Edwina Abou Haidar, Sevda Lule, Gayathri Mani, Katia Maalouf, Anat Stemmer-Rachamimov, David H Jung, D Bradley Welling, Marco Giovannini, Scott R Plotkin, Casey A Maguire, Vijaya Ramesh, Xandra O Breakefield
[This corrects the article DOI: 10.1016/j.omtm.2022.06.012.].
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38745895/development-of-novel-lipoplex-formulation-methodologies-to-improve-large-scale-transient-transfection-for-lentiviral-vector-manufacture
#15
JOURNAL ARTICLE
Thomas Williams-Fegredo, Lee Davies, Carol Knevelman, Kyriacos Mitrophanous, James Miskin, Qasim A Rafiq
Large-scale transient transfection has advanced significantly over the last 20 years, enabling the effective production of a diverse range of biopharmaceutical products, including viral vectors. However, a number of challenges specifically related to transfection reagent stability and transfection complex preparation times remain. New developments and improved transfection technologies are required to ensure that transient gene expression-based bioprocesses can meet the growing demand for viral vectors. In this paper, we demonstrate that the growth of cationic lipid-based liposomes, an essential step in many cationic lipid-based transfection processes, can be controlled through adoption of low pH (pH 6...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38745894/rescue-of-myocytes-and-locomotion-through-aav2-9-2yf-intracisternal-gene-therapy-in-a-rat-model-of-creatine-transporter-deficiency
#16
JOURNAL ARTICLE
Gabriella Fernandes-Pires, Marcelo Duarte Azevedo, Marc Lanzillo, Clothilde Roux-Petronelli, Pierre-Alain Binz, Cristina Cudalbu, Carmen Sandi, Liliane Tenenbaum, Olivier Braissant
Creatine deficiency syndromes (CDS), caused by mutations in GATM (AGAT), GAMT , and SLC6A8 , mainly affect the central nervous system (CNS). CDS show brain creatine (Cr) deficiency, intellectual disability with severe speech delay, behavioral troubles, epilepsy, and motor dysfunction. AGAT/GAMT-deficient patients lack brain Cr synthesis but express the Cr transporter SLC6A8 at the blood-brain barrier and are thus treatable by oral supplementation of Cr. In contrast, no satisfactory treatment has been identified for Cr transporter deficiency (CTD), the most frequent of CDS...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38745893/a-novel-high-titer-bifunctional-lentiviral-vector-for-autologous-hematopoietic-stem-cell-gene-therapy-of-sickle-cell-disease
#17
JOURNAL ARTICLE
Kevyn L Hart, Boya Liu, Devin Brown, Beatriz Campo-Fernandez, Kevin Tam, Katherine Orr, Roger P Hollis, Christian Brendel, David A Williams, Donald B Kohn
A major limitation of gene therapy for sickle cell disease (SCD) is the availability and access to a potentially curative one-time treatment, due to high treatment costs. We have developed a high-titer bifunctional lentiviral vector (LVV) in a vector backbone that has reduced size, high vector yields, and efficient gene transfer to human CD34+ hematopoietic stem and progenitor cells (HSPCs). This LVV contains locus control region cores expressing an anti-sickling βAS3 -globin gene and two microRNA-adapted short hairpin RNA simultaneously targeting BCL11A and ZNF410 transcripts to maximally induce fetal hemoglobin (HbF) expression...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38737799/car-t-cell-manufacturing-landscape-lessons-from-the-past-decade-and-considerations-for-early-clinical-development
#18
REVIEW
Juliana Dias, John Garcia, Giulia Agliardi, Claire Roddie
CAR-T cell therapies have consolidated their position over the last decade as an effective alternative to conventional chemotherapies for the treatment of a number of hematological malignancies. With an exponential increase in the number of commercial therapies and hundreds of phase 1 trials exploring CAR-T cell efficacy in different settings (including autoimmunity and solid tumors), demand for manufacturing capabilities in recent years has considerably increased. In this review, we explore the current landscape of CAR-T cell manufacturing and discuss some of the challenges limiting production capacity worldwide...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38715734/epigenetic-control-of-multiple-genes-with-a-lentiviral-vector-encoding-transcriptional-repressors-fused-to-compact-zinc-finger-arrays
#19
JOURNAL ARTICLE
Davide Monteferrario, Marion David, Satish K Tadi, Yuanyue Zhou, Irène Marchetti, Caroline Jeanneau, Gaëlle Saviane, Coralie F Dupont, Angélique E Martelli, Lynn N Truong, Jason A Eshleman, Colman C Ng, Marshall W Huston, Gregory D Davis, Jason D Fontenot, Andreas Reik, Maurus de la Rosa, David Fenard
Gene silencing without gene editing holds great potential for the development of safe therapeutic applications. Here, we describe a novel strategy to concomitantly repress multiple genes using zinc finger proteins fused to Krüppel-Associated Box repression domains (ZF-Rs). This was achieved via the optimization of a lentiviral system tailored for the delivery of ZF-Rs in hematopoietic cells. We showed that an optimal design of the lentiviral backbone is crucial to multiplex up to three ZF-Rs or two ZF-Rs and a chimeric antigen receptor...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
https://read.qxmd.com/read/38699288/metabolic-priming-of-gd2-trac-car-t%C3%A2-cells-during-manufacturing-promotes-memory-phenotypes-while-enhancing-persistence
#20
JOURNAL ARTICLE
Dan Cappabianca, Dan Pham, Matthew H Forsberg, Madison Bugel, Anna Tommasi, Anthony Lauer, Jolanta Vidugiriene, Brookelyn Hrdlicka, Alexandria McHale, Quaovi H Sodji, Melissa C Skala, Christian M Capitini, Krishanu Saha
Manufacturing chimeric antigen receptor (CAR) T cell therapies is complex, with limited understanding of how medium composition impacts T cell phenotypes. CRISPR-Cas9 ribonucleoproteins can precisely insert a CAR sequence while disrupting the endogenous T cell receptor alpha constant ( TRAC ) gene resulting in TRAC -CAR T cells with an enriched stem cell memory T cell population, a process that could be further optimized through modifications to the medium composition. In this study we generated anti-GD2 TRAC -CAR T cells using "metabolic priming" (MP), where the cells were activated in glucose/glutamine-low medium and then expanded in glucose/glutamine-high medium...
June 13, 2024: Molecular Therapy. Methods & Clinical Development
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