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Volume 32, In Progress

  • Editorial

    Disseminating transformative gene and cell therapy research

    • Mohamed Abou-el-Enein
    First published: April 17, 2024
    Over the years, it has become clear to all stakeholders—scientists, clinicians, industry professionals, and policymakers—that scientific discovery and medical innovation are only possible through a synergistic blend of passion, expertise, and collaboration, leading to transformative breakthroughs. As I step into the role of Editor-in-Chief for Molecular Therapy Methods and Clinical Development, this understanding deeply informs my approach and vision for the journal. This role offers me a unique vantage point to influence the dynamic and ever-evolving field of gene and cell therapy—a field that not only represents the cutting edge of biomedical research but also holds the keys to unlocking treatments for some of the most intractable diseases facing humanity today.
  • Commentary

    Promise of gene therapy for congenital neurologic disease due to GPI deficiency

    • Daria V. Babushok,
    • Denise E. Sabatino
    First published: March 25, 2024
    A recent study by Murakami et al.1 describes a novel genetic treatment for inherited glycophosphatidylinositol (GPI) deficiency (IGD) using adeno-associated virus (AAV)-based gene therapy.1 PIGA is an X-linked gene required for the first step of GPI anchor biosynthesis, a multistep process requiring at least 27 different genes.2 Disruption of PIGA or other genes in the GPI biosynthesis process leads to the loss of approximately 150 different GPI-anchored surface proteins (GPI-APs) in humans.
  • Commentary

    It’s all about location: Targeting the right spot for Wiskott-Aldrich syndrome

    • Asma Naseem,
    • Alessia Cavazza
    First published: April 18, 2024
    Wiskott-Aldrich syndrome (WAS) is a complex primary immunodeficiency disorder caused by mutations in the WAS gene, which encodes the WAS protein (WASP). The WASP is expressed in nearly all hematopoietic cells and functions as a major effector of actin polymerization. Deficiency of the WASP in blood cells distresses actin cytoskeleton integrity, leading to defects in a broad range of cellular processes including cell movement, immune response, and blood clotting.1 Management of WAS often involves a comprehensive approach that addresses both the immune system deficiencies and potential autoimmune complications.
  • Opinion

    Strengthening health systems for access to gene therapy in rare genetic disorders

    • Sonal Bhatia,
    • Yann Le Cam,
    • Juan Carrion,
    • Lauren Diamond,
    • Paul Fennessy,
    • Safiyya Gassman,
    • Felix Gutzwiller,
    • Stephen Kagan,
    • Diana Pankevich,
    • Jennifer Young Maloney,
    • Nitin Mahadev,
    • Martin Schulz,
    • Durhane Wong-Rieger,
    • Paolo Morgese
    First published: March 13, 2024
    After decades of innovation, the promise of gene therapy is becoming a reality for patients with certain rare genetic disorders. Several cell and gene therapies have already been approved by regulators worldwide,1 with many more expected at a rate of up to 10%–20% annually by 2025.2 These therapies have the potential to be transformative, changing the course of a disease and reducing the long-term patient and health system burdens associated with chronic disease management (Figure 1).2
  • Review

    Embryo and fetal gene editing: Technical challenges and progress toward clinical applications

    • Citra N.Z. Mattar,
    • Wei Leong Chew,
    • Poh San Lai
    First published: March 04, 2024
    Mattar and colleagues discuss how embryo and fetal editing represent paradigm shifts in hereditary disease management. Embryo editing, useful for understanding embryogenesis, has higher translational barriers than fetal editing with its appreciable benefits. Long-term effects of both must be studied to determine safety and efficacy, including germline transmission and genotoxicity.
  • Original Article

    Automated manufacture of ΔNPM1 TCR-engineered T cells for AML therapy

    • Isabella Elias Yonezawa Ogusuku,
    • Vera Herbel,
    • Simon Lennartz,
    • Caroline Brandes,
    • Eva Argiro,
    • Caroline Fabian,
    • Carola Hauck,
    • Conny Hoogstraten,
    • Sabrina Veld,
    • Lois Hageman,
    • Karin Teppert,
    • Georgia Koutsoumpli,
    • Marieke Griffioen,
    • Nadine Mockel-Tenbrinck,
    • Thomas Schaser,
    • Rosa de Groot,
    • Ian C.D. Johnston,
    • Dominik Lock
    First published: February 26, 2024
    Lock and colleagues describe the development of a T cell transduction-large scale (TCT-LS) process on the CliniMACS Prodigy platform for the automated, GMP-compliant manufacture of potent ΔNPM1 TCR-engineered T cells at clinical scale.
  • Original Article

    Endovascular transplantation of mRNA-enhanced mesenchymal stromal cells results in superior therapeutic protein expression in swine heart

    • Jonathan Al-Saadi,
    • Mathias Waldén,
    • Mikael Sandell,
    • Jesper Sohlmér,
    • Rikard Grankvist,
    • Ida Friberger,
    • Agneta Andersson,
    • Mattias Carlsten,
    • Kenneth Chien,
    • Johan Lundberg,
    • Nevin Witman,
    • Staffan Holmin
    First published: February 26, 2024
    Holmin and colleagues used a minimally invasive endovascular approach to successfully deliver mRNA therapies using mesenchymal stem cells as vectors to swine hearts. This method, showing minimal tissue impact and enhanced protein expression, offers a promising avenue for advancing cardiac disease treatments.
  • Original Article

    Peptide-encoding gene transfer to modulate intracellular protein-protein interactions

    • Toshihiko Taya,
    • Daisuke Kami,
    • Fumiya Teruyama,
    • Satoaki Matoba,
    • Satoshi Gojo
    First published: February 28, 2024
    Intracellular PPIs have a vast number of drug discovery targets, but only a few drugs have been successfully developed to date due to technical difficulties. In this study, Gojo and colleagues succeeded in creating a platform for stable and efficient introduction of peptides into cells using mRNA.
  • Original Article

    A robust and flexible baculovirus-insect cell system for AAV vector production with improved yield, capsid ratios and potency

    • Yoko Marwidi,
    • Hoang-Oanh B. Nguyen,
    • David Santos,
    • Tenzin Wangzor,
    • Sumita Bhardwaj,
    • Gabriel Ernie,
    • Gregg Prawdzik,
    • Garrett Lew,
    • David Shivak,
    • Michael Trias,
    • Jada Padilla,
    • Hung Tran,
    • Kathleen Meyer,
    • Richard Surosky,
    • Alex Michael Ward
    First published: March 04, 2024
    Ward and colleagues have developed an improved helper system for AAV manufacturing in insect cells—the SGMO Helper—with superior yields, potency, and capsid integrity to enable delivery of cutting-edge gene and cell therapies to patients.
  • Original Article

    A toxicology study of Csf2ra complementation and pulmonary macrophage transplantation therapy of hereditary PAP in mice

    • Paritha Arumugam,
    • Brenna C. Carey,
    • Kathryn A. Wikenheiser-Brokamp,
    • Jeffrey Krischer,
    • Matthew Wessendarp,
    • Kenjiro Shima,
    • Claudia Chalk,
    • Jennifer Stock,
    • Yan Ma,
    • Diane Black,
    • Michelle Imbrogno,
    • Margaret Collins,
    • Dan Justin Kalenda Yombo,
    • Haripriya Sakthivel,
    • Takuji Suzuki,
    • Carolyn Lutzko,
    • Jose A. Cancelas,
    • Michelle Adams,
    • Elizabeth Hoskins,
    • Dawn Lowe-Daniels,
    • Lilith Reeves,
    • Anne Kaiser,
    • Bruce C. Trapnell
    First published: February 16, 2024
    This study demonstrated Csf2ra gene complementation and pulmonary macrophage transplantation was safe and efficacious as disease-specific therapy of hereditary pulmonary alveolar proteinosis in mice, and that transplanted macrophages remained in the lungs and did not cause an immune response to the transgene product (GM-CSF receptor α) and established a no adverse effect level.
  • Original Article

    Novel AAV variants with improved tropism for human Schwann cells

    • Matthieu Drouyer,
    • Tak-Ho Chu,
    • Elodie Labit,
    • Florencia Haase,
    • Renina Gale Navarro,
    • Deborah Nazareth,
    • Nicole Rosin,
    • Jessica Merjane,
    • Suzanne Scott,
    • Marti Cabanes-Creus,
    • Adrian Westhaus,
    • Erhua Zhu,
    • Rajiv Midha,
    • Ian E. Alexander,
    • Jeff Biernaskie,
    • Samantha L. Ginn,
    • Leszek Lisowski
    First published: March 12, 2024
    Lisowski and colleagues developed novel AAV variants, Pep2hSC1 and Pep2hSC2, using a directed-evolution strategy in primary hSCs, for effective gene delivery to SCs, aiding in the treatment of related disorders and nerve injuries.
  • Original Article

    AAV-delivered hepato-adrenal cooperativity in steroidogenesis: Implications for gene therapy for congenital adrenal hyperplasia

    • Lara E. Graves,
    • Eva B. van Dijk,
    • Erhua Zhu,
    • Sundar Koyyalamudi,
    • Tiffany Wotton,
    • Dinah Sung,
    • Shubha Srinivasan,
    • Samantha L. Ginn,
    • Ian E. Alexander
    First published: March 13, 2024
    Graves and colleagues demonstrate that intravenous administration of a liver-targeted AAV vector encoding human 21-hydroxylase cDNA restores steroidogenic function in 21-hydroxylase-deficient mice. Liver transduction has the potential to overcome the limitations imposed by adrenocortical cellular turnover. This also has implications for data interpretation in adrenally targeted gene transfer studies.
  • Original Article

    Producing high-quantity and high-quality recombinant adeno-associated virus by low-cis triple transfection

    • Hao Liu,
    • Yue Zhang,
    • Mitchell Yip,
    • Lingzhi Ren,
    • Jialing Liang,
    • Xiupeng Chen,
    • Nan Liu,
    • Ailing Du,
    • Jiaming Wang,
    • Hao Chang,
    • Hyejin Oh,
    • Chen Zhou,
    • Ruxiao Xing,
    • Mengyao Xu,
    • Peiyi Guo,
    • Dominic Gessler,
    • Jun Xie,
    • Phillip W.L. Tai,
    • Guangping Gao,
    • Dan Wang
    First published: March 13, 2024
    Liu and colleagues present a broadly applicable and cost-effective strategy for rAAV production. By dramatically cutting the pCis plasmid input, this low-cis triple transfection method significantly improves the titer of rAAV expressing inhibitory transgenes and decreases the rAAV impurity of plasmid backbone encapsidation.
  • Original Article

    mtDNA analysis using Mitopore

    • Jochen Dobner,
    • Thach Nguyen,
    • Mario Gustavo Pavez-Giani,
    • Lukas Cyganek,
    • Felix Distelmaier,
    • Jean Krutmann,
    • Alessandro Prigione,
    • Andrea Rossi
    First published: March 12, 2024
    Rossi and colleagues describe a streamlined approach for the analysis of mtDNA using noisy long-read sequencing data. They introduce Mitopore, a user-friendly webserver for efficient, cost-effective mtDNA analysis of SNVs, indels, and haplogroups. The economic efficiency of Mitopore holds great promise to advance research and clinical mtDNA diagnosis.
  • Original Article

    Protein phosphatase 2A anchoring disruptor gene therapy for familial dilated cardiomyopathy

    • Xueyi Li,
    • Jinliang Li,
    • Anne-Maj Samuelsson,
    • Hrishikesh Thakur,
    • Michael S. Kapiloff
    First published: March 12, 2024
    Dr. Kapiloff and his colleagues describe a new gene therapy for familial dilated cardiomyopathy that is etiology agnostic. Expression of a PP2A anchoring disruptor peptide using a cardiomyocyte-directed AAV vector improves the structure and function of the heart in a mouse cardiomyopathy model, providing proof-of-concept for the new therapy.
  • Original Article

    Combining CRISPR-Cas-mediated terminal resolution with a novel genetic workflow to achieve high-diversity adenoviral libraries

    • Julian Fischer,
    • Ariana Fedotova,
    • Lena Jaki,
    • Erwan Sallard,
    • Anja Erhardt,
    • Jonas Fuchs,
    • Zsolt Ruzsics
    First published: March 18, 2024
    Ruzsics and colleagues present a novel method for cloning large DNA bacmids based on naturally occurring features. This allows seamless mutagenesis of target sequences, showcased by modification and tagging of an adenoviral genome. Efficiencies are sufficient to generate high diversity viral libraries allowing for in vitro evolution-based screening.
  • Original Article

    Subretinal AAV delivery of RNAi-therapeutics targeting VEGFA reduces choroidal neovascularization in a large animal model

    • Silja Hansen Haldrup,
    • Bjørn K. Fabian-Jessing,
    • Thomas Stax Jakobsen,
    • Anna Bøgh Lindholm,
    • Rikke L. Adsersen,
    • Lars Aagaard,
    • Toke Bek,
    • Anne Louise Askou,
    • Thomas J. Corydon
    First published: March 23, 2024
    Corydon and colleagues explored the anti-angiogenic effect of novel VEGFA-targeting RNAi effectors. Robust VEGFA knockdown was observed in vitro and in vivo. Notably, AAV-based delivery efficiently reduced choroidal neovascularization area in a porcine model thereby suggesting its therapeutic relevance for the management of neovascular age-related macular degeneration.
  • Original Article

    Development of adenoviral vectors that transduce Purkinje cells and other cerebellar cell-types in the cerebellum of a humanized mouse model

    • Emre Kul,
    • Uchechi Okoroafor,
    • Amanda Dougherty,
    • Lauren Palkovic,
    • Hao Li,
    • Paula Valiño-Ramos,
    • Leah Aberman,
    • Samuel M. Young Jr.
    First published: March 26, 2024
    Young and colleagues developed a novel adenovirus vector that transduces Purkinje cells in a humanized mouse model. Since commonly used adenovirus vectors do not transduce Purkinje cells, these vectors offer immense promise toward developing gene therapy approaches for cerebellar disorders and potentially other neurological disorders requiring expression of large transgenes.
  • Original Article

    Durable transgene expression and efficient re-administration after rAAV2.5T-mediated fCFTRΔR gene delivery to adult ferret lungs

    • Yinghua Tang,
    • Mehrnoosh Ebadi,
    • Junying Lei,
    • Zehua Feng,
    • Shahab Fakhari,
    • Peipei Wu,
    • Mark D. Smith,
    • Maria P. Limberis,
    • Roland Kolbeck,
    • Katherine J. Excoffon,
    • Ziying Yan,
    • John F. Engelhardt
    First published: March 28, 2024
    Engelhardt and colleagues assessed the durability of AAV2.5T vector-mediated transgene expression for at least 5 months in ferret lungs, as well as the associated immune responses induced by the vector. They also efficiently re-administered the same AAV2.5T vector with a reporter gene after a 5-month interval.
  • Original Article

    An investigation of the immune epitopes of adeno-associated virus capsid-derived peptides among hemophilia patients

    • Li Liu,
    • Bingqi Xu,
    • Lingling Chen,
    • Jia Liu,
    • Wei Liu,
    • Feng Xue,
    • Sizhou Feng,
    • Erlie Jiang,
    • Mingzhe Han,
    • Wenwei Shao,
    • Lei Zhang,
    • Xiaolei Pei
    First published: April 02, 2024
    Xiaolei Pei and colleagues collected serum and PBMCs from 89 patients with hemophilia and analyzed the antibodies of AAV2 or its derived peptides through neutralizing antibody assay, binding antibody assay, BCR flow cytometry, and B cell ELISpot assay and the inhibitory capacity of peptides against AAV2 transduction both in vitro and in vivo.
  • Original Article

    Dose-response evaluation of intravenous gene therapy in a symptomatic mouse model of metachromatic leukodystrophy

    • Emilie Audouard,
    • Nicolas Khefif,
    • Charlotte Mansat,
    • Océane Nelcha,
    • Elena-Gaia Banchi,
    • Camille Lupiet,
    • Dominique Farabos,
    • Antonin Lamaziere,
    • Caroline Sevin,
    • Françoise Piguet
    First published: April 05, 2024
    Piguet and colleagues describe a gene therapy approach based on intravenous delivery of AAVPHP.eB-ARSA gene for MLD, a rare neurodegenerative disease caused by ARSA deficiency. Piguet and colleagues demonstrate a broad transduction of the vector in CNS, a complete correction of sulfatide storage, and a significant improvement of neuroinflammation in all conditions.
  • Original Article

    Metabolic priming of GD2 TRAC-CAR T cells during manufacturing promotes memory phenotypes while enhancing persistence

    • 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
    First published: April 09, 2024
    Cappabianca and colleagues manufactured virus-free CAR T cells at scale with CRISPR-Cas9 and “metabolically primed” them by attenuating activation in low-glucose/glutamine medium with expansion in high-glucose/glutamine medium. Priming made CAR T cells with increased stem cell memory properties, including enriched central memory phenotypes in vivo while lysing solid tumors.
  • Brief Report

    Manufacturing DNA in E. coli yields higher-fidelity DNA than in vitro enzymatic synthesis

    • Steven J. Hersch,
    • Siddarth Chandrasekaran,
    • Jamie Lam,
    • Nafiseh Nafissi,
    • Roderick A. Slavcev
    First published: February 28, 2024
    Hersch and colleagues introduce a new method examining the accuracy of DNA replication. Their findings show that DNA production in E. coli results in significantly fewer mutations compared to enzymatic DNA replication methods. Therefore, using DNA starting material produced in E. coli mitigates mutation-related risk in biotechnology and biomanufacturing.
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