Effective gene therapy for metachromatic leukodystrophy achieved with minimal lentiviral genomic integrations
Metachromatic leukodystrophy (MLD) is a fatal lysosomal storage disease characterized by the deficient enzymatic activity of arylsulfatase A (ARSA). Combined autologous hematopoietic stem cell transplantion (HSCT) with lentiviral (LV)-based gene therapy has great potential to treat MLD. Achieving th...
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253125000186 |
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| author | Lucas Tricoli Sunetra Sase Julia L. Hacker Vi Pham Maxwell Chappell Laura Breda Stephanie N. Hurwitz Naoto Tanaka Carlo Castruccio Castracani Amaliris Guerra Zhongqi Hou Lars Schlotawa Karthikeyan Radhakrishnan Matthew Hogenauer Aoife Roche John Everett Frederic Bushman Peter Kurre Rebecca Ahrens-Nicklas Laura A. Adang Adeline L. Vanderver Stefano Rivella |
| author_facet | Lucas Tricoli Sunetra Sase Julia L. Hacker Vi Pham Maxwell Chappell Laura Breda Stephanie N. Hurwitz Naoto Tanaka Carlo Castruccio Castracani Amaliris Guerra Zhongqi Hou Lars Schlotawa Karthikeyan Radhakrishnan Matthew Hogenauer Aoife Roche John Everett Frederic Bushman Peter Kurre Rebecca Ahrens-Nicklas Laura A. Adang Adeline L. Vanderver Stefano Rivella |
| author_sort | Lucas Tricoli |
| collection | DOAJ |
| description | Metachromatic leukodystrophy (MLD) is a fatal lysosomal storage disease characterized by the deficient enzymatic activity of arylsulfatase A (ARSA). Combined autologous hematopoietic stem cell transplantion (HSCT) with lentiviral (LV)-based gene therapy has great potential to treat MLD. Achieving the optimal balance between high enzyme production for therapeutic efficacy and maintaining a low vector copy number (VCN) is crucial. Insufficient enzyme levels can lead to the progression of motor symptoms, undermining treatment goals. Conversely, elevated VCN increases the risk of genotoxicity, which poses safety concerns, and contributes to higher production costs, making the therapy less accessible. Striking this balance is essential to maximize clinical benefit while minimizing risks and costs. To address this need, we increased the expression of ARSA cDNA at single integration by generating novel LVs, optimizing ARSA expression and enhancing safety. In addition, our vectors achieved optimal transduction in mouse and human hematopoietic stem cells (HSCs) with minimal multiplicity of infection (MOI). Our top-performing vector (EA1) showed at least 4× more ARSA activity than the currently US and European Union (EU)-approved vector and a superior ability to secrete vesicle-associated ARSA, a critical modality to transfer functional enzymes from microglia to oligodendrocytes. Three-month-old Arsa-knockout (KO) MLD mice transplanted with Arsa-KO bone marrow (BM) cells transduced with 0.6 VCN of EA1 demonstrated behavior and CNS histology matching wild-type (WT) mice. Our novel vector boosts efficacy while improving safety as a robust approach for treating MLD patients. |
| format | Article |
| id | doaj-art-b59f946719ad4f259d2bf5d4829f0c32 |
| institution | Kabale University |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
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| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-b59f946719ad4f259d2bf5d4829f0c322025-02-09T05:00:03ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-03-01361102464Effective gene therapy for metachromatic leukodystrophy achieved with minimal lentiviral genomic integrationsLucas Tricoli0Sunetra Sase1Julia L. Hacker2Vi Pham3Maxwell Chappell4Laura Breda5Stephanie N. Hurwitz6Naoto Tanaka7Carlo Castruccio Castracani8Amaliris Guerra9Zhongqi Hou10Lars Schlotawa11Karthikeyan Radhakrishnan12Matthew Hogenauer13Aoife Roche14John Everett15Frederic Bushman16Peter Kurre17Rebecca Ahrens-Nicklas18Laura A. Adang19Adeline L. Vanderver20Stefano Rivella21Department of Pediatrics, Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, USADepartment of Pediatrics, Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USADepartment of Pediatrics, Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USADepartment of Pediatrics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA; Cell and Molecular Biology affinity group (CAMB), University of Pennsylvania, Philadelphia, PA, USADepartment of Pediatrics, Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, USADepartment of Pediatrics, Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, USADepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA; Comprehensive Bone Marrow Failure Center, CHOP, Philadelphia, PA, USADepartment of Pediatrics, Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, USADepartment of Pediatrics, Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, USADepartment of Pediatrics, Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, USADepartment of Pediatrics, Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USAUniversity Medical Centre Göttingen, Göttingen, Germany; Fraunhofer Institute for Translational Medicine – Translational Neuroinflammation and Automated Microscopy, Göttingen, GermanyBielefeld University, Bielefeld, GermanyDepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Pediatrics, Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA; Comprehensive Bone Marrow Failure Center, CHOP, Philadelphia, PA, USADepartment of Pediatrics, Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USADepartment of Pediatrics, Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Pediatrics, Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USADepartment of Pediatrics, Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA; Hospital of the University of Pennsylvania, Philadelphia, PA, USA; RNA Institute, University of Pennsylvania, Philadelphia, PA, USA; Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA; Penn Center for Musculoskeletal Disorders, CHOP, Philadelphia, PA, USA; Raymond G. Perelman Center for Cellular and Molecular Therapeutics-CHOP, Philadelphia, PA, USA; Corresponding author: Stefano Rivella, Department of Pediatrics, Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.Metachromatic leukodystrophy (MLD) is a fatal lysosomal storage disease characterized by the deficient enzymatic activity of arylsulfatase A (ARSA). Combined autologous hematopoietic stem cell transplantion (HSCT) with lentiviral (LV)-based gene therapy has great potential to treat MLD. Achieving the optimal balance between high enzyme production for therapeutic efficacy and maintaining a low vector copy number (VCN) is crucial. Insufficient enzyme levels can lead to the progression of motor symptoms, undermining treatment goals. Conversely, elevated VCN increases the risk of genotoxicity, which poses safety concerns, and contributes to higher production costs, making the therapy less accessible. Striking this balance is essential to maximize clinical benefit while minimizing risks and costs. To address this need, we increased the expression of ARSA cDNA at single integration by generating novel LVs, optimizing ARSA expression and enhancing safety. In addition, our vectors achieved optimal transduction in mouse and human hematopoietic stem cells (HSCs) with minimal multiplicity of infection (MOI). Our top-performing vector (EA1) showed at least 4× more ARSA activity than the currently US and European Union (EU)-approved vector and a superior ability to secrete vesicle-associated ARSA, a critical modality to transfer functional enzymes from microglia to oligodendrocytes. Three-month-old Arsa-knockout (KO) MLD mice transplanted with Arsa-KO bone marrow (BM) cells transduced with 0.6 VCN of EA1 demonstrated behavior and CNS histology matching wild-type (WT) mice. Our novel vector boosts efficacy while improving safety as a robust approach for treating MLD patients.http://www.sciencedirect.com/science/article/pii/S2162253125000186MT: Delivery Strategiesgene therapygene complementationnovel lentiviral vectormetachromatic leukodystrophyMLD |
| spellingShingle | Lucas Tricoli Sunetra Sase Julia L. Hacker Vi Pham Maxwell Chappell Laura Breda Stephanie N. Hurwitz Naoto Tanaka Carlo Castruccio Castracani Amaliris Guerra Zhongqi Hou Lars Schlotawa Karthikeyan Radhakrishnan Matthew Hogenauer Aoife Roche John Everett Frederic Bushman Peter Kurre Rebecca Ahrens-Nicklas Laura A. Adang Adeline L. Vanderver Stefano Rivella Effective gene therapy for metachromatic leukodystrophy achieved with minimal lentiviral genomic integrations Molecular Therapy: Nucleic Acids MT: Delivery Strategies gene therapy gene complementation novel lentiviral vector metachromatic leukodystrophy MLD |
| title | Effective gene therapy for metachromatic leukodystrophy achieved with minimal lentiviral genomic integrations |
| title_full | Effective gene therapy for metachromatic leukodystrophy achieved with minimal lentiviral genomic integrations |
| title_fullStr | Effective gene therapy for metachromatic leukodystrophy achieved with minimal lentiviral genomic integrations |
| title_full_unstemmed | Effective gene therapy for metachromatic leukodystrophy achieved with minimal lentiviral genomic integrations |
| title_short | Effective gene therapy for metachromatic leukodystrophy achieved with minimal lentiviral genomic integrations |
| title_sort | effective gene therapy for metachromatic leukodystrophy achieved with minimal lentiviral genomic integrations |
| topic | MT: Delivery Strategies gene therapy gene complementation novel lentiviral vector metachromatic leukodystrophy MLD |
| url | http://www.sciencedirect.com/science/article/pii/S2162253125000186 |
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