Screening chimeric GAA variants in preclinicalstudy results in hematopoietic stem cell genetherapy candidate vectors for Pompe disease
Pompe disease is a rare genetic neuromuscular disorder caused by acid α-glucosidase (GAA) deficiency resulting in lysosomal glycogen accumulation and progressive myopathy. Enzyme replacement therapy, the current standard of care, penetrates poorly into the skeletal muscles and the peripheral and cen...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050122001590 |
| _version_ | 1797984182753820672 |
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| author | Yildirim Dogan Cecilia N. Barese Jeffrey W. Schindler John K. Yoon Zeenath Unnisa Swaroopa Guda Mary E. Jacobs Christine Oborski Tim Maiwald Diana L. Clarke Axel Schambach Richard Pfeifer Claudia Harper Chris Mason Niek P. van Til |
| author_facet | Yildirim Dogan Cecilia N. Barese Jeffrey W. Schindler John K. Yoon Zeenath Unnisa Swaroopa Guda Mary E. Jacobs Christine Oborski Tim Maiwald Diana L. Clarke Axel Schambach Richard Pfeifer Claudia Harper Chris Mason Niek P. van Til |
| author_sort | Yildirim Dogan |
| collection | DOAJ |
| description | Pompe disease is a rare genetic neuromuscular disorder caused by acid α-glucosidase (GAA) deficiency resulting in lysosomal glycogen accumulation and progressive myopathy. Enzyme replacement therapy, the current standard of care, penetrates poorly into the skeletal muscles and the peripheral and central nervous system (CNS), risks recombinant enzyme immunogenicity, and requires high doses and frequent infusions. Lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy was investigated in a Pompe mouse model using a clinically relevant promoter driving nine engineered GAA coding sequences incorporating distinct peptide tags and codon optimizations. Vectors solely including glycosylation-independent lysosomal targeting tags enhanced secretion and improved reduction of glycogen, myofiber, and CNS vacuolation in key tissues, although GAA enzyme activity and protein was consistently lower compared with native GAA. Genetically modified microglial cells in brains were detected at low levels but provided robust phenotypic correction. Furthermore, an amino acid substitution introduced in the tag reduced insulin receptor-mediated signaling with no evidence of an effect on blood glucose levels in Pompe mice. This study demonstrated the therapeutic potential of lentiviral HSPC gene therapy exploiting optimized GAA tagged coding sequences to reverse Pompe disease pathology in a preclinical mouse model, providing promising vector candidates for further investigation. |
| first_indexed | 2024-04-11T06:57:27Z |
| format | Article |
| id | doaj.art-19aee40652b94df1a4979d0e41238f5c |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-11T06:57:27Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-19aee40652b94df1a4979d0e41238f5c2022-12-22T04:38:57ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012022-12-0127464487Screening chimeric GAA variants in preclinicalstudy results in hematopoietic stem cell genetherapy candidate vectors for Pompe diseaseYildirim Dogan0Cecilia N. Barese1Jeffrey W. Schindler2John K. Yoon3Zeenath Unnisa4Swaroopa Guda5Mary E. Jacobs6Christine Oborski7Tim Maiwald8Diana L. Clarke9Axel Schambach10Richard Pfeifer11Claudia Harper12Chris Mason13Niek P. van Til14AVROBIO, Inc., Cambridge, MA 02139, USAAVROBIO, Inc., Cambridge, MA 02139, USAAVROBIO, Inc., Cambridge, MA 02139, USAAVROBIO, Inc., Cambridge, MA 02139, USAAVROBIO, Inc., Cambridge, MA 02139, USAAVROBIO, Inc., Cambridge, MA 02139, USAAVROBIO, Inc., Cambridge, MA 02139, USAAVROBIO, Inc., Cambridge, MA 02139, USAAVROBIO, Inc., Cambridge, MA 02139, USAAVROBIO, Inc., Cambridge, MA 02139, USAInstitute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany; Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, USAAVROBIO, Inc., Cambridge, MA 02139, USAAVROBIO, Inc., Cambridge, MA 02139, USAAVROBIO, Inc., Cambridge, MA 02139, USA; Advanced Centre for Biochemical Engineering, University College London, London WC1E 6AE, UK; Corresponding author Chris Mason, Advanced Centre for Biochemical Engineering, University College London, London WC1E 6AE, UKAVROBIO, Inc., Cambridge, MA 02139, USA; Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children’s Hospital, Amsterdam University Medical Centers, VU University, and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, 1081 HV Amsterdam, the Netherlands; Corresponding author Niek P. van Til, Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children’s Hospital, Amsterdam University Medical Centers, VU University, and Amsterdam Neuroscience, Cellular & Molecular Mechanisms, 1081 HV Amsterdam, the NetherlandsPompe disease is a rare genetic neuromuscular disorder caused by acid α-glucosidase (GAA) deficiency resulting in lysosomal glycogen accumulation and progressive myopathy. Enzyme replacement therapy, the current standard of care, penetrates poorly into the skeletal muscles and the peripheral and central nervous system (CNS), risks recombinant enzyme immunogenicity, and requires high doses and frequent infusions. Lentiviral vector-mediated hematopoietic stem and progenitor cell (HSPC) gene therapy was investigated in a Pompe mouse model using a clinically relevant promoter driving nine engineered GAA coding sequences incorporating distinct peptide tags and codon optimizations. Vectors solely including glycosylation-independent lysosomal targeting tags enhanced secretion and improved reduction of glycogen, myofiber, and CNS vacuolation in key tissues, although GAA enzyme activity and protein was consistently lower compared with native GAA. Genetically modified microglial cells in brains were detected at low levels but provided robust phenotypic correction. Furthermore, an amino acid substitution introduced in the tag reduced insulin receptor-mediated signaling with no evidence of an effect on blood glucose levels in Pompe mice. This study demonstrated the therapeutic potential of lentiviral HSPC gene therapy exploiting optimized GAA tagged coding sequences to reverse Pompe disease pathology in a preclinical mouse model, providing promising vector candidates for further investigation.http://www.sciencedirect.com/science/article/pii/S2329050122001590hematopoietic stem and progenitor cellslentiviral vectorPompe diseasetag technologyglycosylation-independent lysosomal targeting |
| spellingShingle | Yildirim Dogan Cecilia N. Barese Jeffrey W. Schindler John K. Yoon Zeenath Unnisa Swaroopa Guda Mary E. Jacobs Christine Oborski Tim Maiwald Diana L. Clarke Axel Schambach Richard Pfeifer Claudia Harper Chris Mason Niek P. van Til Screening chimeric GAA variants in preclinicalstudy results in hematopoietic stem cell genetherapy candidate vectors for Pompe disease Molecular Therapy: Methods & Clinical Development hematopoietic stem and progenitor cells lentiviral vector Pompe disease tag technology glycosylation-independent lysosomal targeting |
| title | Screening chimeric GAA variants in preclinicalstudy results in hematopoietic stem cell genetherapy candidate vectors for Pompe disease |
| title_full | Screening chimeric GAA variants in preclinicalstudy results in hematopoietic stem cell genetherapy candidate vectors for Pompe disease |
| title_fullStr | Screening chimeric GAA variants in preclinicalstudy results in hematopoietic stem cell genetherapy candidate vectors for Pompe disease |
| title_full_unstemmed | Screening chimeric GAA variants in preclinicalstudy results in hematopoietic stem cell genetherapy candidate vectors for Pompe disease |
| title_short | Screening chimeric GAA variants in preclinicalstudy results in hematopoietic stem cell genetherapy candidate vectors for Pompe disease |
| title_sort | screening chimeric gaa variants in preclinicalstudy results in hematopoietic stem cell genetherapy candidate vectors for pompe disease |
| topic | hematopoietic stem and progenitor cells lentiviral vector Pompe disease tag technology glycosylation-independent lysosomal targeting |
| url | http://www.sciencedirect.com/science/article/pii/S2329050122001590 |
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