Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction
Pompe disease results from acid α-glucosidase (GAA) deficiency, and enzyme replacement therapy (ERT) with recombinant human (rh) GAA has clinical benefits, although its limitations include the short half-life of GAA and the formation of antibody responses. The present study compared the efficacy of...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-03-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050117300049 |
| _version_ | 1811267750521208832 |
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| author | Sang-oh Han Giuseppe Ronzitti Benjamin Arnson Christian Leborgne Songtao Li Federico Mingozzi Dwight Koeberl |
| author_facet | Sang-oh Han Giuseppe Ronzitti Benjamin Arnson Christian Leborgne Songtao Li Federico Mingozzi Dwight Koeberl |
| author_sort | Sang-oh Han |
| collection | DOAJ |
| description | Pompe disease results from acid α-glucosidase (GAA) deficiency, and enzyme replacement therapy (ERT) with recombinant human (rh) GAA has clinical benefits, although its limitations include the short half-life of GAA and the formation of antibody responses. The present study compared the efficacy of ERT against gene transfer with an adeno-associated viral (AAV) vector containing a liver-specific promoter. GAA knockout (KO) mice were administered either a weekly injection of rhGAA (20 mg/kg) or a single injection of AAV2/8-LSPhGAA (8 × 1011 vector genomes [vg]/kg). Both treatments significantly reduced glycogen content of the heart and diaphragm. Although ERT triggered anti-GAA antibody formation, there was no detectable antibody response following AAV vector administration. The efficacy of three lower dosages of AAV2/8-LSPhGAA was evaluated in GAA-KO mice, either alone or in combination with ERT. The minimum effective dose (MED) identified was 8 × 1010 vg/kg to reduce glycogen content in the heart and diaphragm of GAA-KO mice. A 3-fold higher dose was required to suppress antibody responses to ERT. Efficacy from liver gene therapy was slightly greater in male mice than in female mice. Vector dose correlated inversely with anti-GAA antibody formation, whereas higher vector doses suppressed previously formed anti-GAA antibodies as late as 25 weeks after the start of ERT and achieved biochemical correction of glycogen accumulation. In conclusion, we identified the MED for effective AAV2/8-LSPhGAA-mediated tolerogenic gene therapy in Pompe disease mice. |
| first_indexed | 2024-04-12T21:09:41Z |
| format | Article |
| id | doaj.art-9139c3ce594942769f879f7b29b34fed |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-04-12T21:09:41Z |
| publishDate | 2017-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-9139c3ce594942769f879f7b29b34fed2022-12-22T03:16:38ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012017-03-014C12613610.1016/j.omtm.2016.12.010Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance InductionSang-oh Han0Giuseppe Ronzitti1Benjamin Arnson2Christian Leborgne3Songtao Li4Federico Mingozzi5Dwight Koeberl6Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USAGenethon and INSERM U951, 91002 Evry, FranceDivision of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USAGenethon and INSERM U951, 91002 Evry, FranceDivision of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USAGenethon and INSERM U951, 91002 Evry, FranceDivision of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USAPompe disease results from acid α-glucosidase (GAA) deficiency, and enzyme replacement therapy (ERT) with recombinant human (rh) GAA has clinical benefits, although its limitations include the short half-life of GAA and the formation of antibody responses. The present study compared the efficacy of ERT against gene transfer with an adeno-associated viral (AAV) vector containing a liver-specific promoter. GAA knockout (KO) mice were administered either a weekly injection of rhGAA (20 mg/kg) or a single injection of AAV2/8-LSPhGAA (8 × 1011 vector genomes [vg]/kg). Both treatments significantly reduced glycogen content of the heart and diaphragm. Although ERT triggered anti-GAA antibody formation, there was no detectable antibody response following AAV vector administration. The efficacy of three lower dosages of AAV2/8-LSPhGAA was evaluated in GAA-KO mice, either alone or in combination with ERT. The minimum effective dose (MED) identified was 8 × 1010 vg/kg to reduce glycogen content in the heart and diaphragm of GAA-KO mice. A 3-fold higher dose was required to suppress antibody responses to ERT. Efficacy from liver gene therapy was slightly greater in male mice than in female mice. Vector dose correlated inversely with anti-GAA antibody formation, whereas higher vector doses suppressed previously formed anti-GAA antibodies as late as 25 weeks after the start of ERT and achieved biochemical correction of glycogen accumulation. In conclusion, we identified the MED for effective AAV2/8-LSPhGAA-mediated tolerogenic gene therapy in Pompe disease mice.http://www.sciencedirect.com/science/article/pii/S2329050117300049gene therapyadeno-associated virusacid α-glucosidaseacid maltaseglycogen storage disease type IIimmune tolerance induction |
| spellingShingle | Sang-oh Han Giuseppe Ronzitti Benjamin Arnson Christian Leborgne Songtao Li Federico Mingozzi Dwight Koeberl Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction Molecular Therapy: Methods & Clinical Development gene therapy adeno-associated virus acid α-glucosidase acid maltase glycogen storage disease type II immune tolerance induction |
| title | Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction |
| title_full | Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction |
| title_fullStr | Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction |
| title_full_unstemmed | Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction |
| title_short | Low-Dose Liver-Targeted Gene Therapy for Pompe Disease Enhances Therapeutic Efficacy of ERT via Immune Tolerance Induction |
| title_sort | low dose liver targeted gene therapy for pompe disease enhances therapeutic efficacy of ert via immune tolerance induction |
| topic | gene therapy adeno-associated virus acid α-glucosidase acid maltase glycogen storage disease type II immune tolerance induction |
| url | http://www.sciencedirect.com/science/article/pii/S2329050117300049 |
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