AAV Gene Transfer with Tandem Promoter Design Prevents Anti-transgene Immunity and Provides Persistent Efficacy in Neonate Pompe Mice
Hepatocyte-restricted, AAV-mediated gene transfer is being used to provide sustained, tolerogenic transgene expression in gene therapy. However, given the episomal status of the AAV genome, this approach cannot be applied to pediatric disorders when hepatocyte proliferation may result in significant...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-03-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050118301141 |
| id |
doaj-a3d927f9d1284167b0026e3289c81292 |
|---|---|
| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Pasqualina Colella Pauline Sellier Helena Costa Verdera Francesco Puzzo Laetitia van Wittenberghe Nicolas Guerchet Nathalie Daniele Bernard Gjata Solenne Marmier Severine Charles Marcelo Simon Sola Isabella Ragone Christian Leborgne Fanny Collaud Federico Mingozzi |
| spellingShingle |
Pasqualina Colella Pauline Sellier Helena Costa Verdera Francesco Puzzo Laetitia van Wittenberghe Nicolas Guerchet Nathalie Daniele Bernard Gjata Solenne Marmier Severine Charles Marcelo Simon Sola Isabella Ragone Christian Leborgne Fanny Collaud Federico Mingozzi AAV Gene Transfer with Tandem Promoter Design Prevents Anti-transgene Immunity and Provides Persistent Efficacy in Neonate Pompe Mice Molecular Therapy: Methods & Clinical Development |
| author_facet |
Pasqualina Colella Pauline Sellier Helena Costa Verdera Francesco Puzzo Laetitia van Wittenberghe Nicolas Guerchet Nathalie Daniele Bernard Gjata Solenne Marmier Severine Charles Marcelo Simon Sola Isabella Ragone Christian Leborgne Fanny Collaud Federico Mingozzi |
| author_sort |
Pasqualina Colella |
| title |
AAV Gene Transfer with Tandem Promoter Design Prevents Anti-transgene Immunity and Provides Persistent Efficacy in Neonate Pompe Mice |
| title_short |
AAV Gene Transfer with Tandem Promoter Design Prevents Anti-transgene Immunity and Provides Persistent Efficacy in Neonate Pompe Mice |
| title_full |
AAV Gene Transfer with Tandem Promoter Design Prevents Anti-transgene Immunity and Provides Persistent Efficacy in Neonate Pompe Mice |
| title_fullStr |
AAV Gene Transfer with Tandem Promoter Design Prevents Anti-transgene Immunity and Provides Persistent Efficacy in Neonate Pompe Mice |
| title_full_unstemmed |
AAV Gene Transfer with Tandem Promoter Design Prevents Anti-transgene Immunity and Provides Persistent Efficacy in Neonate Pompe Mice |
| title_sort |
aav gene transfer with tandem promoter design prevents anti-transgene immunity and provides persistent efficacy in neonate pompe mice |
| publisher |
Elsevier |
| series |
Molecular Therapy: Methods & Clinical Development |
| issn |
2329-0501 |
| publishDate |
2019-03-01 |
| description |
Hepatocyte-restricted, AAV-mediated gene transfer is being used to provide sustained, tolerogenic transgene expression in gene therapy. However, given the episomal status of the AAV genome, this approach cannot be applied to pediatric disorders when hepatocyte proliferation may result in significant loss of therapeutic efficacy over time. In addition, many multi-systemic diseases require widespread expression of the therapeutic transgene that, when provided with ubiquitous or tissue-specific non-hepatic promoters, often results in anti-transgene immunity. Here we have developed tandem promoter monocistronic expression cassettes that, packaged in a single AAV, provide combined hepatic and extra-hepatic tissue-specific transgene expression and prevent anti-transgene immunity. We validated our approach in infantile Pompe disease, a prototype disease caused by lack of the ubiquitous enzyme acid-alpha-glucosidase (GAA), presenting multi-systemic manifestations and detrimental anti-GAA immunity. We showed that the use of efficient tandem promoters prevents immune responses to GAA following systemic AAV gene transfer in immunocompetent Gaa−/− mice. Then we demonstrated that neonatal gene therapy with either AAV8 or AAV9 in Gaa−/− mice resulted in persistent therapeutic efficacy when using a tandem liver-muscle promoter (LiMP) that provided high and persistent transgene expression in non-dividing extra-hepatic tissues. In conclusion, the tandem promoter design overcomes important limitations of AAV-mediated gene transfer and can be beneficial when treating pediatric conditions requiring persistent multi-systemic transgene expression and prevention of anti-transgene immunity. Keywords: tandem promoters, transgene immunity, transgene persistence, AAV, gene therapy |
| url |
http://www.sciencedirect.com/science/article/pii/S2329050118301141 |
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doaj-a3d927f9d1284167b0026e3289c812922020-11-24T22:28:49ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012019-03-011285101AAV Gene Transfer with Tandem Promoter Design Prevents Anti-transgene Immunity and Provides Persistent Efficacy in Neonate Pompe MicePasqualina Colella0Pauline Sellier1Helena Costa Verdera2Francesco Puzzo3Laetitia van Wittenberghe4Nicolas Guerchet5Nathalie Daniele6Bernard Gjata7Solenne Marmier8Severine Charles9Marcelo Simon Sola10Isabella Ragone11Christian Leborgne12Fanny Collaud13Federico Mingozzi14Genethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, France; Corresponding author: Pasqualina Colella, Genethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, France.Genethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, France; University Pierre and Marie Curie Paris 6 and INSERM U974, 75651, Paris, FranceGenethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, France; University Pierre and Marie Curie Paris 6 and INSERM U974, 75651, Paris, FranceGenethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, FranceGenethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, FranceGenethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, FranceGenethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, FranceGenethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, FranceUniversity Pierre and Marie Curie Paris 6 and INSERM U974, 75651, Paris, FranceGenethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, FranceGenethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, FranceGenethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, FranceGenethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, FranceGenethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, FranceGenethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, France; University Pierre and Marie Curie Paris 6 and INSERM U974, 75651, Paris, France; Spark Therapeutics, Philadelphia, PA 19103, USA; Corresponding author: Federico Mingozzi, Genethon, INSERM U951 Integrare, University of Evry, Université Paris-Saclay, 91002, Evry, France.Hepatocyte-restricted, AAV-mediated gene transfer is being used to provide sustained, tolerogenic transgene expression in gene therapy. However, given the episomal status of the AAV genome, this approach cannot be applied to pediatric disorders when hepatocyte proliferation may result in significant loss of therapeutic efficacy over time. In addition, many multi-systemic diseases require widespread expression of the therapeutic transgene that, when provided with ubiquitous or tissue-specific non-hepatic promoters, often results in anti-transgene immunity. Here we have developed tandem promoter monocistronic expression cassettes that, packaged in a single AAV, provide combined hepatic and extra-hepatic tissue-specific transgene expression and prevent anti-transgene immunity. We validated our approach in infantile Pompe disease, a prototype disease caused by lack of the ubiquitous enzyme acid-alpha-glucosidase (GAA), presenting multi-systemic manifestations and detrimental anti-GAA immunity. We showed that the use of efficient tandem promoters prevents immune responses to GAA following systemic AAV gene transfer in immunocompetent Gaa−/− mice. Then we demonstrated that neonatal gene therapy with either AAV8 or AAV9 in Gaa−/− mice resulted in persistent therapeutic efficacy when using a tandem liver-muscle promoter (LiMP) that provided high and persistent transgene expression in non-dividing extra-hepatic tissues. In conclusion, the tandem promoter design overcomes important limitations of AAV-mediated gene transfer and can be beneficial when treating pediatric conditions requiring persistent multi-systemic transgene expression and prevention of anti-transgene immunity. Keywords: tandem promoters, transgene immunity, transgene persistence, AAV, gene therapyhttp://www.sciencedirect.com/science/article/pii/S2329050118301141 |