Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome
Rett syndrome (RTT), caused by loss-of-function mutations in the MECP2 gene, is a neurological disorder characterized by severe impairment of motor and cognitive functions. The aim of this study was to investigate the impact of vector design, dosage, and delivery route on the efficacy and safety of...
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doaj-c7439aa4d23147af8550aac8afe957c52020-11-24T22:36:09ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012017-06-015C18019010.1016/j.omtm.2017.04.007Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett SyndromeKamal K.E. Gadalla0Thishnapha Vudhironarit1Ralph D. Hector2Sarah Sinnett3Noha G. Bahey4Mark E.S. Bailey5Steven J. Gray6Stuart R. Cobb7Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKInstitute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKInstitute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAInstitute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKSchool of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAInstitute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UKRett syndrome (RTT), caused by loss-of-function mutations in the MECP2 gene, is a neurological disorder characterized by severe impairment of motor and cognitive functions. The aim of this study was to investigate the impact of vector design, dosage, and delivery route on the efficacy and safety of gene augmentation therapy in mouse models of RTT. Our results show that AAV-mediated delivery of MECP2 to Mecp2 null mice by systemic administration, and utilizing a minimal endogenous promoter, was associated with a narrow therapeutic window and resulted in liver toxicity at higher doses. Lower doses of this vector significantly extended the survival of mice lacking MeCP2 or expressing a mutant T158M allele but had no impact on RTT-like neurological phenotypes. Modifying vector design by incorporating an extended Mecp2 promoter and additional regulatory 3′ UTR elements significantly reduced hepatic toxicity after systemic administration. Moreover, direct cerebroventricular injection of this vector into neonatal Mecp2-null mice resulted in high brain transduction efficiency, increased survival and body weight, and an amelioration of RTT-like phenotypes. Our results show that controlling levels of MeCP2 expression in the liver is achievable through modification of the expression cassette. However, it also highlights the importance of achieving high brain transduction to impact the RTT-like phenotypes.http://www.sciencedirect.com/science/article/pii/S2329050117300621Rett syndrome. MECP2adeno-associated virusgene therapyneurodevelopmental disorderautismvector |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kamal K.E. Gadalla Thishnapha Vudhironarit Ralph D. Hector Sarah Sinnett Noha G. Bahey Mark E.S. Bailey Steven J. Gray Stuart R. Cobb |
spellingShingle |
Kamal K.E. Gadalla Thishnapha Vudhironarit Ralph D. Hector Sarah Sinnett Noha G. Bahey Mark E.S. Bailey Steven J. Gray Stuart R. Cobb Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome Molecular Therapy: Methods & Clinical Development Rett syndrome. MECP2 adeno-associated virus gene therapy neurodevelopmental disorder autism vector |
author_facet |
Kamal K.E. Gadalla Thishnapha Vudhironarit Ralph D. Hector Sarah Sinnett Noha G. Bahey Mark E.S. Bailey Steven J. Gray Stuart R. Cobb |
author_sort |
Kamal K.E. Gadalla |
title |
Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome |
title_short |
Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome |
title_full |
Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome |
title_fullStr |
Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome |
title_full_unstemmed |
Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome |
title_sort |
development of a novel aav gene therapy cassette with improved safety features and efficacy in a mouse model of rett syndrome |
publisher |
Elsevier |
series |
Molecular Therapy: Methods & Clinical Development |
issn |
2329-0501 |
publishDate |
2017-06-01 |
description |
Rett syndrome (RTT), caused by loss-of-function mutations in the MECP2 gene, is a neurological disorder characterized by severe impairment of motor and cognitive functions. The aim of this study was to investigate the impact of vector design, dosage, and delivery route on the efficacy and safety of gene augmentation therapy in mouse models of RTT. Our results show that AAV-mediated delivery of MECP2 to Mecp2 null mice by systemic administration, and utilizing a minimal endogenous promoter, was associated with a narrow therapeutic window and resulted in liver toxicity at higher doses. Lower doses of this vector significantly extended the survival of mice lacking MeCP2 or expressing a mutant T158M allele but had no impact on RTT-like neurological phenotypes. Modifying vector design by incorporating an extended Mecp2 promoter and additional regulatory 3′ UTR elements significantly reduced hepatic toxicity after systemic administration. Moreover, direct cerebroventricular injection of this vector into neonatal Mecp2-null mice resulted in high brain transduction efficiency, increased survival and body weight, and an amelioration of RTT-like phenotypes. Our results show that controlling levels of MeCP2 expression in the liver is achievable through modification of the expression cassette. However, it also highlights the importance of achieving high brain transduction to impact the RTT-like phenotypes. |
topic |
Rett syndrome. MECP2 adeno-associated virus gene therapy neurodevelopmental disorder autism vector |
url |
http://www.sciencedirect.com/science/article/pii/S2329050117300621 |
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