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Mol Ther Methods Clin Dev. 2017 Apr 22;5:180-190. doi: 10.1016/j.omtm.2017.04.007. eCollection 2017 Jun 16.

Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome.

Author information

1
Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
2
Pharmacology Department, Faculty of Medicine, Tanta University, Tanta 31527, Egypt.
3
Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
4
Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
5
Histology Department, Faculty of Medicine, Tanta University, Tanta 31527, Egypt.
6
School of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
7
Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.

Abstract

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.

KEYWORDS:

Rett syndrome. MECP2; adeno-associated virus; autism; gene therapy; neurodevelopmental disorder; vector

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