Development of a novel AAV gene therapy cassette with improved safety features and efficacy in a mouse model of Rett syndrome

Gadalla, K. K.E. , Vudhironarit, T., Hector, R. D. , Sinnett, S., Bahey, N. G., Bailey, M. E.S. , Gray, S. J. and Cobb, S. R. (2017) Development of a novel AAV gene therapy cassette with improved safety features and efficacy in a mouse model of Rett syndrome. Molecular Therapy: Methods and Clinical Development, 5, pp. 180-190. (doi: 10.1016/j.omtm.2017.04.007) (PMID:28497075) (PMCID:PMC5423329)

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 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 bodyweight 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bahey, Mrs Noha and Cobb, Dr Stuart and Gadalla, Dr Kamal and Hector, Dr Ralph and Bailey, Dr Mark
• Authors: Gadalla, K. K.E., Vudhironarit, T., Hector, R. D., Sinnett, S., Bahey, N. G., Bailey, M. E.S., Gray, S. J., and Cobb, S. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience; College of Medical Veterinary and Life Sciences > School of Life Sciences; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Molecular Therapy: Methods and Clinical Development
• Publisher: Elsevier
• ISSN: 2329-0501
• ISSN (Online): 2329-0501
• Published Online: 22 April 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Molecular Therapy: Methods and Clinical Development 5:180-190
• Publisher Policy: Reproduced under a Creative Commons License