Improved MECP2 gene therapy extends the survival of MeCP2-null mice without apparent toxicity after intracisternal delivery

Sinnett, S. E., Hector, R. D. , Gadalla, K. K.E. , Heindel, C., Chen, D., Zaric, V., Bailey, M. E.S. , Cobb, S. R. and Gray, S. J. (2017) Improved MECP2 gene therapy extends the survival of MeCP2-null mice without apparent toxicity after intracisternal delivery. Molecular Therapy: Methods and Clinical Development, 5, pp. 106-115. (doi: 10.1016/j.omtm.2017.04.006) (PMID:28497072) (PMCID:PMC5424572)

Abstract

Intravenous administration of AAV9/hMECP2 has been shown to extend the lifespan of Mecp2-/y mice, but this delivery route induces liver toxicity in wild-type (WT) mice. To reduce peripheral transgene expression, we explored the safety and efficacy of AAV9/hMECP2 injected into the cisterna magna (ICM). AAV9/hMECP2 (1 x 1012 vg; ICM) extended Mecp2-/y survival, but aggravated hindlimb clasping and abnormal gait phenotypes. In WT mice, 1 x 1012 vg of AAV9/hMECP2 induced clasping and abnormal gait. A lower dose mitigated these adverse phenotypes but failed to extend survival of Mecp2-/y mice. Thus, ICM delivery of this vector is impractical as a treatment for Rett syndrome (RTT). To improve the safety of MeCP2 gene therapy, the gene expression cassette was modified to include more endogenous regulatory elements believed to modulate MeCP2 expression in vivo. In Mecp2-/y mice, ICM injection of the modified vector extended lifespan and was well tolerated by the liver, but did not rescue RTT behavioral phenotypes. In WT mice, these same doses of the modified vector had no adverse effects on survival or neurological phenotypes. In summary, we identified limitations of the original vector and demonstrated that an improved vector design extends Mecp2-/y survival without apparent toxicity.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cobb, Dr Stuart and Gadalla, Dr Kamal and Hector, Dr Ralph and Bailey, Dr Mark
• Authors: Sinnett, S. E., Hector, R. D., Gadalla, K. K.E., Heindel, C., Chen, D., Zaric, V., Bailey, M. E.S., Cobb, S. R., and Gray, S. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience; 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: 19 April 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Molecular Therapy: Methods and Clinical Development 5: 106-115
• Publisher Policy: Reproduced under a Creative Commons License