Improved MECP2 Gene Therapy Extends the Survival of MeCP2-Null Mice without Apparent Toxicity after Intracisternal Delivery

Molecular Therapy. Methods & Clinical Development
Sarah SinnettSteven J Gray

Abstract

Intravenous administration of adeno-associated virus serotype 9 (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 × 10(12) viral genomes [vg]; ICM) extended Mecp2(-/y) survival but aggravated hindlimb clasping and abnormal gait phenotypes. In WT mice, 1 × 10(12) 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 ori...Continue Reading

Citations

Mar 30, 2018·Human Gene Therapy Methods·Dan WangGuangping Gao
Jun 15, 2019·Journal of Drug Targeting·Stefanie A PenaAdrien A Eshraghi
Jun 24, 2020·The European Journal of Neuroscience·Fabián NishidaEnrique L Portiansky
Oct 29, 2017·Proceedings of the National Academy of Sciences of the United States of America·John R SinnamonGail Mandel
Apr 26, 2020·European Journal of Human Genetics : EJHG·Susanna CrociIlaria Meloni
Oct 20, 2017·Frontiers in Molecular Neuroscience·Xu-Rui JinLan Xiao
May 20, 2018·Journal of Neurodevelopmental Disorders·Erik Allen LykkenSteven James Gray
Mar 2, 2019·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Neeti Vashi, Monica J Justice
Jun 17, 2020·European Journal of Human Genetics : EJHG·Susanna CrociIlaria Meloni
Aug 9, 2020·Frontiers in Neuroanatomy·Hyojin KimBenjamin D Philpot
Apr 11, 2018·F1000Research·Yann EhingerJean-Christophe Roux
Nov 14, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Xin ChenSteven J Gray
Sep 29, 2020·BMJ Paediatrics Open·Cary FuTimothy Benke
May 1, 2021·International Journal of Molecular Sciences·Ana Rita GomesMaria Margarida Diogo
May 11, 2021·Frontiers in Genetics·Osman Sharifi, Dag H Yasui
May 5, 2021·Genes, Brain, and Behavior·Bridget E CollinsJeffrey L Neul
Feb 28, 2021·Journal of Neurochemistry·Santosh R D'Mello
Sep 14, 2021·Frontiers in Neuroscience·Florencia D HaaseWendy A Gold
Nov 23, 2021·Human Genetics·Laura FitzPatrick, Adrian Bird
May 19, 2021·Genes, Brain, and Behavior·Sheryl Anne D VermudezColleen M Niswender

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Methods Mentioned

BETA
transgenic
PCR

Software Mentioned

Graphpad Prism

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