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

Sarah E. Sinnett, Ralph D. Hector, Kamal K.E. Gadalla, Clifford Heindel, Daphne Chen, Violeta Zaric, Mark E.S. Bailey, Stuart R. Cobb, Steven J. Gray

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 × 1012 viral genomes [vg]; ICM) extended Mecp2−/y survival but aggravated hindlimb clasping and abnormal gait phenotypes. In WT mice, 1 × 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.

Original languageEnglish (US)
Pages (from-to)106-115
Number of pages10
JournalMolecular Therapy - Methods and Clinical Development
Volume5
DOIs
StatePublished - Jun 16 2017

Fingerprint

Genetic Therapy
Cisterna Magna
Dependovirus
Rett Syndrome
Phenotype
Viral Genome
Gait
Safety
Liver
Hindlimb
Transgenes
Intravenous Administration
Gene Expression
Injections
Serogroup

Keywords

  • AAV
  • cisterna magna
  • intrathecal
  • MeCP2
  • Mecp2
  • microRNA
  • Rett syndrome
  • viral vector

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Improved MECP2 Gene Therapy Extends the Survival of MeCP2-Null Mice without Apparent Toxicity after Intracisternal Delivery. / Sinnett, Sarah E.; Hector, Ralph D.; Gadalla, Kamal K.E.; Heindel, Clifford; Chen, Daphne; Zaric, Violeta; Bailey, Mark E.S.; Cobb, Stuart R.; Gray, Steven J.

In: Molecular Therapy - Methods and Clinical Development, Vol. 5, 16.06.2017, p. 106-115.

Research output: Contribution to journalArticle

Sinnett, Sarah E. ; Hector, Ralph D. ; Gadalla, Kamal K.E. ; Heindel, Clifford ; Chen, Daphne ; Zaric, Violeta ; Bailey, Mark E.S. ; Cobb, Stuart R. ; Gray, Steven J. / Improved MECP2 Gene Therapy Extends the Survival of MeCP2-Null Mice without Apparent Toxicity after Intracisternal Delivery. In: Molecular Therapy - Methods and Clinical Development. 2017 ; Vol. 5. pp. 106-115.
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