PMID- 28497072
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240216
IS  - 2329-0501 (Print)
IS  - 2329-0501 (Electronic)
IS  - 2329-0501 (Linking)
VI  - 5
DP  - 2017 Jun 16
TI  - Improved MECP2 Gene Therapy Extends the Survival of MeCP2-Null Mice without 
      Apparent Toxicity after Intracisternal Delivery.
PG  - 106-115
LID - 10.1016/j.omtm.2017.04.006 [doi]
AB  - 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 x 10(12) viral genomes [vg]; ICM) extended 
      Mecp2(-/y) survival but aggravated hindlimb clasping and abnormal gait 
      phenotypes. In WT mice, 1 x 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 original 
      vector and demonstrated that an improved vector design extends Mecp2(-/y) 
      survival, without apparent toxicity.
FAU - Sinnett, Sarah E
AU  - Sinnett SE
AD  - University of North Carolina (UNC) Gene Therapy Center, Chapel Hill, NC 27599, 
      USA.
AD  - Carolina Institute for Developmental Disabilities, Chapel Hill, NC 27510, USA.
FAU - Hector, Ralph D
AU  - Hector RD
AD  - Institute of Neuroscience and Psychology, University of Glasgow, Glasgow G12 8QQ, 
      UK.
FAU - Gadalla, Kamal K E
AU  - Gadalla KKE
AD  - Institute of Neuroscience and Psychology, University of Glasgow, Glasgow G12 8QQ, 
      UK.
AD  - Pharmacology Department, Faculty of Medicine, Tanta University, Tanta 31111, 
      Egypt.
FAU - Heindel, Clifford
AU  - Heindel C
AD  - University of North Carolina (UNC) Gene Therapy Center, Chapel Hill, NC 27599, 
      USA.
FAU - Chen, Daphne
AU  - Chen D
AD  - University of North Carolina (UNC) Gene Therapy Center, Chapel Hill, NC 27599, 
      USA.
FAU - Zaric, Violeta
AU  - Zaric V
AD  - University of North Carolina (UNC) Gene Therapy Center, Chapel Hill, NC 27599, 
      USA.
FAU - Bailey, Mark E S
AU  - Bailey MES
AD  - School of Life Sciences, College of Medical, Veterinary and Life Sciences, 
      University of Glasgow, Glasgow G12 8QQ, UK.
FAU - Cobb, Stuart R
AU  - Cobb SR
AD  - Institute of Neuroscience and Psychology, University of Glasgow, Glasgow G12 8QQ, 
      UK.
FAU - Gray, Steven J
AU  - Gray SJ
AD  - University of North Carolina (UNC) Gene Therapy Center, Chapel Hill, NC 27599, 
      USA.
AD  - Carolina Institute for Developmental Disabilities, Chapel Hill, NC 27510, USA.
AD  - Department of Ophthalmology, University of North Carolina, Chapel Hill, NC 27517, 
      USA.
LA  - eng
GR  - P30 CA016086/CA/NCI NIH HHS/United States
GR  - P30 NS045892/NS/NINDS NIH HHS/United States
GR  - T32 HD040127/HD/NICHD NIH HHS/United States
PT  - Journal Article
DEP - 20170419
PL  - United States
TA  - Mol Ther Methods Clin Dev
JT  - Molecular therapy. Methods & clinical development
JID - 101624857
PMC - PMC5424572
OTO - NOTNLM
OT  - AAV
OT  - MeCP2
OT  - Mecp2-/y
OT  - Rett syndrome
OT  - cisterna magna
OT  - intrathecal
OT  - microRNA
OT  - viral vector
EDAT- 2017/05/13 06:00
MHDA- 2017/05/13 06:01
PMCR- 2017/04/19
CRDT- 2017/05/13 06:00
PHST- 2017/02/24 00:00 [received]
PHST- 2017/04/13 00:00 [accepted]
PHST- 2017/05/13 06:00 [entrez]
PHST- 2017/05/13 06:00 [pubmed]
PHST- 2017/05/13 06:01 [medline]
PHST- 2017/04/19 00:00 [pmc-release]
AID - S2329-0501(17)30061-X [pii]
AID - 10.1016/j.omtm.2017.04.006 [doi]
PST - epublish
SO  - Mol Ther Methods Clin Dev. 2017 Apr 19;5:106-115. doi: 
      10.1016/j.omtm.2017.04.006. eCollection 2017 Jun 16.