PMID- 26010264
OWN - NLM
STAT- MEDLINE
DCOM- 20151006
LR  - 20231213
IS  - 1531-8249 (Electronic)
IS  - 0364-5134 (Linking)
VI  - 78
IP  - 2
DP  - 2015 Aug
TI  - Intraneural GJB1 gene delivery improves nerve pathology in a model of X-linked 
      Charcot-Marie-Tooth disease.
PG  - 303-16
LID - 10.1002/ana.24441 [doi]
AB  - OBJECTIVE: X-linked Charcot-Marie-Tooth disease (CMT1X) is a common inherited 
      neuropathy caused by mutations in the GJB1 gene encoding the gap junction protein 
      connexin32 (Cx32). Clinical studies and disease models indicate that neuropathy 
      mainly results from Schwann cell autonomous, loss-of-function mechanisms; 
      therefore, CMT1X may be treatable by gene replacement. METHODS: A lentiviral 
      vector LV.Mpz-GJB1 carrying the GJB1 gene under the Schwann cell-specific myelin 
      protein zero (Mpz) promoter was generated and delivered into the mouse sciatic 
      nerve by a single injection immediately distal to the sciatic notch. Enhanced 
      green fluorescent protein (EGFP) reporter gene expression was quantified and Cx32 
      expression was examined on a Cx32 knockout (KO) background. A gene therapy trial 
      was performed in a Cx32 KO model of CMT1X. RESULTS: EGFP was expressed throughout 
      the length of the sciatic nerve in up to 50% of Schwann cells starting 2 weeks 
      after injection and remaining stable for up to 16 weeks. Following LV.Mpz-GJB1 
      injection into Cx32 KO nerves, we detected Cx32 expression and correct 
      localization in non-compact myelin areas where gap junctions are normally formed. 
      Gene therapy trial by intraneural injection in groups of 2-month-old Cx32 KO 
      mice, before demyelination onset, significantly reduced the ratio of abnormally 
      myelinated fibers (p = 0.00148) and secondary inflammation (p = 0.0178) at 6 
      months of age compared to mock-treated animals. INTERPRETATION: Gene delivery 
      using a lentiviral vector leads to efficient gene expression specifically in 
      Schwann cells. Restoration of Cx32 expression ameliorates nerve pathology in a 
      disease model and provides a promising approach for future treatments of CMT1X 
      and other inherited neuropathies.
CI  - (c) 2015 American Neurological Association.
FAU - Sargiannidou, Irene
AU  - Sargiannidou I
AD  - Neuroscience Laboratory.
FAU - Kagiava, Alexia
AU  - Kagiava A
AD  - Neuroscience Laboratory.
FAU - Bashiardes, Stavros
AU  - Bashiardes S
AD  - Department of Molecular Virology, Cyprus Institute of Neurology and Genetics and 
      Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Richter, Jan
AU  - Richter J
AD  - Department of Molecular Virology, Cyprus Institute of Neurology and Genetics and 
      Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Christodoulou, Christina
AU  - Christodoulou C
AD  - Department of Molecular Virology, Cyprus Institute of Neurology and Genetics and 
      Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Scherer, Steven S
AU  - Scherer SS
AD  - Department of Neurology, University of Pennsylvania, Philadelphia, PA.
FAU - Kleopa, Kleopas A
AU  - Kleopa KA
AD  - Neuroscience Laboratory.
AD  - Neurology Clinics, Cyprus Institute of Neurology and Genetics and Cyprus School 
      of Molecular Medicine, Nicosia, Cyprus.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150630
PL  - United States
TA  - Ann Neurol
JT  - Annals of neurology
JID - 7707449
RN  - 0 (Connexins)
RN  - 0 (RNA, Messenger)
RN  - Charcot-Marie-Tooth disease, X-linked, 1
SB  - IM
MH  - Animals
MH  - Charcot-Marie-Tooth Disease/*genetics/metabolism
MH  - Connexins/*genetics
MH  - Disease Models, Animal
MH  - Genetic Therapy
MH  - Genetic Vectors
MH  - Lentivirus
MH  - Mice
MH  - Mice, Knockout
MH  - RNA, Messenger/*metabolism
MH  - Schwann Cells/*metabolism
MH  - Sciatic Nerve/*metabolism
MH  - Gap Junction beta-1 Protein
EDAT- 2015/05/27 06:00
MHDA- 2015/10/07 06:00
CRDT- 2015/05/27 06:00
PHST- 2015/02/17 00:00 [received]
PHST- 2015/05/20 00:00 [revised]
PHST- 2015/05/21 00:00 [accepted]
PHST- 2015/05/27 06:00 [entrez]
PHST- 2015/05/27 06:00 [pubmed]
PHST- 2015/10/07 06:00 [medline]
AID - 10.1002/ana.24441 [doi]
PST - ppublish
SO  - Ann Neurol. 2015 Aug;78(2):303-16. doi: 10.1002/ana.24441. Epub 2015 Jun 30.