PMID- 29462293
OWN - NLM
STAT- MEDLINE
DCOM- 20190208
LR  - 20231213
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Linking)
VI  - 27
IP  - 8
DP  - 2018 Apr 15
TI  - Intrathecal gene therapy in mouse models expressing CMT1X mutations.
PG  - 1460-1473
LID - 10.1093/hmg/ddy056 [doi]
AB  - Gap junction beta-1 (GJB1) gene mutations affecting the gap junction protein 
      connexin32 (Cx32) cause the X-linked Charcot-Marie-Tooth disease (CMT1X), a 
      common inherited neuropathy. Targeted expression of virally delivered Cx32 in 
      Schwann cells following intrathecal injection of lentiviral vectors in the Cx32 
      knockout (KO) mouse model of the disease has led to morphological and functional 
      improvement. To examine whether this approach could be effective in CMT1X 
      patients expressing different Cx32 mutants, we treated transgenic Cx32 KO mice 
      expressing the T55I, R75W or N175D CMT1X mutations. All three mutants were 
      localized in the perinuclear compartment of myelinating Schwann cells consistent 
      with retention in the ER (T55I) or Golgi (R75W, N175D) and loss of physiological 
      expression in the non-compact myelin. Following intrathecal delivery of the GJB1 
      gene we detected the virally delivered wild-type (WT) Cx32 in non-compact myelin 
      of T55I KO mice, but only rarely in N175D KO or R75W KO mice, suggesting 
      dominant-negative effects of the R75W and N175D mutants but not of the T55I 
      mutant on co-expressed WT Cx32. GJB1 treated T55I KO mice showed improved motor 
      performance, lower ratios of abnormally myelinated fibers and reduction of 
      inflammatory cells in spinal roots and peripheral nerves compared with 
      mock-treated littermates. Either partial (N175D KO) or no (R75W KO) improvement 
      was observed in the other two mutant lines. Thus, certain CMT1X mutants may 
      interfere with gene addition therapy for CMT1X. Whereas gene addition can be used 
      for non-interfering CMT1X mutations, further studies will be needed to develop 
      treatments for patients harboring interfering mutations.
FAU - Kagiava, A
AU  - Kagiava A
AD  - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Cyprus 
      School of Molecular Medicine, 1683 Nicosia, Cyprus.
FAU - Karaiskos, C
AU  - Karaiskos C
AD  - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Cyprus 
      School of Molecular Medicine, 1683 Nicosia, Cyprus.
FAU - Richter, J
AU  - Richter J
AD  - Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, 
      Cyprus School of Molecular Medicine, 1683 Nicosia, Cyprus.
FAU - Tryfonos, C
AU  - Tryfonos C
AD  - Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, 
      Cyprus School of Molecular Medicine, 1683 Nicosia, Cyprus.
FAU - Lapathitis, G
AU  - Lapathitis G
AD  - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Cyprus 
      School of Molecular Medicine, 1683 Nicosia, Cyprus.
FAU - Sargiannidou, I
AU  - Sargiannidou I
AD  - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Cyprus 
      School of Molecular Medicine, 1683 Nicosia, Cyprus.
FAU - Christodoulou, C
AU  - Christodoulou C
AD  - Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics, 
      Cyprus School of Molecular Medicine, 1683 Nicosia, Cyprus.
FAU - Kleopa, K A
AU  - Kleopa KA
AD  - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics, Cyprus 
      School of Molecular Medicine, 1683 Nicosia, Cyprus.
AD  - Neurology Clinics, The Cyprus Institute of Neurology and Genetics, Cyprus School 
      of Molecular Medicine, 1683 Nicosia, Cyprus.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Connexins)
SB  - IM
MH  - Animals
MH  - Charcot-Marie-Tooth Disease/genetics/metabolism/pathology/*therapy
MH  - Connexins/deficiency/*genetics
MH  - Disease Models, Animal
MH  - Endoplasmic Reticulum/metabolism
MH  - Gap Junctions/metabolism/pathology/ultrastructure
MH  - Gene Expression
MH  - Genetic Therapy/*methods
MH  - Genetic Vectors/administration & dosage/chemistry/metabolism
MH  - Golgi Apparatus/metabolism
MH  - Humans
MH  - Injections, Spinal
MH  - Lentivirus/genetics/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - *Mutation
MH  - Schwann Cells/*metabolism/pathology/ultrastructure
MH  - Gap Junction beta-1 Protein
EDAT- 2018/02/21 06:00
MHDA- 2019/02/09 06:00
CRDT- 2018/02/21 06:00
PHST- 2017/12/12 00:00 [received]
PHST- 2018/02/10 00:00 [accepted]
PHST- 2018/02/21 06:00 [pubmed]
PHST- 2019/02/09 06:00 [medline]
PHST- 2018/02/21 06:00 [entrez]
AID - 4861152 [pii]
AID - 10.1093/hmg/ddy056 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2018 Apr 15;27(8):1460-1473. doi: 10.1093/hmg/ddy056.