PMID- 31411673
OWN - NLM
STAT- MEDLINE
DCOM- 20200526
LR  - 20231213
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Linking)
VI  - 28
IP  - 21
DP  - 2019 Nov 1
TI  - Gene replacement therapy after neuropathy onset provides therapeutic benefit in a 
      model of CMT1X.
PG  - 3528-3542
LID - 10.1093/hmg/ddz199 [doi]
AB  - X-linked Charcot-Marie-Tooth disease (CMT1X), one of the commonest forms of 
      inherited demyelinating neuropathy, results from GJB1 gene mutations causing loss 
      of function of the gap junction protein connexin32 (Cx32). The aim of this study 
      was to examine whether delayed gene replacement therapy after the onset of 
      peripheral neuropathy can provide a therapeutic benefit in the Gjb1-null/Cx32 
      knockout model of CMT1X. After delivery of the LV-Mpz.GJB1 lentiviral vector by a 
      single lumbar intrathecal injection into 6-month-old Gjb1-null mice, we confirmed 
      expression of Cx32 in lumbar roots and sciatic nerves correctly localized at the 
      paranodal myelin areas. Gjb1-null mice treated with LV-Mpz.GJB1 compared with 
      LV-Mpz.Egfp (mock) vector at the age of 6 months showed improved motor 
      performance at 8 and 10 months. Furthermore, treated mice showed increased 
      sciatic nerve conduction velocities, improvement of myelination and reduced 
      inflammation in lumbar roots and peripheral nerves at 10 months of age, along 
      with enhanced quadriceps muscle innervation. Plasma neurofilament light (NEFL) 
      levels, a clinically relevant biomarker, were also ameliorated in fully treated 
      mice. Intrathecal gene delivery after the onset of peripheral neuropathy offers a 
      significant therapeutic benefit in this disease model, providing a proof of 
      principle for treating patients with CMT1X at different ages.
CI  - (c) The Author(s) 2019. Published by Oxford University Press. All rights reserved. 
      For Permissions, please email: journals.permissions@oup.com.
FAU - Kagiava, A
AU  - Kagiava A
AD  - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics and 
      Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Richter, J
AU  - Richter J
AD  - Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics 
      and Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Tryfonos, C
AU  - Tryfonos C
AD  - Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics 
      and Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Karaiskos, C
AU  - Karaiskos C
AD  - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics and 
      Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Heslegrave, A J
AU  - Heslegrave AJ
AD  - Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, 
      London, United Kingdom.
FAU - Sargiannidou, I
AU  - Sargiannidou I
AD  - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics and 
      Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Rossor, A M
AU  - Rossor AM
AD  - Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, 
      London, United Kingdom.
FAU - Zetterberg, H
AU  - Zetterberg H
AD  - Department of Neurodegenerative Disease, UCL Institute of Neurology, London, 
      United Kingdom.
AD  - UK Dementia Research Institute at UCL, London, United Kingdom.
AD  - Department of Psychiatry and Neurochemistry, Institute of Neuroscience and 
      Physiology, the Sahlgrenska Academy at the University of Gothenburg, Molndal, 
      Sweden.
AD  - Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Molndal, 
      Sweden.
FAU - Reilly, M M
AU  - Reilly MM
AD  - Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, 
      London, United Kingdom.
FAU - Christodoulou, C
AU  - Christodoulou C
AD  - Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics 
      and Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Kleopa, K A
AU  - Kleopa KA
AD  - Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics and 
      Cyprus School of Molecular Medicine, Nicosia, Cyprus.
AD  - Neurology Clinics, The 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
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/*genetics/metabolism
MH  - Disease Models, Animal
MH  - Female
MH  - *Genetic Therapy
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myelin Sheath/metabolism
MH  - Spinal Nerve Roots/metabolism/pathology
MH  - Gap Junction beta-1 Protein
EDAT- 2019/08/15 06:00
MHDA- 2020/05/27 06:00
CRDT- 2019/08/15 06:00
PHST- 2019/06/04 00:00 [received]
PHST- 2019/07/26 00:00 [revised]
PHST- 2019/07/31 00:00 [accepted]
PHST- 2019/08/15 06:00 [pubmed]
PHST- 2020/05/27 06:00 [medline]
PHST- 2019/08/15 06:00 [entrez]
AID - 5549642 [pii]
AID - 10.1093/hmg/ddz199 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2019 Nov 1;28(21):3528-3542. doi: 10.1093/hmg/ddz199.