PMID- 33692503
OWN - NLM
STAT- MEDLINE
DCOM- 20220301
LR  - 20230129
IS  - 1476-5462 (Electronic)
IS  - 0969-7128 (Print)
IS  - 0969-7128 (Linking)
VI  - 28
IP  - 10-11
DP  - 2021 Nov
TI  - AAV9-mediated Schwann cell-targeted gene therapy rescues a model of demyelinating 
      neuropathy.
PG  - 659-675
LID - 10.1038/s41434-021-00250-0 [doi]
AB  - Mutations in the GJB1 gene, encoding the gap junction (GJ) protein connexin32 
      (Cx32), cause X-linked Charcot-Marie-Tooth disease (CMT1X), an inherited 
      demyelinating neuropathy. We developed a gene therapy approach for CMT1X using an 
      AAV9 vector to deliver the GJB1/Cx32 gene under the myelin protein zero (Mpz) 
      promoter for targeted expression in Schwann cells. Lumbar intrathecal injection 
      of the AAV9-Mpz.GJB1 resulted in widespread biodistribution in the peripheral 
      nervous system including lumbar roots, sciatic and femoral nerves, as well as in 
      Cx32 expression in the paranodal non-compact myelin areas of myelinated fibers. A 
      pre-, as well as post-onset treatment trial in Gjb1-null mice, demonstrated 
      improved motor performance and sciatic nerve conduction velocities along with 
      improved myelination and reduced inflammation in peripheral nerve tissues. Blood 
      biomarker levels were also significantly ameliorated in treated mice. This study 
      provides evidence that a clinically translatable AAV9-mediated gene therapy 
      approach targeting Schwann cells could potentially treat CMT1X.
CI  - (c) 2021. The Author(s).
FAU - Kagiava, Alexia
AU  - Kagiava A
AUID- ORCID: 0000-0002-3903-1299
AD  - Neuroscience Department, The Cyprus Institute of Neurology and Genetics and 
      Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Karaiskos, Christos
AU  - Karaiskos C
AD  - Neuroscience Department, The 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, The Cyprus Institute of Neurology and Genetics 
      and Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Tryfonos, Christina
AU  - Tryfonos C
AD  - Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics 
      and Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Jennings, Matthew J
AU  - Jennings MJ
AD  - Department of Clinical Neurosciences, University of Cambridge, Cambridge, United 
      Kingdom.
FAU - Heslegrave, Amanda J
AU  - Heslegrave AJ
AD  - Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, 
      London, United Kingdom.
FAU - Sargiannidou, Irene
AU  - Sargiannidou I
AD  - Neuroscience Department, The Cyprus Institute of Neurology and Genetics and 
      Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Stavrou, Marina
AU  - Stavrou M
AD  - Neuroscience Department, The Cyprus Institute of Neurology and Genetics and 
      Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Zetterberg, Henrik
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, Mary M
AU  - Reilly MM
AD  - Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, 
      London, United Kingdom.
FAU - Christodoulou, Christina
AU  - Christodoulou C
AD  - Department of Molecular Virology, The Cyprus Institute of Neurology and Genetics 
      and Cyprus School of Molecular Medicine, Nicosia, Cyprus.
FAU - Horvath, Rita
AU  - Horvath R
AD  - Department of Clinical Neurosciences, University of Cambridge, Cambridge, United 
      Kingdom.
FAU - Kleopa, Kleopas A
AU  - Kleopa KA
AUID- ORCID: 0000-0002-4103-8094
AD  - Neuroscience Department, The Cyprus Institute of Neurology and Genetics and 
      Cyprus School of Molecular Medicine, Nicosia, Cyprus. kleopa@cing.ac.cy.
AD  - Center for Neuromuscular Disorders, The Cyprus Institute of Neurology and 
      Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus. 
      kleopa@cing.ac.cy.
LA  - eng
GR  - MR/N010035/1/MRC_/Medical Research Council/United Kingdom
GR  - G1000848/MRC_/Medical Research Council/United Kingdom
GR  - MR/N025431/2/MRC_/Medical Research Council/United Kingdom
GR  - 109915/Z/15/Z/WT_/Wellcome Trust/United Kingdom
GR  - MR/V009346/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/N025431/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/K000608/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210310
PL  - England
TA  - Gene Ther
JT  - Gene therapy
JID - 9421525
RN  - 0 (Connexins)
SB  - IM
MH  - Animals
MH  - *Charcot-Marie-Tooth Disease/genetics/metabolism/therapy
MH  - Connexins/genetics/metabolism
MH  - Genetic Therapy/methods
MH  - Mice
MH  - Mice, Knockout
MH  - *Schwann Cells/metabolism
MH  - Tissue Distribution
PMC - PMC8599011
COIS- The study is part of a PCT/EP2020/065312 application in which AK, IS and KAK are 
      co-inventors.
EDAT- 2021/03/12 06:00
MHDA- 2022/03/03 06:00
PMCR- 2021/03/10
CRDT- 2021/03/11 06:28
PHST- 2020/12/17 00:00 [received]
PHST- 2021/02/19 00:00 [accepted]
PHST- 2021/02/15 00:00 [revised]
PHST- 2021/03/12 06:00 [pubmed]
PHST- 2022/03/03 06:00 [medline]
PHST- 2021/03/11 06:28 [entrez]
PHST- 2021/03/10 00:00 [pmc-release]
AID - 10.1038/s41434-021-00250-0 [pii]
AID - 250 [pii]
AID - 10.1038/s41434-021-00250-0 [doi]
PST - ppublish
SO  - Gene Ther. 2021 Nov;28(10-11):659-675. doi: 10.1038/s41434-021-00250-0. Epub 2021 
      Mar 10.