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Gene replacement therapy after neuropathy onset provides therapeutic benefit in a model of CMT1X

Journal article
Authors A. Kagiava
J. Richter
C. Tryfonos
C. Karaiskos
A. J. Heslegrave
I. Sargiannidou
A. M. Rossor
Henrik Zetterberg
M. M. Reilly
C. Christodoulou
K. A. Kleopa
Published in Human molecular genetics
Volume 28
Issue 21
Pages 3528-3542
ISSN 0964-6906
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Clinical Neuroscience
Pages 3528-3542
Language en
Keywords marie-tooth-disease, schwann-cells, phenotypic-expression, gap-junctions, mice lacking, mouse model, connexin32, gjb1, mutation, myelin, Biochemistry & Molecular Biology, Genetics & Heredity
Subject categories Medical Genetics, Neurosciences


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.

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