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Gene replacement th...
Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathy
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Schiza, N. (author)
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Georgiou, E. (author)
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Kagiava, A. (author)
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- Medard, J. J. (author)
- Karolinska Institutet
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Richter, J. (author)
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Tryfonos, C. (author)
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Sargiannidou, I. (author)
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Heslegrave, A. J. (author)
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Rossor, A. M. (author)
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- Zetterberg, Henrik, 1973 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
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Reilly, M. M. (author)
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Christodoulou, C. (author)
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- Chrast, R. (author)
- Karolinska Institutet
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Kleopa, K. A. (author)
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(creator_code:org_t)
- 2019-03-25
- 2019
- English.
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In: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 142, s. 1227-1241
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Abstract
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- Charcot-Marie-Tooth disease type 4C is the most common recessively inherited demyelinating neuropathy that results from loss of function mutations in the SH3TC2 gene. Sh3tc2(-/-) mice represent a well characterized disease model developing early onset progressive peripheral neuropathy with hypo- and demyelination, slowing of nerve conduction velocities and disturbed nodal architecture. The aim of this project was to develop a gene replacement therapy for treating Charcot-Marie-Tooth disease type 4C to rescue the phenotype of the Sh3tc2(-/-) mouse model. We generated a lentiviral vector LV-Mpz.SH3TC2.myc to drive expression of the human SH3TC2 cDNA under the control of the Mpz promoter specifically in myelinating Schwann cells. The vector was delivered into 3-week-old Sh3tc2(-/-) mice by lumbar intrathecal injection and gene expression was assessed 4-8 weeks after injection. Immunofluorescence analysis showed presence of myc-tagged human SH3TC2 in sciatic nerves and lumbar roots in the perinuclear cytoplasm of a subset of Schwann cells, in a dotted pattern co-localizing with physiologically interacting protein Rab11. Quantitative PCR analysis confirmed SH3TC2 mRNA expression in different peripheral nervous system tissues. A treatment trial was initiated in 3 weeks old randomized Sh3tc2(-/-) littermate mice which received either the full or mock (LV-Mpz.Egfp) vector. Behavioural analysis 8 weeks after injection showed improved motor performance in rotarod and foot grip tests in treated Sh3tc2(-/-) mice compared to mock vector-treated animals. Moreover, motor nerve conduction velocities were increased in treated Sh3tc2(-/-) mice. On a structural level, morphological analysis revealed significant improvement in g-ratios, myelin thickness, and ratios of demyelinated fibres in lumbar roots and sciatic nerves of treated Sh3tc2(-/-) mice. Finally, treated mice also showed improved nodal molecular architecture and reduction of blood neurofilament light levels, a clinically relevant biomarker for axonal injury/degeneration. This study provides a proof of principle for viral gene replacement therapy targeted to Schwann cells to treat Charcot-Marie-Tooth disease type 4C and potentially other similar demyelinating inherited neuropathies.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- Charcot-Marie-Tooth 4C disease
- peripheral neuropathy
- gene therapy
- Schwann cells
- biomarkers
- plasma-membrane
- na+ channels
- spinal-cord
- disease
- sh3tc2
- protein
- myelination
- delivery
- mutations
- gliomedin
- Neurosciences & Neurology
Publication and Content Type
- ref (subject category)
- art (subject category)
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Brain
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- By the author/editor
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Schiza, N.
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Georgiou, E.
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Kagiava, A.
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Medard, J. J.
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Richter, J.
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Tryfonos, C.
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show more...
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Sargiannidou, I.
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Heslegrave, A. J ...
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Rossor, A. M.
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Zetterberg, Henr ...
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Reilly, M. M.
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Christodoulou, C ...
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Chrast, R.
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Kleopa, K. A.
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
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Brain
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University of Gothenburg
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Karolinska Institutet