Schiza N, Georgiou E, Kagiava A, Médard JJ, Richter J,
Tryfonos C, Sargiannidou I, Heslegrave AJ, Rossor AM, Zetterberg H,
Reilly MM, Christodoulou C, Chrast R, Kleopa KA. Gene replacement therapy in a model
of Charcot-Marie-Tooth 4C neuropathy. Brain. 2019 May
1;142(5):1227-1241.
Abstract
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.
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