Abstract
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 6months showed improved motor performance at 8 and 10months. Furthermore, treated mice showed increased sciatic nerve conduction velocities, improvement of myelination and reduced inflammation in lumbar roots and peripheral nerves at 10months 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.
Highlights
X-linked Charcot-Marie Tooth (CMT1X) disease is one of the commonest inherited neuropathies, characterized by progressive weakness and atrophy of distal limb muscles, loss of reflexes, sensory loss and reduced nerve conduction velocities
Induced expression of GJB1 gene in 6 month-old Gjb1-null mice We have previously shown that lentiviral vector delivery of the human GJB1 gene in 2 month-old Cx32 KO mice, before the onset of peripheral neuropathy, results in stable expression of Cx32 [18]
In the current study we used a lentiviral vector-mediated gene replacement therapy targeting Schwann cells to treat for the first time post-onset Cx32 KO mice, the mouse model for CMT1X
Summary
X-linked Charcot-Marie Tooth (CMT1X) disease is one of the commonest inherited neuropathies, characterized by progressive weakness and atrophy of distal limb muscles, loss of reflexes, sensory loss and reduced nerve conduction velocities. Disability increases with age mainly resulting from motor unit loss [1]. In addition to peripheral neuropathy, a number of CMT1X mutations result in central nervous system (CNS) phenotypes characterized by spasticity, hyperactive reflexes, extensor plantar responses, ataxia, or acute reversible encephalopathy [2,3,4,5,6]. Cx32 forms intracellular GJ channels through the non-compact myelin layers at paranodal loops and Schmidt–Lanterman incisures of Schwann cells [12, 13]. These channels serve important homeostatic and axon-glial signaling functions in peripheral myelinated fibers.
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