Abstract
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.
Highlights
ObjectivesThe aim of this study was to examine whether a gene addition therapy can treat peripheral neuropathy or prevent the development of peripheral neuropathy in the mouse model of CMT1X neuropathy both at early and late stages, before and after the onset of the neuropathy
X-linked Charcot-Marie-Tooth (CMT1X) is the second most common inherited demyelinating neuropathy [1] characterized by slowly progressive muscle weakness and atrophy, loss of reflexes, and reduced nerve conduction
AAV9-myelin protein zero (Mpz).Egfp was delivered by lumbar intrathecal injection into wild type (WT) mice in order to study the biodistribution of the vector throughout the peripheral nervous system (PNS)
Summary
The aim of this study was to examine whether a gene addition therapy can treat peripheral neuropathy or prevent the development of peripheral neuropathy in the mouse model of CMT1X neuropathy both at early and late stages, before and after the onset of the neuropathy
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