Gene therapy will constitute the treatment of choice in the next few years for many hereditary diseases. Protein replacement will be highly effective in all those disorders due to a loss of function mechanism. Unfortunately, many hereditary disorders are caused by gain of function mechanism. The dominant negative or toxic effect of a mutated protein could render the efficacy of replacement therapy unpredictable. Point mutations affecting the extracellular domain of P0 glycoprotein cause hereditary neuropathies such as Charcot-Marie-Tooth 1B (CMT1B). The majority of these patients are heterozygous for the mutation and the disorder segregates dominantly. Hence, most of these neuropathies are the consequence of a gain of function mechanism. We created a transgenic line of mice that manifested behavioral, electrophysiological, and morphological abnor- malities typical of subtypes of human CMT1B. The transgene encodes for a wild-type P0 with a myc epitope tag at the mature amino-terminus (P0-myc). The P0-myc allele likely behaves as a dominant-negative and is responsible for myelin uncompaction and abnormal myelin folding of the peripheral nerve. Interestingly, increasing the dosage of wild-type P0 by genetic crosses ameliorates the phenotype of these mice. The number of uncompacted or excessive folded fibers is progressively reduced. Unfortunately, the efficacy of this approach is limited by a threshold for P0 over-dosage, which causes developmental dysmyelination when it exceeds by 50% the normal level. Dysmyelination is severe, dose-dependent, and affects the early events of nerve development. In conclusion, we demonstrate for the first time that protein replacement may also benefit CMT neuropathies associated with a gain of function mechanism. Nevertheless, P0 dosage is still limiting for gene therapy. However, since dysmyelination is the consequence of the early excessive expression of P0, the increase in P0 dosage may have a reduced effect in the adult nerve.
|Issue number||4 SUPPL.|
|Publication status||Published - 2000|
ASJC Scopus subject areas
- Clinical Neurology