Whither hope for pharmacological treatment of Charcot-Marie-Tooth disease type 1A?

Charcot-Marie-Tooth disease type 1A (CMT1A) is a dominantly inherited, slowly progressive, often-disabling symmetrical distal sensorimotor polyneuropathy, caused by duplication of 1.5 Mb on the short arm of chromosome 17 with consequent trisomy for PMP22 (peripheral myelin protein 22) encoding a peripheral nervous system myelin protein, that affects about 1 in 2000 people. Other than braces and other orthopedic interventions, no effective treatments of CMT1A are available. A report in 2004 by Passage et al1 found that treating PMP22 transgenic mice with a dose of ascorbic acid (AA; vitamin C) that would be equivalent to administration of 4 g of AA per day to an average adult human diminished peripheral nerve PMP22 mRNA abundance 10-fold. The findings that it also restored the peripheral nerve myelin sheath thickness to normal, improved clinical neurological function, and enhanced life span were greeted with great excitement among neuromuscular physicians. In this issue of JAMA Neurology, Lewis and colleagues2 report the results of a tri-institutional, 2-year double-blind randomized trial of high-dose (4-g/d) oral AA administration to 13to 70-year-old individuals with CMT1A. Sixty-nine of 87 AAtreated subjects and 16 of 23 placebo-treated concurrent control subjects completed the trial. The primary outcome measure that was used, the CMT Neuropathy Score (CMTNS), is a composite score that factors in clinical deficits and sensorimotor nerve action potential amplitudes.3 Both AA-treated and concurrent placebo groups performed better, as graded by the CMTNS, than did historical CMT1A control subjects, and results in the AAtreated group were not significantly different than in the concurrent control group. Ascorbic acid treatment also did not significantly alter the abundance of PMP22 mRNA in skin biopsies. A weakness of this trial was that, by calculating trial power on the basis of historical CMTNS data, the choice of a 4:1 allocation of AA-treated to placebo control subjects proved to be ill advised. Furthermore, even if the placebo control subjects in this study had conformed to historical CMTNS data, the number of AA-treated subjects who completed the trial was lower than had originally been calculated to be sufficient. But, setting these minor weaknesses aside, the present study, in conjunction with 4 prior CMT1A AA trials,4-7 indicates that therapy of children and adults with well-tolerated doses of AA for up to 2 years does not demonstrably alter disease progression. Disability in CMT1A is largely due to axon loss rather than demyelination. As currently performed in the clinic, nerve action potential amplitude, the electrophysiological criterion included in the CMTNS, does not provide a definitive assay for axon loss, and it is not ideal for serial studies, particularly in children. Quantification of fingertip Meissner corpuscles by in vivo confocal microscopy8 addresses this issue and should prove to be a valuable adjunct to future CMT1A clinical trials. What explains the discrepancy between the robust therapeutic response to AA in the CMT1A transgenic mice and the failure of this treatment in the human disorder? A recent study that compared myelin and axon pathology in 2 different mouse models of CMT1A for 1.5 years may be relevant.9 C22 mice bearing 7 copies of the human PMP22 gene were found to be much more severely affected than C3-PMP mice with 3 to 4 copies of the gene, with signs of impairment at 3 weeks and significant axonal loss in early life. The pathology in C3-PMP mice was most similar to that in most patients with CMT1A. The genome of the C22 mice used by Passage et al1 contains 7 copies of the yeast artificial chromosome YAC49G7, consisting of the 40-kb human PMP22 gene, 300 kb of upstream sequence, and 100 kb of downstream sequence.10 Both cis-regulation of the human PMP22 by enhancers or repressors outside this sequence and PMP22 transregulation by sequences on other chromosomes may differ substantially from that in humans. We are justified in concluding that this particular mouse model provided misleading information with respect to the use of AA therapy in CMT1A, but these and other mouse lines, such as the C3-PMP mice, may well prove useful, in the future, for pretranslational testing of other therapeutic approaches to CMT1A. Are there other prospects for the medical treatment of individuals with CMT1A? Such treatments have 3 goals in mind: (1) overcoming the defect in myelination due to PMP22 overexpression by reducing production of PMP22 (as was found in the AA-treated PMP22 transgenic mice and hoped for, but not found, in AA-treated humans with CMT1A); (2) reducing the misfolded and/or aggregated PMP22; and (3) reducing the loss of axons. Research targeted at reducing production of PMP22 in CMT1A patients has focused on several fronts. Progesterone is known to increase PMP22 expression in Schwann cells. Treatment of the CMT1A rat model with the progesterone antagonist onapristone was found to significantly increase muscle strength and muscle mass and to prevent axonal loss. Surprisingly, there was no concomitant improvement in myelin sheath thickness.11,12 Onapristone is not safe in humans; hence, lesstoxic substitutes are needed. A second approach has aimed to identify transcriptional inhibitors specific for PMP22. Jang et al13 targeted a regulatory element within the largest intron of the PMP22 gene by developing reporter assays that included Related article page 981 Opinion