PMP22 messenger RNA levels in skin biopsies: testing the effectiveness of a Charcot-Marie-Tooth 1A biomarker

Abstract

Charcot-Marie-Tooth disease type 1A (CMT1A) is associated with increased gene dosage for PMP22. Therapeutic approaches are currently aiming at correcting PMP22 over-expression. It is unknown whether PMP22 can be used as a biological marker of disease progression and therapy efficacy. We performed quantitative real-time polymerase chain reaction on skin biopsies of 45 patients with CMT1A, obtained at study entry and after 24-months of treatment either with ascorbic acid or placebo. Data of a subgroup of patients were also compared with matched healthy subjects. Finally, we analysed PMP22 messenger RNA levels in sural nerve biopsies. We did not find significant differences in the levels of any known PMP22 transcripts in treated or untreated patients with CMT1A, thus confirming that ascorbic acid does not impact on the molecular features of CMT1A. Most importantly, we did not observe any correlation between PMP22 messenger RNA levels and the different clinical and electrophysiological outcome measures, underscoring the weakness of PMP22 to mirror the phenotypic variability of patients with CMT1A. We did not find increased PMP22 messenger RNA levels in skin and sural nerve biopsies of patients with CMT1A compared with relative controls. In conclusion, this study shows that ascorbic acid does not impact on PMP22 transcriptional regulation and PMP22 is not a suitable biomarker for CMT1A.

Schwann cell transcript biomarkers for hereditary neuropathy skin biopsies

“…Biomarkers can be used to not only measure disease process (NEFL levels) and disease burden (MRI), but also target engagement for a given therapy. 15 The analysis of skin biopsies is hampered by variable amounts of SCs in skin, as well as the variable amount of PMP22 in SC as previously established by immuno-EM in CMT1A skin biopsies. Several candidate therapies reduce PMP22 levels in CMT1A rodent models and thereby ameliorate the symptoms of PMP22 overexpression.…”

“…5,6 However, given that neuropathy is slowly progressive, there is a clear need for sensitive biomarkers that measure disease progression and target engagement in patients. 15 However, in the antisense oligonucleotide study, improvement of neuropathy was accompanied by a measurable reduction of Pmp22 by qPCR of foot-pad skin. For example, magnetic resonance imaging (MRI) measurements of intramuscular fat accumulation fraction of calf muscles are a sensitive biomarker that increases over 12 months in patients with CMT1A.…”

PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models

“…For instance, PMP22 overexpression in rodent models can be reduced by high-dose ascorbic acid (18); however, in clinical trials, ascorbic acid did not reduce the level of PMP22 mRNA in skin biopsies from treated CMT1A patients (19)(20)(21). Progesterone antagonists and GABA B agonists have also been shown to reduce PMP22 mRNA expression (22,23), but their potential is hampered by diverse effects on the gene-regulation program of Schwann cells and possibly other cell types, which may complicate a chronic treatment of an inherited disease.…”

Caveats in the Established Understanding of CMT1A

“…Again, the levels of PMP22 mRNA were highly variable 1, 2. One might argue that these negative findings in PMP22 levels were secondarily resulted from nerve fiber degeneration in patients with CMT1A.…”

“…There have been two studies done in a large cohort of patients with Charcot‐Marie‐Tooth type‐1A (CMT1A) lately 1, 2. Both studies utilized human materials collected from CMT1A patients who participated in the ascorbic acid clinical trial.…”