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1. Biomarkers predict outcome in Charcot-Marie-Tooth disease 1A

Author

Tim Beissbarth, Pavel Seeman, José Berciano, Radim Mazanec, Jana Haberlová, Jean-Yves Hogrel, Ana L. Pelayo-Negro, Rita Horvath, Robert Fledrich, Michael E. Shy, Peter Young, Walter Paulus, Davide Pareyson, Beate Schlotter-Weigel, Alessandra Solari, Dirk Czesnik, Thomas Prukop, Michael W. Sereda, Angelo Schenone, Maggie C. Walter, Tuuli J. Schnizer, Cmt Triaal, Manoj Mannil, Peter De Jonghe, Odile Dubourg, Natalia Garcia-Angarita, Andreas Leha, Caroline Ehbrecht, Jonathan Baets, and CMT-TRIAAL

Subjects
Male, 0301 basic medicine, Oncology, Pathology, Transcription, Genetic, Biopsy, Messenger, Cathepsin A, Disease, 0302 clinical medicine, Charcot-Marie-Tooth Disease, biomarker, Charcot Marie Tooth disease 1A, disease progression, disease severity, skin biopsy, Adult, Aged, Female, Genetic Markers, Glutathione Transferase, Glycoproteins, Humans, Middle Aged, Neuregulin-1, PPAR gamma, Phosphoric Diester Hydrolases, Prognosis, Pyrophosphatases, RNA, Messenger, Real-Time Polymerase Chain Reaction, Skin, Disease Progression, Treatment Outcome, Surgery, Neurology (clinical), Psychiatry and Mental Health, Medicine, medicine.diagnostic_test, Nuclear Proteins, 3. Good health, Psychiatry and Mental health, Cohort, Biomarker (medicine), Transcription, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Disease cluster, Article, 03 medical and health sciences, Genetic, Internal medicine, business.industry, Therapeutic effect, Clinical trial, 030104 developmental biology, Skin biopsy, RNA, Human medicine, business, 030217 neurology & neurosurgery
Abstract

Background Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited neuropathy, a debilitating disease without known cure. Among patients with CMT1A, disease manifestation, progression and severity are strikingly variable, which poses major challenges for the development of new therapies. Hence, there is a strong need for sensitive outcome measures such as disease and progression biomarkers, which would add powerful tools to monitor therapeutic effects in CMT1A. Methods We established a pan-European and American consortium comprising nine clinical centres including 311 patients with CMT1A in total. From all patients, the CMT neuropathy score and secondary outcome measures were obtained and a skin biopsy collected. In order to assess and validate disease severity and progression biomarkers, we performed qPCR on a set of 16 animal model-derived potential biomarkers in skin biopsy mRNA extracts. Results In 266 patients with CMT1A, a cluster of eight cutaneous transcripts differentiates disease severity with a sensitivity and specificity of 90% and 76.1%, respectively. In an additional cohort of 45 patients with CMT1A, from whom a second skin biopsy was taken after 2-3 years, the cutaneous mRNA expression of GSTT2, CTSA, PPARG, CDA, ENPP1 and NRG1-Iis changing over time and correlates with disease progression. Conclusions In summary, we provide evidence that cutaneous transcripts in patients with CMT1A serve as disease severity and progression biomarkers and, if implemented into clinical trials, they could markedly accelerate the development of a therapy for CMT1A.

Published
2017

2. Reliability of clinical outcome measures in Charcot-Marie-Tooth disease

Author

Solari, A, Laurà, M, Salsano, E, Radice, D, Pareyson, D, The CMT TRIAAL Study, G, Cavaletti, G, Marelli, C, Scaioli, V, Ciano, C, Rimoldi, M, Lauria, G, Rizzetto, E, Camozzi, F, Schenone, A, Grandis, M, Narciso, E, Nobbio, L, Benedetti, L, Rizzuto, N, Fabrizi, G, Cavallaro, T, Bertolasi, L, Casano, A, Santoro, L, Manganelli, F, Pisciotta, C, Nolano, M, Vita, G, Mazzeo, A, Di Leo, R, Girlanda, P, Majorana, G, Aguennouz, M, Ciranni, A, Lanzano, N, Quattrone, A, Valentino, P, Nisticò, R, Pirritano, D, Clodomiro, A, Canino, M, Padua, L, Pazzaglia, C, Mignogna, T, Gemignani, F, Brindani, F, Vitetta, F, Bogani, P, Hughes, R, Visioli, F, Mancardi, G, Galimberti, S, Calabrese, D, Ferrari, G, Sereda, M, The CMT TRIAAL Study Group, Fabrizi, GM, Hughes, RAC, Mancardi, GL, GALIMBERTI, STEFANIA, Sereda, MW, CAVALETTI, GUIDO ANGELO, Solari, A, Laurà, M, Salsano, E, Radice, D, Pareyson, D, The CMT TRIAAL Study, G, Cavaletti, G, Marelli, C, Scaioli, V, Ciano, C, Rimoldi, M, Lauria, G, Rizzetto, E, Camozzi, F, Schenone, A, Grandis, M, Narciso, E, Nobbio, L, Benedetti, L, Rizzuto, N, Fabrizi, G, Cavallaro, T, Bertolasi, L, Casano, A, Santoro, L, Manganelli, F, Pisciotta, C, Nolano, M, Vita, G, Mazzeo, A, Di Leo, R, Girlanda, P, Majorana, G, Aguennouz, M, Ciranni, A, Lanzano, N, Quattrone, A, Valentino, P, Nisticò, R, Pirritano, D, Clodomiro, A, Canino, M, Padua, L, Pazzaglia, C, Mignogna, T, Gemignani, F, Brindani, F, Vitetta, F, Bogani, P, Hughes, R, Visioli, F, Mancardi, G, Galimberti, S, Calabrese, D, Ferrari, G, Sereda, M, The CMT TRIAAL Study Group, Fabrizi, GM, Hughes, RAC, Mancardi, GL, GALIMBERTI, STEFANIA, Sereda, MW, and CAVALETTI, GUIDO ANGELO

Abstract

We assessed inter- and intra-rater reliability of outcome measures in Charcot-Marie-Tooth disease (CMT) patients. In 40 CMT patients, we assessed reliability of Overall Neuropathy Limitations Scale (ONLS), 10-m timed walk (T10MW), 9-hole-peg test (9-HPT), maximal voluntary isometric contraction (MVIC) of arm (elbow flexion, hand-grip, and three-point pinch) and leg (knee extension, foot dorsiflexion/plantar flexion). Reliability was substantial for ONLS, excellent for T10MW and 9-HPT. For MVIC, inter and intra-rater reliability was excellent for hand contractions; for leg contractions, intra-rater agreement was moderate to substantial, whereas inter-rater agreement was poor. An ad hoc device was produced to immobilize the foot and MVIC reliability was re-assessed in 26 CMT patients, resulting in excellent inter-rater and intra-rater reliability for foot dorsiflexion, and clear inter-rater improvement for foot plantar flexion. All outcome measures appear adequate for CMT assessment. Use of an immobilization device improves foot MVIC reliability, preventing biased findings in patients with greater strength.

Published
2008

3. Nerve conduction velocity in CMT1A: what else can we tell?

Author

Manganelli, F, Pisciotta, C, Reilly, Mm, Tozza, S, Schenone, A, Fabrizi, Gm, Cavallaro, T, Vita, G, Padua, Luca, Gemignani, F, Laurà, M, Hughes, Ra, Solari, A, Pareyson, D, Santoro, L, Cmt, Triaal, CMT TRAUK, Group, Padua, Luca (ORCID:0000-0003-2570-9326), Manganelli, F, Pisciotta, C, Reilly, Mm, Tozza, S, Schenone, A, Fabrizi, Gm, Cavallaro, T, Vita, G, Padua, Luca, Gemignani, F, Laurà, M, Hughes, Ra, Solari, A, Pareyson, D, Santoro, L, Cmt, Triaal, CMT TRAUK, Group, and Padua, Luca (ORCID:0000-0003-2570-9326)

Abstract

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease (CMT) type 1A is characterized by uniformly reduced nerve conduction velocity (NCV) that is fully penetrant since the first years of life, remains fairly stable through the life and does not correlate with disability whereas compound muscular action potential (CMAP) amplitude does. The aim of the present study was to analyze the large amount of electrophysiological data collected in the ascorbic acid trial in Italy and the UK (CMT-TRIAAL/CMT-TRAUK) and to use these data to gain insights into the pathophysiology of NCV in CMT1A. METHODS: Baseline electrophysiological data from 271 patients were analysed. Electrophysiological recordings were taken from the motor ulnar, median and peroneal nerves and the sensory ulnar nerve. Distal motor latency (DML), motor (MNCV) and sensory (SNCV) nerve conduction velocity, and amplitudes of CMAPs and sensory action potentials were assessed. Electrophysiological findings were correlated with age of patients at examination and the Charcot-Marie-Tooth Examination Score (CMTES). RESULTS: NCV was markedly and uniformly reduced. CMAP amplitudes were overall reduced but more severely in lower limbs. DML decreased and MNCV and SNCV increased with age of the patients, whereas CMAP amplitudes worsened with age and also correlated with CMTES. CONCLUSIONS: This is the largest sample of electrophysiological data obtained so far from CMT1A patients. Axonal degeneration as assessed by means of CMAP amplitude reflected clinical impairment and was consistent with a slowly progressive length-dependent neuropathy. All patients typically had markedly slowed NCV that did, however, slightly increase with age of the patients. The improvement of NCV might depend on myelin thickness remodelling that occurs during the adult life of CMT1A patients.

Published
2016

5. Reliability of clinical outcome measures in Charcot-Marie-Tooth disease

Author

Solari A, Laurà M, Salsano E, Radice D, Pareyson D and CMT-TRIAAL Study Group.

Subjects
body regions, education
Abstract

We assessed inter- and intra-rater reliability of outcome measures in Charcot-Marie-Tooth disease (CMT) patients. In 40 CMT patients, we assessed reliability of Overall Neuropathy Limitations Scale (ONLS), 10-m timed walk (T10MW), 9-hole-peg test (9-HPT), maximal voluntary isometric contraction (MVIC) of arm (elbow flexion, hand-grip, and three-point pinch) and leg (knee extension, foot dorsiflexion/plantar flexion). Reliability was substantial for ONLS, excellent for T10MW and 9-HPT. For MVIC, inter and intra-rater reliability was excellent for hand contractions; for leg contractions, intra-rater agreement was moderate to substantial, whereas inter-rater agreement was poor. An ad hoc device was produced to immobilize the foot and MVIC reliability was re-assessed in 26 CMT patients, resulting in excellent inter-rater and intra-rater reliability for foot dorsiflexion, and clear inter-rater improvement for foot plantar flexion. All outcome measures appear adequate for CMT assessment. Use of an immobilization device improves foot MVIC reliability, preventing biased findings in patients with greater strength.

Published
2008

8. A multicenter, randomized, double-blind, placebo-controlled trial of long-term ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL): the study protocol [EudraCT no.: 2006-000032-27]

Author

Pareyson D, Schenone A, Fabrizi GM, Santoro L, Padua L, Quattrone A, Vita G, Gemignani F, Visioli F, Solari A and CMT-TRIAAL Group.

Subjects
congenital, hereditary, and neonatal diseases and abnormalities
Abstract

There is no treatment for Charcot-Marie-Tooth disease 1A (CMT1A), but ascorbic acid (AA) is efficacious in the transgenic mouse model. Thus, a clinical trial of AA in CMT1A is warranted. The CMT-TRIAAL is a phase III randomized, double-blind, placebo-controlled study involving 222 CMT1A adults from eight Italian centers. Eligible for the study are symptomatic adults with genetically confirmed CMT1A. Treatment consists of 2-year oral AA (1500mg/day) or placebo. The primary trial endpoint is an improvement in CMT Neuropathy Score. Secondary efficacy endpoints are changes in distal arm and leg maximum voluntary isometric contraction; 10m timed walking; 9-hole-peg test; overall neuropathy limitations scale; pain and fatigue visual analog scales; health-related quality of life (SF-36); and electrophysiology. Clinical-electrophysiological assessments are performed at baseline and every 6 months thereafter. In consenting patients from three centers, skin biopsy is performed to evaluate PMP22 expression. The study will last 34 months, starting from March 2006.

Published
2006

9. Biomarkers predict outcome in Charcot-Marie-Tooth disease 1A.

Author

Fledrich, Robert, Mannil, Manoj, Leha, Andreas, Ehbrecht, Caroline, Solari, Alessandra, Pelayo-Negro, Ana L., Berciano, José, Schlotter-Weigel, Beate, Schnizer, Tuuli J., Prukop, Thomas, Garcia-Angarita, Natalia, Czesnik, Dirk, Haberlová, Jana, Mazanec, Radim, Paulus, Walter, Beissbarth, Tim, Walter, Maggie C., CMT-TRIAAL, Hogrel, Jean-Yves, and Dubourg, Odile

Subjects
CHARCOT-Marie-Tooth disease, BIOMARKERS, NEUROPATHY, MESSENGER RNA, SKIN biopsy
Abstract

Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited neuropathy, a debilitating disease without known cure. Among patients with CMT1A, disease manifestation, progression and severity are strikingly variable, which poses major challenges for the development of new therapies. Hence, there is a strong need for sensitive outcome measures such as disease and progression biomarkers, which would add powerful tools to monitor therapeutic effects in CMT1A.Methods: We established a pan-European and American consortium comprising nine clinical centres including 311 patients with CMT1A in total. From all patients, the CMT neuropathy score and secondary outcome measures were obtained and a skin biopsy collected. In order to assess and validate disease severity and progression biomarkers, we performed qPCR on a set of 16 animal model-derived potential biomarkers in skin biopsy mRNA extracts.Results: In 266 patients with CMT1A, a cluster of eight cutaneous transcripts differentiates disease severity with a sensitivity and specificity of 90% and 76.1%, respectively. In an additional cohort of 45 patients with CMT1A, from whom a second skin biopsy was taken after 2-3 years, the cutaneous mRNA expression of GSTT2, CTSA, PPARG, CDA, ENPP1 and NRG1-Iis changing over time and correlates with disease progression.Conclusions: In summary, we provide evidence that cutaneous transcripts in patients with CMT1A serve as disease severity and progression biomarkers and, if implemented into clinical trials, they could markedly accelerate the development of a therapy for CMT1A. [ABSTRACT FROM AUTHOR]

Published
2017
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10. Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial

Author

Pareyson, D, Reilly, M, Schenone, A, Fabrizi, G, Cavallaro, T, Santoro, L, Vita, G, Quattrone, A, Padua, L, Gemignani, F, Visioli, F, Laurà, M, Radice, D, Calabrese, D, Hughes, R, Solari, A, Cavaletti, G, for the CMT, T, CMT TRAUK, G, Reilly, MM, Fabrizi, GM, Hughes, RAC, CAVALETTI, GUIDO ANGELO, for the CMT TRIAAL, CMT TRAUK groups, Pareyson, D, Reilly, M, Schenone, A, Fabrizi, G, Cavallaro, T, Santoro, L, Vita, G, Quattrone, A, Padua, L, Gemignani, F, Visioli, F, Laurà, M, Radice, D, Calabrese, D, Hughes, R, Solari, A, Cavaletti, G, for the CMT, T, CMT TRAUK, G, Reilly, MM, Fabrizi, GM, Hughes, RAC, CAVALETTI, GUIDO ANGELO, for the CMT TRIAAL, and CMT TRAUK groups

Abstract

Background Ascorbic acid reduced the severity of neuropathy in transgenic mice overexpressing peripheral myelin protein 22 (PMP22), a model of Charcot-Marie-Tooth disease type 1A (CMT1A) associated with the PMP22 duplication. However, in three 1-year trials, ascorbic acid had no benefit in human beings. We did a multicentre 2-year trial to test the efficacy and tolerability of ascorbic acid in patients with CMT1A. Methods Adult patients (aged 18-70 years) with symptomatic CMT1A were enrolled from nine centres in Italy and the UK, and were randomly assigned (1:1 ratio) to receive 1.5 g/day oral ascorbic acid or matching placebo for 24 months. The randomisation sequence was computer generated by block randomisation, stratified by centre and disease severity, and patients were allocated to treatment by telephone. The primary outcome was change in the CMT neuropathy score (CMTNS) at 24 months. Secondary outcomes were timed 10 m walk test, nine-hole peg test, overall neuropathy limitations scale, distal maximal voluntary isometric contraction, visual analogue scales for pain and fatigue, 36-item short-form questionnaire, and electrophysiological measurements. Patients, treating physicians, and physicians assessing outcome measures were masked to treatment allocation. Analysis of the primary outcome was done on all randomised patients who received at least one dose of study drug. This study is registered, numbers ISRCTN61074476 (CMT-TRAUK) and EudraCT 2006-000032-27 (CMT-TRIAAL). Findings We enrolled and randomly assigned 277 patients, of whom six (four assigned to receive ascorbic acid) withdrew consent before receiving treatment; 138 receiving ascorbic acid and 133 receiving placebo were eligible for analysis. Treatment was well tolerated: 241 of 271 patients (89% in each group) completed the study; 20 patients (nine receiving ascorbic acid) dropped out because of adverse events. Mean CMTNS at baseline with missing data imputed was 14.7 (SD 4.8) in the ascorbic acid gro

Published
2011

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

Author

Nobbio, Lucilla, Visigalli, Davide, Radice, Davide, Fiorina, Elisabetta, Solari, Alessandra, Lauria, Giuseppe, Reilly, Mary M, Santoro, Lucio, Schenone, Angelo, Pareyson, Davide, and CMT-TRIAAL Group

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. [ABSTRACT FROM AUTHOR]

Published
2014
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12. Ascorbic acid for treatment in CMT1A: what's next?

Author

de Visser, Marianne, Verhamme, Camiel, Pareyson, Davide, Reilly, Mary M, Schenone, Angelo, Fabrizi, Gian Maria, Cavallaro, Tiziana, Santoro, Lucio, Vita, Giuseppe, Quattrone, Aldo, Padua, Luca, Gemignani, Franco, Visioli, Francesco, Laurà, Matilde, Radice, Davide, Calabrese, Daniela, Hughes, Richard A C, Solari, Alessandra, CMT-TRIAAL, and CMT-TRAUK groups

Subjects
*THERAPEUTIC use of antioxidants, *THERAPEUTIC use of vitamin C, *CHARCOT-Marie-Tooth disease, *COMPARATIVE studies, *RESEARCH methodology, *MEDICAL cooperation, *RESEARCH, *RESEARCH funding, *EVALUATION research, *RANDOMIZED controlled trials, *TREATMENT effectiveness, *BLIND experiment
Abstract

Background: Ascorbic acid reduced the severity of neuropathy in transgenic mice overexpressing peripheral myelin protein 22 (PMP22), a model of Charcot-Marie-Tooth disease type 1A (CMT1A) associated with the PMP22 duplication. However, in three 1-year trials, ascorbic acid had no benefit in human beings. We did a multicentre 2-year trial to test the efficacy and tolerability of ascorbic acid in patients with CMT1A.Methods: Adult patients (aged 18-70 years) with symptomatic CMT1A were enrolled from nine centres in Italy and the UK, and were randomly assigned (1:1 ratio) to receive 1·5 g/day oral ascorbic acid or matching placebo for 24 months. The randomisation sequence was computer generated by block randomisation, stratified by centre and disease severity, and patients were allocated to treatment by telephone. The primary outcome was change in the CMT neuropathy score (CMTNS) at 24 months. Secondary outcomes were timed 10 m walk test, nine-hole peg test, overall neuropathy limitations scale, distal maximal voluntary isometric contraction, visual analogue scales for pain and fatigue, 36-item short-form questionnaire, and electrophysiological measurements. Patients, treating physicians, and physicians assessing outcome measures were masked to treatment allocation. Analysis of the primary outcome was done on all randomised patients who received at least one dose of study drug. This study is registered, numbers ISRCTN61074476 (CMT-TRAUK) and EudraCT 2006-000032-27 (CMT-TRIAAL).Findings: We enrolled and randomly assigned 277 patients, of whom six (four assigned to receive ascorbic acid) withdrew consent before receiving treatment; 138 receiving ascorbic acid and 133 receiving placebo were eligible for analysis. Treatment was well tolerated: 241 of 271 patients (89% in each group) completed the study; 20 patients (nine receiving ascorbic acid) dropped out because of adverse events. Mean CMTNS at baseline with missing data imputed was 14·7 (SD 4·8) in the ascorbic acid group and 13·9 (4·2) in the placebo group. Mean worsening of CMTNS was 0·2 (SD 2·8, 95% CI -0·3 to 0·7) in the ascorbic acid group and 0·2 (2·7, -0·2 to 0·7) in the placebo group (mean difference 0·0, 95% CI -0·6 to 0·7; p=0·93). We recorded no differences between the groups for the secondary outcomes at 24 months. 21 serious adverse events occurred in 20 patients, eight in the ascorbic acid group and 13 in the placebo group.Interpretation: Ascorbic acid supplementation had no significant effect on neuropathy compared with placebo after 2 years, suggesting that no evidence is available to support treatment with ascorbic acid in adults with CMT1A.Funding: Telethon-UILDM and AIFA (Italian Medicines Agency) for CMT-TRIAAL, and Muscular Dystrophy Campaign for CMT-TRAUK. [ABSTRACT FROM AUTHOR]

Published
2011
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13. Vitamin C and Charcot-Marie-Tooth 1A: Pharmacokinetic considerations

Author

Visioli, F, Reilly, Mm, Rimoldi, M, Solari, A, Pareyson, D, Marchesi, C, Salsano, E, Nanetti, L, Marelli, C, Scaioli, V, Ciano, C, Lauria, G, Rizzetto, E, Camozzi, F, Schenone, Angelo, Narciso, E, Grandis, Marina, Monti Bragadin, M, Nobbio, Lucilla, Fabrizi, Gm, Cavallaro, T, Casano, A, Bertolasi, L, Cabrini, I, Corrà, K, Rizzuto, N, Santoro, L, Manganelli, F, Pisciotta, C, Nolano, M, Vita, G, Mazzeo A, ., Aguennouz, M, Di Leo, R, Majorana, G, Lanzano N, ., Valenti, F, Quattrone, A, Valentino, P, Nisticò, R, Pirritano, D, Lucisano, A, Canino, M, Padua, L, Pazzaglia, C, Granata, G, Foschini, M, Gemignani, F, Brindani, F, Vitetta, F, Allegri, I, Bogani, P. ., Visioli, F, Reilly, Mm, Rimoldi, M, Solari, A, Pareyson, D, Manganelli, Fiore, Cmt, Triaal2, CMT TRAUK, Group, Pisciotta, Chiara, Santoro, Lucio, and for the CMT, Triaal

Subjects
Drug, congenital, hereditary, and neonatal diseases and abnormalities, Ascorbic acid, Charcot-Marie-Tooth disease, Myelin, Neuromuscular disorders, Pharmacology, Pharmacology (medical), Food Science, media_common.quotation_subject, Disease, Charcot–Marie–Tooth disease, Article, law.invention, Randomized controlled trial, Pharmacokinetics, law, Medicine, media_common, Vitamin C, business.industry, Clinical trial, Tolerability, business
Abstract

Highlights ► Charcot-Marie-Tooth 1A cannot rely on effective pharmacological treatment. ► Several human trials failed to provide evidence of a therapeutic role of vitamin C. ► Human vitamin C's pharmacokinetics are tightly regulated. ► Ascorbic acid should not be given in excess of its transport system capacity., Charcot–Marie–Tooth 1A disease (CMT1A) is a disease for which no drug treatments are available. In 2004, it was reported that ascorbic acid reduced the severity of neuropathy in transgenic mice overexpressing PMP22, an animal model of human CMT1A, compared with untreated mice. Based on those results, clinical trials were undertaken at different centers worldwide and four of them have been completed, but none of them resulted in significant improvements. Based on the pharmacokinetics of ascorbic acid, we propose that the randomized clinical trial carried out thus far confirmed the tight control of ascorbic acid's absorption and proved its tolerability at one and two years. The pharmacokinetic considerations discussed in this article might largely explain the disappointing results of the recent CMT1A trials.

Published
2013

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