Ascorbic acid, a first generation medication for Charcot Marie Tooth disease type 1A?

From CMTUS comes word of a Med Sci (Paris) article about the effects of ascorbic acid (vitamin C) on CMT1A in mice. Transgenic mice with the disease given ascorbic acid performed significantly better on treadmill and muscle grip tests. Furthermore, nerve biopsies of the sciatic nerve showed remyelination of the nerves with normal-shaped myelin.
Though this study focused on CMT1A, it might have ramifications for Dejerine-Sottas (considered by some to be CMT3) as the gene they focused on was PMP22, which is also affected in Dejerine-Sottas. Please do not take this article as medical advice and self-medicate without consulting your doctor; further studies need to be done.
Click “more” to read the translated article.

Below is the English translation article From Med Sci (Paris). 2004 Oct;20(10):843-844 on Ascorbic Acid/Vitamin C.(with generous thanks to Joyce in Sweden for her outstanding help!) (Thanks too, to Dr. Fontes, for his generosity in sharing his review with us) Footnotes and the Figures from the article are in pdf format along with the original article in the CMTUS Files section. ~ Gretchen

Ascorbic acid; a first generation medication for Charcot Marie Tooth disease type 1A?

by Michel Fontès

(Inserm U. 491 Génétique médicale et développement Faculté de Médécine de la Tirnone, 27, boulevard Jean Moulin, 13385 Marseille Cedex 5, France
Charcot-Marie Tooth (CMT) is the most frequent form of peripheral demyelinating neuropathy and the neuomuscular disorder which affects 1 out of 2,500 persons) [1]. It is characterized by a progressive atrophy of the distal muscles. The first symptoms appear between 20 and 30 years, but about 10% of the cases concerns children or teen-agers. This disease is genetically heterogenous, but half of the patients are affected by the disease type 1A.
It is a demyelinating form which is due to a partial trisomy of a little region of the short arm of the chromosome 17 [2, 3], including the gene PMP22 that is implied in the myelination processes [4]. In order to understand more the physiopathology of CMT and to propose therapeutical solutions, in 1996, along with collaboration with C. Huxley, we have built an animal model of this disease, by inserting a
YAC (yeast artificial chromosome) of 560 kb containing the gene PMP22 human, in the genome murin [3]. This strategy of producing "humanized" mice has been developed in such a manner that the observed abnormalities have the same origin as by the patients, i.e. an abnormality in a human gene.
In this case, the therapeutical target is identical by a humanized mouse and by the patients in our study concerning the gene PMP22 human. Many lineages of mice have been obtained and the animals have developed a peripheral neuropathy resembling to CMT1A [6]. We have used essentially the lineage showing the most severe phenotype (lineage C22).
We have used mice CMT C22 as a pre-clinical model in order to test in “clinical mice assays”, a therapeutic approach that could be applicable by the human. Taking into account the difficulties of a genetic therapy approach, we are privileged to use classical pharmacology.
In a prior intention, we researched the bibliography of data concerning molecules “bound” to the myelinisation. Two publications have drawn our attention [7, 8], showing that the ascorbic acid was an absolutely necessary factor to the myelinisation in vitro in the cocultures between axons and Schwann cells. Further research has revealed that persons affected by the disease presented demyelinating peripheral neuropathies.
The toxicity of this molecule being well known, we were able to perform immediate clinical tests of phase II/III. Hence, we carried out with the following experience: animals (males and females) of the lineage C22 transgenic for the gene PMP22 human, have been administrated orally once a week a dose of ascorbic acid corresponding to four grams by the human (no toxicological data exists for larger doses).
On the other arm of the test, the animals were receiving a placebo. The animals’ locomotoric abilities were evaluated at the end of three months by using the well-known test of the rotarod (one measures the time during which an animal is capable of staying on a tread mill turning at a certain speed).
The males (more severely affected than the females) that were treated by a placebo, or those that were not treated, were only able to stay on the tread mill during an average of nine seconds whereas the animals which received the ascorbic acid were able to stay 46 seconds in average. We have carried out a second series of tests: males aged of two months belonging to the same litter, divided into two groups, one treated by a placebo, and the other by ascorbic acid. After three months of treatment, the males that were not treated were not able to stay more than one second on the tread mill (we have chosen litters that were very affected) whereas the animals that were treated stayed 45 seconds (Figure A).
At last, a test concerning the muscular force (grip test) showed us that the treated animals had doubled their muscular force during three months of treatment (Figure 1B) [9]. The total of this data showed an undiscussable therapeutical effect of the ascorbic acid. But what was the mechanism?
In a first period of time, we have helped ourselves with the histologic analysis. Slices of sciatic nerve taken from transgenic animals treated by ascorbic acid have shown a remyelination of fibers that did not exist by non-transgenic animals, or by the transgenic animals treated by a placebo. Furthermore, the gain of myelin found again in a normal shape by the animals treated by the ascorbic acid. At last, the last test concerning the effect of ascorbic acid, the restauration of the duration of a normal life by the animals males of the lineage C22 treated by the ascorbic acid, which is remarkable, because in this lineage, the lethality of the affected males is very important, and this occurs for unknown reasons [9].
The question remains concerning the molecular mechanism leading to the remyelination and to the correction of the phenotype. The hypothesis that came immediately to the mind was an action of the ascorbic acid on the gene PMP22; this one possesses a minimal promoter of 300 pb allowing a specific expression in the Schwann cells. However, this promoter’s activity is repressed if the cells are not stimulated by some dibutyril AMPc or forskolin [10]. However, the ascorbic acid interacts with the pool of AMPc [11].
Hence, we have transfected the Schwann cells by a construction in which the transcription of a (rapporteur) promoter gene is placed under the control of a promoter of PMP22. The cells are incubated with dibutyril AMPc used alone or in association with the ascorbic acid. In these conditions, the ascorbic acid enters in competition with the stimulation of the expression of PMP22 by the AMPc, diminishing it by half. Afterwards we have showed by RT-PCR quantitative in real time that the quantity of transcripts of PMP22 were weaker by the animals treated by ascorbic cid than by those that have received the placebo. The phenotypical correction that is observed by the animals receiving the ascorbic acid is then explained by its action on the expression of the gene PMP22 [9].
In conclusion, the ascorbic acid in a strong dose is capable of correcting the phenotype of animals affected by a disease neighboring that of the CMT1A human. So the road is open for clinical human tests, which we hope that we can carry out with as soon as possible. It is interesting to conclude by underlining that the results of many studies have recently been published, making a reality of similar therapeutical approaches for many genetic diseases.
These works are all based on the same strategy: The use of known molecules, or in development for other applications, in animal models that have genetic diseases. Would the treatments of the first generation for many genetic diseases be based on classical pharmacology?

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