Ascorbic Acid (Vit C): Orphan drug labelled for CMT 1A

[Guest guest]

Orphan drug labelled for Charcot-Marie-Tooth type 1A disease

http://first.aster.it/news/show_news.php?ID=18250

Description

HEALTH- 2009-2.4.4-2: Preclinical development of substances with a

clear potential as orphan drugs. FP7-HEALTH-2009-single-stage.

We recently suggested that the use of high doses of ascorbic acid

(AA) could be a treatment for Charcot-Marie-Tooth type 1A disease.

The rationale of this proposition was based on the reversion of a CMT

mouse model obtained after treatment by high doses of AA (Passage et

al, 2004). This reversal does not appear to be due to the antioxidant

properties of AA, but to its presently unknown capacity to modulate

the intracellular pool of cAMP (Kaya et al, 2007, 2008). These data

made possible the first clinical trial on adult CMT patients,

launched in 2006. This discovery has been patented (EP1526850) and AA

has been designated by EMEA as an orphan drug for CMT1A in April 2008

(EU/3/08/53).

These data open new insights into AA functions and roles in different

biological situations. Once the efficiency confirmed, the next step

is to precise the effects of the use in the long-term of high doses

of ascorbic acid in different situations; hence the need for new

preclinical studies of this drug in peculiar cases (especially high

dose prescription, long-term use, prescription for children and

during pregnancy).

Objectives and Work Plan:

We would like to improve our preclinical knowledge of recurrent

treatment of CMT1A patient by high doses of AA in order to provide

data to answer the following questions:

What is the exact mechanism and nature of AA action?

What is the bioaccumulation and metabolism of AA in Schwann cells and

peripheral nerves?

Is there situation were high doses of AA could be toxic?

In order to answer these questions, we plan to perform the following

experiments and thus to put the following competences together:

I - Mode of action of AA on PMP22 expression and CMT1A.

Is it AA or an intermediate of AA degradation that is active on PMP22

expression? We will characterize the metabolism of AA in peripheral

nerve. We will isolate or synthesize these molecules and we will test

their action on PMP22 expression, using system available in the

laboratory.

Is the mechanism of AA due to a structural similarity between AA and

ATP? To answer this question we will synthesize structural

intermediates between AA and ATP, and test their action on PMP22

expression. For this part of the work we require a collaboration

between researcher from the metabolomic field (to be found), chemist

our lab.

II - Phamacodynamics, cell localisation and metabolomic of AA in

Schwann cells and peripheral nerves.

This will be evaluated through a collaboration between a lab involved

in a lab with competences in pharmacodynamics (to be found)

performent in cell and tissues imaging (to be found) and our lab.

III - Impact of AA treatment on embryogenesis and growth of

mammalians.

A - Embryogenesis.

Pregnant mouse or rats, will be fed with high doses of AA.

Morphogenesis, expression of developmental genes ..., will be

analyzed at different stages. This step requires competences into

rodents embryogenesis, specially in terms of embryos morphology (to

be found).

B - Growth.

Due to the inhibitory effect of AA on cell proliferation, two

parameters will be evaluated:

Growth performance of young mouse/rats, after treatment with a

placebo or with increasing doses of AA

Analysis of cognitive performances ( water maze? others?) of

rats after treatment with a placebo or with increasing doses of AA

These two questions will be treated in collaboration with two labs

(to be found) and our lab.

Organisation Type: Università

Partner Sought: Several expertises are still required. Partner search

is not restricted to SMEs, academia are welcome:

Metabolomic analysis. An EU designed metabolomic platform will be

preferred. The task will be to define the metabolism of AA in sciatic

nerves

Organic Chemist. They will be in charge of synthesizing intermediates

and analogues of these molecules

Pharmacodynamics. This structure will analyze the distribution of AA

and intermediates in Schwann cells, sciatic nerves, and more

generally peripheric nervous system

Mouse/rat embryologist. This structure will analyze morphology of

embryos treated with high doses of AA. Teratogenesis and toxicity

will be determined

Neonatal and growth period. This group will analyze the impact of AA

on growth

Behavioral analysis. This group will analysis cognitive function in

AA treated rats vs placebo.