new ongoing research?

[Guest guest]

Dear Gretchen

I wanted to send you an article, but the no-attachment policy is

preventing me. So i will put here the link and after it i will try to

paste the text.

Well, at least someone is addressing (willing to address) the

biochemical research path.

P.S. Do you have any CONSISTENT((i.e. reliable) news about " overwork

weakness " ? thank you

http://www.cuni.cz/UK-2910-version1-mail_partner_searchv2.doc

Orphan Drug project Proposal

Contact:

Prof. Michel Fontès

Génétique Médicale et Développement

Université de la Méditerranée,

Faculté de Médecine de la Timone

Tel: +33 (0)4 91 32 44 30

e-mail: michel.fontes@... <mailto:michel.fontes@...>

Ms. Céline Damon

Member of the French NCP for Health

Université de la Méditerranée, Research Department, European

Affairs

Tél : +33 (0)4-91-31-97-97

e-mail: celine.damon@... <mailto:celine.damon@...>

1- Call overview

The researcher wishes to submit a proposal in the frame of the Health

Call for Proposals, 2009, based on his orphan drug labelled for

Charcot-Marie-Tooth type 1A disease.

Deadline: December, 3rd 2009

Call line: HEALTH-2009-2.4.4-2: Preclinical development of substances

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

Support will be provided to preclinical studies (pharmacological,

pharmacokinetics and toxicological) of EU designated orphan medicinal

products12. Involvement of industry is strongly recommended. Cancer

therapies will not be considered. The orphan medicinal product will need

to be granted the EU orphan designation at the latest on the date of the

call closure. Funding scheme: Collaborative Project (Small or

medium-scale – 3M€).

2- Project concept

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.

1 - 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.

2 - 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:

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

placebo or with increasing doses of AA

2 - 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.

3 - Partnership.

The project already involved several teams involved in chemistry,

biology, genomics, molecular biology and pharmacologic preparation.

However, to answer the needs of the call (strong involvement of

industries) and to wider our partnership, we would like to extend our

consortium.

We listed the following competences which are crucial for the success of

the project:

- 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

4- Recent publication of the lab on the subject.

F.Kaya, S.Belin, G.Diamantidis, M.Fontes. Ascorbic acid is a regulator

of the intracellular cAMP concentration: old molecule, new functions?

Submitted.

Sophie Belin, Ferdinand Kaya, Ghislaine Duisit, Giacometti, ph

Ciccolini and Michel Fontés. Antiproliferative property of ascorbic

acid is mediated by inhibition of the expression of genes necessary to

cell cycle progression. Submitted.

Ferdinand Kaya, Sophie Belin, le Micallef, Olivier Blin, Michel

Fontés. Analysis of the benefits of vitamin cocktails in treating

Charcot-Marie-Tooth disease type 1A. Muscle an Nerve, in press.

Kaya F, Belin S, Bourgeois P, Micaleff J, Blin O, Fontes M. Neuromuscul

Disord. 2007 Mar;17(3):248-53.

Passage E, Norreel JC, Noack-Fraissignes P, Sanguedolce V, Pizant J,

Thirion X, Robaglia-Schlupp A, Pellissier JF, Fontes M. Related Ascorbic

acid treatment corrects the phenotype of a mouse model of

Charcot-Marie-Tooth disease. Nat Med. 2004 Apr;10(4):396-401.

Fontes M. Ascorbic acid: a first generation drug for Charcot-Marie-Tooth

disease. Med Sci (Paris). 2004 Oct;20(10):843-4.