Download Orphan Drug project Proposal

FP7 Project Proposal :
Partner Search
Service de la Recherche / Cellule Europe
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: [email protected]
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: [email protected]
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.
1
FP7 Project Proposal :
Partner Search
Service de la Recherche / Cellule Europe
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 (Morris 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, Sarah Giacometti, Joseph 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, Joelle 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):24853.
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.
2