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Topic Name: Novel therapy has been developed to treat cystic fibrosis and carrying various nonsense mutations.
Category: Genetic Engineering
Research persons: Aleksander Edelman & Jean-Pierre Rousset
Location: Headquarters: 3, rue Michel-Ange ,75794 Paris cedex 16,Telephone: +33 1 44 96 40 00 ,Fax: +33 1 44 96 53 90, France
Details
Genetic tests
could enable the targeting of effective treatments for patients with cystic
fibrosis. This has been suggested by Aleksander Edelman, CNRS Director of
Research at INSERM Unit 845 "Growth and Signalling Research Centre" and his
colleague Isabelle Sermet-Gaudelus1, working in collaboration with the team led
by Jean-Pierre Rousset (Genetics and Microbiology Institute, CNRS / Université
Paris 11) and several major hospitals. They have demonstrated that some patients
with cystic fibrosis who present with a highly specific type of mutation to the
CFTR2 gene might benefit from treatment with gentamicin, a widely employed
antibiotic. Published in BMC Medicine on March 30, 2007, this study opens new
therapeutic perspectives for not only cystic fibrosis but also for other "stop
codon" diseases, such a certain types of myopathy.
Some
genetic diseases cause the synthesis of truncated and inactive proteins: they
are then referred to as "stop codon" diseases"3. These diseases are linked to
stop or nonsense mutations in the gene pool. For some years now, a novel
therapy has been developed to treat patients affected by these diseases.
This
consists in thwarting the effects of these nonsense mutations via the
transcription mechanism4, using antibiotics from the aminoglycoside family such
as gentamicin. The aim is to reexpress the "inactive" proteins, i.e. to render
them functional. However, this approach has one major limitation: only certain
mutations referred to as "good responders" can achieve the reexpression of a
functional protein. According to the results of several studies, a lack of
response to this treatment is induced by the sequence surrounding the mutation.
More specifically, cystic fibrosis is caused by the presence of mutations in the
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. More than 1500
mutations of this gene are known at present: 10% correspond to the appearance of
a stop codon. Based on these findings, the teams led by Aleksander Edelman and
Jean-Pierre Rousset joined forces with Isabelle Semert-Gaudelus in order to
study the results of gentamicin therapy in a panel of nine patients suffering
from cystic fibrosis and carrying various nonsense mutations.
Using
a cell culture test, they were thus able to reveal that only a particular
mutation in the CFTR gene – the Y122X mutation which is mainly detected in
patients originating from
Reunion
Island
– made it possible to achieve a high transcription rate. These patients were
then treated with an intravenous infusion of gentamicin for 15 days, the study
being carried out simultaneously in Hôpital Necker in Paris and the Saint Denis
and Saint Pierre Hospital in Reunion. A significant therapeutic benefit,
particularly at a respiratory level, was observed in six of the nine patients
treated. This was linked to reexpression of the protein previously absent from
these patients. On the other hand, none of the patients with a nonsense mutation
other than the Y122X mutation, or with a mutation of a different type, presented
with any clinical improvement.
Another important result was that a simple, in vitro cell culture test could
predict if it were possible to suppress the nonsense mutations detected in
patients. This method may constitute an initial step in the development of
effective therapy for patients suffering from cystic fibrosis or other "stop
codon" diseases.
Furthermore, gentamicin presented the advantage of already being widely used in
hospitals. However, it is certainly not the ideal compound: in some patients,
it causes serious adverse effects such as kidney disease or deafness. Other
compounds with a comparable mode of action and involving fewer adverse effects
are thus under study, such as PTC124 and amikacin, an antibiotic from the same
family as gentamicin. It is still necessary to determine whether these
compounds present the same therapeutic potential as gentamicin…
Notes :
1) All belong to the "Growth and Signalling Research Centre" (INSERM Unit 845,
Hôpital Necker-Enfants Malades / Université Paris Descartes / AP-HP Paris). The
clinical studies received financial support from several of the patient
associations concerned: ABCF Protéines, the Association pour l'aide à la
recherche contre la mucoviscidose et l'assistance aux malades, the Association
pour la recherche sur le cancer and the 'Association française contre les
myopathies.
2) Cystic Fibrosis Transmembrane Conductance Regulator
3) A stop codon or nonsense codon is a triplet of bases which signals the end of
a genetic message on messenger RNA (mRNA). It does not correspond to any amino
acid, so that translation of the mRNA into a protein thus ceases as from this
nonsense codon.
4) This mechanism enables the pursuit of protein synthesis until the next stop
codon.
References :
In vitro prediction of stop-codon suppression by intravenous gentamicin in
patients with cystic fibrosis : a pilot study. Isabelle Sermet-Gaudelus (1,2),
Michel Renouil (3), Anne Fajac (4), Laure Bidou (5,6), Bastien Parbaille (5,6),
Sébastien Pierrot (7), Nolwen Davy (3), Elise Bismuth (3), Philippe Reinert (8),
Gérard Lenoir (1), Jean-François Lesure (9), Jean-Pierre Rousset (5,6),
Aleksander Edelman (2,10). BMC Medicine. 30 mars 2007.
1) Centre de ressources et de compétence en mucoviscidose, Hôpital
Necker-Enfants Malades, AP-HP, Paris, France.
2) Unité Inserm 845 "Centre de recherche croissance et signalisation",
Université Paris Descartes, site Necker, Paris, France.
3) Centre de ressources et de compétence en mucoviscidose, Groupe hospitalier
Sud Réunion, Saint Pierre, France.
4) Service d'histologie-biologie tumorale, Hôpital Tenon, AP-HP, UPRES EA 3499,
Université Pierre et Marie Curie, Paris, France.
5) IGM, Université Paris-Sud, UMR 8621, Orsay, France.
6) CNRS, Orsay, France.
7) Service d'ORL, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
8) Centre de ressources et de compétence en mucoviscidose, Centre hospitalier
intercommunal, 40, avenue de Verdun, Créteil, France.
9) Centre de ressources et de compétence en mucoviscidose, Hôpital d'enfants,
Saint Denis, France.
10) Université Paris Descartes, Faculté de médecine René Descartes, Paris,
France.
About
Researcher s:
Aleksander Edelman
T 01 40 61 56 21
edelman@necker.fr
Jean-Pierre Rousset
T 01 69 15 50 51
jean-pierre.rousset@igmors.u-psud.fr
Funded:
This funding comes from
various sources:
- Government and public funding
- CNRS funds, primarily from industrial and EU
research contracts and royalties on patents, licenses, and services provided.
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