|
JPMorgan 24th Annual Healthcare Conference GenOdyssee will be attending the JPMorgan 24th Annual Healthcare Conference to be held in San Francisco (CA, USA) from Jan 9 to Jan 12. Fore more information or if you would like to set up a meeting with us during the conference, please contact: Jean-Louis Escary, Ph.D Chairman & CEOTel/Mobile: +33 (0) 6 16 41 68 57 escary@genodyssee.com or David Brown, Ph.D International Business Executive Advisor tel/mobile +44 (0)7766 686 345 davidbrown1000@btinternet.com |
|
International Symposium on Viral Hepatitis and Liver Disease (12th ISVHLD), July 1-5, 2006.
Abstract N°422 (P 158) "Novel interferon alpha variant with improved
inhibitory activity against HCV genotype 1 replication compared to IFN-alpha
2b therapy, in a subgenomic replicon system".
|
|
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Dec. 2006, Vol. 50, p. 3984–3991
Title: Novel alpha Interferon (IFN-α) Variant with Improved Inhibitory Activity against Hepatitis C Virus Genotype 1 Replication Compared to IFN-a2b Therapy in a Subgenomic Replicon System.
Authors: Vanessa Escuret, Amaury Martin, David Durantel, Romain Parent, Olivier Hantz, Christian Trépo, Thierry Menguy*, Emmanuel Bottius*, Jerome Dardy*, Jean Maral*, Jean Louis Escary*, and Fabien Zoulim
INSERM, U271, Laboratoire des virus hépatiques et pathologies associées, 151 cours Albert Thomas, 69003 Lyon, and Université Lyon 1, Faculté de Médecine Laennec, 69008 Lyon, France.
*GenOdyssee SA, 4 rue Pierre Fontaine, 91058 Evry Cedex, France.
Summary:
Hepatitis C virus (HCV) treatment is based on the association of pegylated alpha interferon (IFN-α) and ribavirin. To improve the level of sustained virological response to treatment, especially in patients infected with HCV genotype 1, new IFNs with improved efficacy and toxicity profiles may be developed. In this report, we show that, in the BM4-5 cell line harboring an HCV subgenomic replicon, a novel and naturally occurring human IFN-α17 variant, GEA007.1, which was discovered by using an original population genetics-based drug discovery approach, inhibits HCV genotype 1 RNA replication more efficiently than does IFN-α2b. Moreover, we show that complete viral clearance is obtained in BM4-5 cells after long-term treatment with GEA007.1, while HCV subgenomic RNA is still detected in cells treated with other IFN-α variants or with standard IFN-α2b. Eventually, we demonstrate that the better inhibitory activity of GEA007.1 compared to that of standard IFN-α is likely to be due to stronger and faster activation of the JAK-STAT signaling pathway and to broader expression of IFN-α responsive genes in cells. Our results demonstrate a superior inhibitory activity of GEA007.1 over that of IFN-α2b in the HCV replicon system. Clinical trials are required to determine whether GEA007.1 could be a potent “next generation” IFN for the treatment of HCV infection, especially in nonresponders or relapsing patients infected with HCV genotype 1 who currently represent a clinical unmet need.
Biochemistry. 2004 Oct 5;43(39):12498-512.
Title: Identification of residues of the IFNAR1 chain of the type I human
interferon receptor critical for ligand binding and biological activity.
Authors: Cajean-Feroldi C, Nosal F*, Nardeux PC, Gallet X*, Guymarho J,
Baychelier F, Sempe P*, Tovey MG, Escary JL*, Eid P.
Laboratory of Viral Oncology, CNRS-UPR 9045, 7 rue Guy Moquet, 94801
Villejuif, France.
Summary:
The antiviral and antiproliferative activities of human type I interferons
(IFNs) are mediated by two transmembrane receptor subunits, IFNAR1 and IFNAR2.
To elucidate the role of IFNAR1 in IFN binding and the establishment of
biological activity, specific residues of IFNAR1 were mutated. Residues (62)
FSSLKLNVY(70) of the S5-S6 loop of the N-terminal subdomain of IFNAR1 and
tryptophan-129 of the second subdomain of IFNAR1 were shown to be crucial for
IFN-alpha binding and signaling and establishment of biological activity.
Mutagenesis of peptide (278)LRV in the third subdomain shows that these
residues are critical for IFN-alpha-induced biological activity but not for
ligand binding. These data, together with the sequence homology of IFNAR1 with
cytokine receptors of known structure and the recently resolved NMR structure
of IFNAR2, led to the establishment of a three-dimensional model of the human
IFN-alpha/IFNAR1/IFNAR2 complex. This model predicts that following binding of
IFN to IFNAR1 and IFNAR2 the receptor complex assumes a "closed form", in
which the N-terminal domain of IFNAR1 acts as a lid, resulting in the
activation of intracellular kinases. Differences in the primary sequence of
individual IFN-alpha subtypes and resulting differences in binding affinity,
duration of ligand/receptor association, or both would explain differences in
intracellular signal intensities and biological activity observed for
individual IFN-alpha subtypes.
Eur Urol. 2003 Oct;44(4):487-90.
Title: Association study of polymorphisms in the human estrogen receptor alpha gene
and prostate cancer risk.
Authors: Cancel-Tassin G, Latil A, Rousseau F*, Mangin P, Bottius E*, Escary JL*,
Berthon P, Cussenot O.
UroGene, 4 rue Pierre Fontaine, 91058 Evry Cedex, France.
Summary:
OBJECTIVES: Prostate cancer is a very common hormone-related malignancy in
Western countries. It is initially dependent on androgen stimulation but in
vitro growth of prostate cancer cells are also dependent on estrogen. Our goal
was to elucidate if some polymorphisms of estrogen receptor alpha gene might
be associated with the risk of prostate cancer.
METHODS: Using DHPLC techniques, each coding exon of the estrogen receptor
alpha gene was screened for new polymorphisms in germline DNA from 96 healthy
controls and 96 sporadic prostate cancer cases. Identified polymorphisms were
then genotyped and their distribution compared between the two populations.
RESULTS: Thirteen polymorphisms were identified. A difference was found in the
distribution of one newly identified polymorphism, namely a GGGA repeat
located in the first intron of the gene. The common wild type genotype
consisted of two alleles with five GGGA repetitions (5/5 genotype). Indeed
this 5/5 genotype was found in 294/296 controls (99.3%) and 285/294 patients
(96.9%; OR, 4.6; 95% CI, 0.99-21.67). Among the nine patients with a different
genotype, one was 4/5, seven were 5/6 and one was 6/6.
CONCLUSION: These results suggest that variants of the GGGA polymorphism from
the estrogen receptor alpha gene may be associated with an increased risk of
developing prostate cancer.
Ann Hum Genet. 2002 Jul;66(Pt 4):307-21.
Title: Accurate power approximations for chi2-tests in case-control association
studies of complex disease genes.
Authors: Jackson MR, Genin E, Knapp M, Escary JL.
GenOdyssee SA, 4 rue Pierre Fontaine, 91058 Evry Cedex, France.
Summary:
A popular method for the analysis of case-control association studies
is to compare the frequencies of the alleles between cases and controls by
means of Pearson's chi2-statistic. Here, an approach for computing the power
of this test is presented, which by computer simulation is shown to be more
reliable than a previously published power approximation. Since the test based
on Pearson's chi2- statistic can be anti-conservative if there is an excess of
homozygotes for the susceptibility allele in the general population, it has
been proposed to analyze case-control association studies by means of a trend
test based on genotypes instead of alleles. We present an accurate power
approximation for the trend test. The power approximations are implemented in
an available computer program 'GenOdyPower', which in addition has an option
to determine the empirical power of these tests by simulations.
|