Pendant le Congrès Myologie 2005, le Dr Béroud a présenté, le vendredi 13 mai 2005, lors du  symposium parallèle "Saut d'exon" une communication dont le titre est : "Les bases de données UMD : des données moléculaires à la thérapie génique par saut d'exon".

 

UMD - LOCUS SPECIFIC DATABASES : FROM MOLECULAR DATA TO GENE THERAPY BY EXON-SKIPPING
Thousands of mutations are identified in diagnostic and research laboratories yearly. The knowledge of these mutations associated with clinical and biological data is essential for clinicians, geneticists and researchers.
In order to collect and analyze these data we developed freely available generic software called Universal Mutation Databases (UMD®) to create locus-specific databases (http://www.umd.be). This tool allows the creation of LSDBs for virtually any gene and includes a large set of analysis tools.
Thus, we have created specific routines to help researchers to design new therapeutic strategies such as exon skipping. The archetype for exon skipping is the DMD gene associated with Duchenne (DMD) and Becker dystrophies (BMD). Most of the DMD mutations consist in large genomic deletions. The “out-of-frame” deletions elicit formation of premature stop codons that result in dystrophin deficiencies and severe phenotype (DMD). In contrast, deletions that produce “in frame” mRNAs leading to shorter proteins are responsible for a milder myopathy (BMD). In many DMD patients as well as in animal models, rare dystrophin-positive fibers have been reported. It has been suggested that restoring the reading-frame by exon skipping is the most likely cause of this natural phenomenon. This has prompted many groups to investigate the possibility of designing strategies for gene repair/modulation based on the use of compounds interfering with splicing, thus inducing exon skipping. Because the DMD gene contains 79 exons, more than 3.000 potential transcripts can be produced by exon skipping and should be investigated to search for frame restoration. We developed an automatic tool which displays the largest in-frame protein resulting from exon-skipping as well as other
combinations potentially restoring the frame. If the skipping of exons can be carried out by various approaches, the choice of the target sequences is of primary importance. Because algorithms searching for ESE, ESS and branch points are based on consensus sequences, it results a strong proportion of false positive signals. In order to optimize these algorithms, we developed collaborations with various teams able to identify functional sequences and validate software predictions. The combination of fully documented molecular and clinical data from DMD and BMD patients, the in vitro assays and bioinformatics approaches should thus make it possible to identify the best target sequences in order to consider clinical trials of patients.