Narrow Results

Duchenne and Becker muscular dystrophies are allelic X-linked disorders resulting from defects in the gene coding for the dystrophin muscle protein. The dystrophin gene is more than 2300kb in size and consists of 79 exons. This large size and complexity presents a challenge to direct identification of point mutations and small deletions that cannot be identified by multiplex deletion testing or Southern blotting. One approach to this problem is to analyse the expression of ectopic dystrophin mRNA transcripts. Although the dystrophin gene transcript is distributed only over approximately 0.1% of the genome, analysis of such ectopic lymphocyte dystrophin transcripts can shed light on the pathogenic events at the transcriptional level.

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease and so far, the treatment of DMD has not yet been established. Here, gene therapy is proposed as a novel treatment for DMD whereby the correction of the translational reading frame transforms severe DMD into the milder Becker muscular dystrophy. Based on the molecular analysis of dystrophin Kobe where the presence of an intra-exon deletion caused exon skipping during splicing, a part of the exon 19 sequence of the dystrophin gene was found to function as a splicing enhancer sequence, a sequence necessary for proper splicing. When oligonucleotides complementary to this sequence were added to the culture medium of lymphoblastoid cells, exon 19 skipping was specifically induced. This raises the possibility of a new therapeutic approach for DMD where dystrophin pre-mRNA splicing can be modulated by an oligonucleotide against a splicing enhancer sequence to produce an in-frame transcript that is able to produce truncated dystrophin. One natural example of this transformation is described.