HGM 2011 - Dubai, UAE
GERTJAN B. VAN OMMEN - Abstract
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Gert-Jan B. van Ommen
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Twenty years after the first wave of Mendelian disease gene discoveries, their translation into therapeutic modalities begins to take hold, greatly aided by the increase in biological insights and advancement of technologies of the genomics era. Antisense-mediated reading frame restoration is presently the most promising therapeutic approach for Duchenne muscular dystrophy (DMD). In this approach, antisense oligoribonucleotides (AONs) induce specific exon skipping during pre-mRNA splicing to restore the disrupted open reading frame and allow synthesis of internally deleted, partly functional Becker-like dystrophin proteins. The approach is theoretically applicable to over 70% of all patients. Proof of concept has been achieved in cultured muscle cells from patients carrying different mutation types, in the mdx mouse and dog models and recently in patients as well. In a first trial published in 2007 (van Deutekom et al. NEJM) we showed exon 51 skipping and dystrophin restoration in four patients after local intramuscular AON injections. A subsequent systemic trial has recently been successfully completed by Prosensa, as a multicenter one-month dose-finding trial, using subcutaneous administration. This better route for self-administration was previously tested to be efficient in reaching proper muscle AON levels, with a lower peak circulation level as intravenous administration. The 12 patients enrolled showed a clear dose response, both of skipping and dystrophin restoration, without adverse effects. preclinical further research now focuses on the next steps in developing and improving therapy: the development of more refined readouts for therapeutic success using transcriptomics and proteomics technology, and supporting treatments to increase myogenesis. Finally, the success of the exon skipping work in DMD has led us to explore applications to genes affected in other diseases. Thus, the translational steps initially taken for rare diseases will also greatly assist therapeutic development for common disease. . Especially in this era of rapidly emerging high-troughput tools and technology, it is becoming increasingly clear that the merging of the fields of complex and rare disease, classically seen as complementary and largely separate, has much to contribute to better defining biology, predict health outcomes and guiding therapy development. |
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Sheikh Hamdan Bin Rashid Al Maktoum |
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Human Genome Organisation |
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Centre for Arab Genomic Studies |
