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RNA-based therapeutics reaching the clinic
New Biotechnology · Volume 27S · April 2010
PLENARY SPEAKER ABSTRACTS
PLENARY SPEAKER ABSTRACTS K1 L. Peltonen Wellcome Trust Sanger Inst., Hinxton, UK
Please see programme book for Title and Abstract. doi:10.1016/j.nbt.2010.01.285
K2 K. Simons Max Planck Institute, Dresden, Germany
Please see programme book for Title and Abstract. doi:10.1016/j.nbt.2010.01.286
K3 RNA-based therapeutics reaching the clinic G.J. van Ommen ∗ , A. Aartsma-Rus, P-Bram ’t Hoen, J. Verschuuren, J. van Deutekom Leiden University Medical Center, The Netherlands
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 1871-6784/$ — see front matter
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. Our 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. Promising results have been obtained in several cases. doi:10.1016/j.nbt.2010.01.287
K4 The evolution of mammalian tissue transcriptomes H. Kaessmann University of Lausanne, Switzerland
Mammals are characterized by specific phenotypic traits that include lactation, hair, and relatively large brains with unique structures. Individual mammalian lineages have, in turn, evolved characteristic traits that distinguish them from others. These include obvious anatomical differences but also differences related to reproduction, life span, cognitive abilities, behavior, and disease susceptibility. The molecular changes underlying these phenotypic shifts and the associated selective pressures have only recently begun to be investigated based on an increasing number of available mammalian genomes. However, while the analysis of genome sequences may rather directly uncover mutations that alter the phenotype by chang-
www.elsevier.com/locate/nbt S1
PLENARY SPEAKER ABSTRACTS
PLENARY SPEAKER ABSTRACTS K1 L. Peltonen Wellcome Trust Sanger Inst., Hinxton, UK
Please see programme book for Title and Abstract. doi:10.1016/j.nbt.2010.01.285
K2 K. Simons Max Planck Institute, Dresden, Germany
Please see programme book for Title and Abstract. doi:10.1016/j.nbt.2010.01.286
K3 RNA-based therapeutics reaching the clinic G.J. van Ommen ∗ , A. Aartsma-Rus, P-Bram ’t Hoen, J. Verschuuren, J. van Deutekom Leiden University Medical Center, The Netherlands
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 1871-6784/$ — see front matter
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. Our 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. Promising results have been obtained in several cases. doi:10.1016/j.nbt.2010.01.287
K4 The evolution of mammalian tissue transcriptomes H. Kaessmann University of Lausanne, Switzerland
Mammals are characterized by specific phenotypic traits that include lactation, hair, and relatively large brains with unique structures. Individual mammalian lineages have, in turn, evolved characteristic traits that distinguish them from others. These include obvious anatomical differences but also differences related to reproduction, life span, cognitive abilities, behavior, and disease susceptibility. The molecular changes underlying these phenotypic shifts and the associated selective pressures have only recently begun to be investigated based on an increasing number of available mammalian genomes. However, while the analysis of genome sequences may rather directly uncover mutations that alter the phenotype by chang-
www.elsevier.com/locate/nbt S1