New papers from Daniel Schumperli group

Two new papers from Daniel Schumperli lab have been recently published:

1. Ittig, D., Schümperli, D. and Leumann, C.J. (2008) Tc-DNA modified siRNA. Nucleic Acids Symp Ser (Oxf). 52, 501-502.

We investigated the biological activity of siRNAscarrying tc-DNA modifications at various positions in the sense strand. The siRNAs were directed to thecoding region of the enhanced green fluorescent protein (EGFP) mRNA. HeLa cells were transfected with the EGFP plasmid and variable concentrations of siRNA duplexes. The antisense effect was quantified on the protein level by fluorescence activated cell sorting (FACS). We found that 3'-end modification as well as modifications at 3–4 further positions either in the 3'- orthe 5'-region of the sequence were well tolerated, some of them leading to higher repression of gene expression than wild type RNA.

2. Meyer, K., Marquis, J., Trüb, J., Nlend Nlend, R., Verp, S., Ruepp, M.-D., Imboden, H., Barde, I., Trono, D. and Schümperli, D. (2008) Rescue of a severe mouse model for Spinal Muscular Atrophy by U7 snRNA-mediated splicing modulation. Human Molecular Genetics 2008, doi: 10.1093/hmg/ddn382.

In Spinal Muscular Atrophy (SMA), the leading genetic cause of early childhood death, the survival motor neuron 1 gene (SMN1) is deleted or inactivated. The nearly identical SMN2 gene has a silent mutation that impairs the utilisation of exon 7 and the production of functional protein. It has been hypothesised that therapies boosting SMN2 exon 7 inclusion might prevent or cure SMA. Exon 7 inclusion can be stimulated in cell culture by oligonucleotides or intracellularly expressed RNAs, but evidence for an in vivo improvement of SMA symptoms is lacking. Here we unambiguously confirm the above hypothesis by showing that a bifunctional U7 snRNA that stimulates exon 7 inclusion, when introduced by germ-line transgenesis, can efficiently complement the most severe mouse SMA model. These results are significant for the development of a somatic SMA therapy, but may also provide new means to study pathophysiological aspects of this devastating disease.