Poster abstracts

Poster number 54 submitted by Thomas Bebee

Generation of a new mouse model to help determine the therapeutic time-point for SMN replacement therapies

Thomas Bebee (Molecular, Cellular, and Developmental Biology/ Columbus Children's Research Institute), Jordan Gladman (Integrated Biomedical Graduate Program), Dawn S. Chadler, Ph. D. (The Department of Pediatrics, The Ohio State University School of Medicine and Public Health, Columbus, Ohio/ Columbus Childrens Research Institute)

Abstract:
Proximal Spinal Muscular Atrophy (SMA), the leading genetic cause of infant mortality in humans, is caused by deletion or mutation of the survival of motor neuron gene-1 (SMN1) (Lefebvre et al. 1995; Jablonka et al. 2000). Homozygous deletion of the homologous gene (SMN) in mouse models leads to early embryonic lethality and thus fails to adequately model the human disease. It has been shown that human SMN2, a nearly identical gene, rescues the mouse knock-out phenotype in a dose dependent manner, where intermediate doses of SMN2 lead to a muscular atrophic phenotype (Hsieh-Li et al. 2000; Monani et al. 2000). Because the human SMN2 gene contains a point mutation that leads to inefficient splicing of the gene, it is thought that the SMN2 gene acts like a hypomorph and produces only enough levels of protein to support embryogenesis, but not the development and maintenance of healthy nerves after birth. Correction of SMN2 splicing is therefore a therapeutic option to reinstate SMN activity in SMA patients. However, the timing of therapeutic intervention will be important. Studies in zebrafish predict that restoration of SMN function during embryogenesis may be important for axonal pathfinding, while the mouse models and normal human disease progression suggest that post-natal treatment may be sufficient for amelioration of the disease phenotype. We have designed a temporally inducible-SMN transgenic mouse model that can be used in the SMA disease model background to determine the timing of potential SMN replacement therapies. In our inducible Smn mouse, wild-type SMN expression is Cre-inducible and will be controlled by adding a drug, tamoxifen. It is our immediate future plan to determine the therapeutic window for SMN replacement. To do this, we will cross currently available SMA mouse models the inducible Smn mouse model.

Keywords: Spinal Muscular Atrophy, Alternative Splicing, Mouse Model