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B. F. EL-KHODOR, S. RAMBOZ, D. KOBAYASHI, M. WINBERG

Spinal Muscular Atrophy (SMA) is an autosomal recessive genetic disorder characterized by motor neuron loss and muscle atrophy, due to a deficit of SMN protein expression. Using a severe early onset mouse model (Le et al., 2005; Jackson Laboratory repository #006025) we established a moderate throughput drug efficacy testing platform (El-Khodor et al., 2008). The SMNΔ7 mice survive for 12.6 + 0.7 days (all animals die by P17 – P18) and show significant deviation in mean body weight from WT controls as early as postnatal day P8 (birth is defined as P0). These findings are similar to what have been previously reported for this strain. Frequency distribution analysis of 100 SMNΔ7 animals showed two distinct peaks of death: one between P8 to 11 (20%) and one at P14 to 17 (60%). We found that several compounds and nutritional supplements treatments starting as early as P3 either abolished or decreased the magnitude of the first peak of death. However, few compounds modulated the percentage of mice dying in the second peak (P14 to P17) and only 20 – 30% of the animals survived past the second peak of death. Our laboratory has recently acquired a novel adult model for SMA (Jackson Laboratory repository # 008604). This new animal model was engineered by replacing mouse Smn exons 7 and 8 by a cassette containing human SMN2 exons 7 and 8 and the genomic region carrying the full length human SMN2 (42kb). The resulting homozygote mutant animal carries 2 hybrids and 2 full length SMN2 alleles Our preliminary data (~140 HOM and WT) showed the body weight growth of HOM animals is indistinguishable from WT littermates from P0 to P16. However, after P16, the mean body weight of HOM animals deviates significantly from WT controls. HOM animals show a significant delay in body weight growth between P16 and P18. The animals’ growth rate increases after this point, however, the mean body weight of the HOM animal remains significantly lower up to 6 month of age (the extent of the current observation period) in comparison to WT controls. These findings raise questions about the importance and relevance of this critical developmental time point (around P16) and provide insight on the role of Smn protein during normal rodent development. The implications of this finding on the efforts of ongoing drug discovery in animal models for SMA will be discussed. This work is supported by SMA Foundation.