TY - JOUR
T1 - Identification of a battery of tests for drug candidate evaluation in the SMNΔ7 neonate model of spinal muscular atrophy
AU - El-Khodor, Bassem F.
AU - Edgar, Nicole
AU - Chen, Angela
AU - Winberg, Margaret L.
AU - Joyce, Cynthia
AU - Brunner, Daniela
AU - Suárez-Fariñas, Mayte
AU - Heyes, Melvyn P.
N1 - Funding Information:
We would like to acknowledge the following SMA Foundation mouse steering committee members for their valuable scientific input: Drs. Arthur Burghes, Mathew Butchbach, Greg Cox, Christine DiDonato, Catherine Hall, Jill Heemskerk, Richard Paylor and Michael Sendtner. We thank Drs. Sylvie Ramboz, Emer Leahy, Karen Chen and Shoshana Shendelman for their critical reading of the manuscript. This work was supported in part by SMA Foundation and NIH/NINDS and PsychoGenics Inc.
PY - 2008/7
Y1 - 2008/7
N2 - Spinal muscular atrophy (SMA) is characterized by selective loss of α-motor neurons and is caused by homozygous loss or mutation in the survival motor neuron (SMN1) gene. Loss of SMN1 is partially compensated by the copy gene, SMN2. Currently, there are no specific treatments for SMA. Key features of SMA are modeled in mice by deletion of murine Smn, and insertion of both full length human SMN2 gene and the major aberrant splice isoform of the SMN2 gene (SMNΔ7; [Le, T.T., Pham, L.T., Butchbach, M.E., Zhang, H.L., Monani, U.R., Coovert, D.D., Gavrilina, T.O., Xing, L., Bassell, G.J., and Burghes, A.H. 2005. SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet 14: 845-857]). The present study identified moderate-throughput, quantitative behavioral tests in neonatal SMN2+/+;SMNΔ7+/+;Smn-/- mice. It also addresses methodological approaches and common interpretational challenges in a neonatal model with motor deficiencies and frequent deaths. Animals were assessed daily for body weight and survival, and every other day for neonatal well-being indices and tests of motor function such as performance on the hind-limb suspension test (a.k.a. tube test) and geotaxis. The tube test is a novel non-invasive motor function test specifically designed for neonatal rodents. We found progressive deterioration in SMA model mice for most measures studied particularly body weight, survival, body temperature and motor function with differences appearing as early as P3. Power analysis showed that body weight, survival, righting reflex, geotaxis and tube test had highest predictive power for drug efficacy studies. This multi-functional component battery of tests provides a rapid and efficient means to identify, evaluate and develop candidate therapies as a prelude to human clinical trials.
AB - Spinal muscular atrophy (SMA) is characterized by selective loss of α-motor neurons and is caused by homozygous loss or mutation in the survival motor neuron (SMN1) gene. Loss of SMN1 is partially compensated by the copy gene, SMN2. Currently, there are no specific treatments for SMA. Key features of SMA are modeled in mice by deletion of murine Smn, and insertion of both full length human SMN2 gene and the major aberrant splice isoform of the SMN2 gene (SMNΔ7; [Le, T.T., Pham, L.T., Butchbach, M.E., Zhang, H.L., Monani, U.R., Coovert, D.D., Gavrilina, T.O., Xing, L., Bassell, G.J., and Burghes, A.H. 2005. SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet 14: 845-857]). The present study identified moderate-throughput, quantitative behavioral tests in neonatal SMN2+/+;SMNΔ7+/+;Smn-/- mice. It also addresses methodological approaches and common interpretational challenges in a neonatal model with motor deficiencies and frequent deaths. Animals were assessed daily for body weight and survival, and every other day for neonatal well-being indices and tests of motor function such as performance on the hind-limb suspension test (a.k.a. tube test) and geotaxis. The tube test is a novel non-invasive motor function test specifically designed for neonatal rodents. We found progressive deterioration in SMA model mice for most measures studied particularly body weight, survival, body temperature and motor function with differences appearing as early as P3. Power analysis showed that body weight, survival, righting reflex, geotaxis and tube test had highest predictive power for drug efficacy studies. This multi-functional component battery of tests provides a rapid and efficient means to identify, evaluate and develop candidate therapies as a prelude to human clinical trials.
KW - Drug screening
KW - Moderate-throughput
KW - Motor neuron disease
KW - Mouse genetic model
KW - Neonate
KW - Novel motor test
KW - Phenotyping
KW - Preclinical development
KW - Tube test
UR - http://www.scopus.com/inward/record.url?scp=44649093889&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2008.02.025
DO - 10.1016/j.expneurol.2008.02.025
M3 - Article
C2 - 18455159
AN - SCOPUS:44649093889
SN - 0014-4886
VL - 212
SP - 29
EP - 43
JO - Experimental Neurology
JF - Experimental Neurology
IS - 1
ER -