Identification of a Rapid-Throughput Battery of Pheontypic Tests for Drug Candidate Evaluation in the Δ-7 Mouse Model of Spinal Muscular Atrophy

Abstract

Spinal muscular atrophy (SMA) is characterized by selective loss of α-motor neurons and is caused by homozygous loss or mutation in the telomeric survival motor neuron (SMN1) gene. Currently, there are no specific treatments for SMA. Drugs that improve α-motor neuron survival and/or connectivity are potential therapeutic candidates. A high capacity and practical in vivo assessment system in the neonates (as early as the day of birth) is important to identify and evaluate therapeutic candidates. Key features of SMA are modeled in mice by deletion of the smn gene and insertion of the human SMN2 gene (smn^–/–; SMN2^+/+). Incorporation of the Δ7 gene into this SMA model improves survival into a more experimentally useful range of symptom progression, severity and drug administration protocols (see Le et al., Hum. Mol. Genet. 14: 845, 2005). In the present study, SMA model mice (smn^–/–; SMN2^+/+; Δ7^+/+) and control mice (smn^+/+; SMN2^+/+; Δ7^+/+) were assessed daily for body weight and survival, and every other day for muscle tone, respiratory rate, gasping, degree of cyanosis, stomach milk content, and performance in a geotaxis test. Hind limb measures of strength, stamina, and general muscle tone were also evaluated. Around postnatal day 7, SMA mice showed lower body weights than controls and had a mean survival time of 13.5 days, as reported previously (Le et al., 2005). SMA mice did not acquire the ability to perform the geotaxis test and exhibited consistently hypotonic hind limbs. Other parameters were more variable and impaired at later time points. Furthermore, there was a significant correlation between body weight change and survival, which predicted the day of death within a 1-2 day period. This battery of tests in the Δ7 mouse model of SMA provides a rapid throughput and efficient means to identify, evaluate, and develop candidate therapies as a prelude to human clinical trials.