Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested that inhibition of epidermal growth factor receptor (EGFR) signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model of ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed to extend ALS mouse survival it did provide a modest but significant delay in the onset of multiple behavioral measures of disease progression. However, given the lack of protection of motor neuron synapses and the lack of survival extension, the small benefits observed after erlotinib treatment appear purely symptomatic, with no modification of disease course.
Highlights
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease primarily affecting motor neurons
Despite the relatively high rate of censoring, the groups were still balanced for litter; there was a slight gender imbalance in the vehicle group only, where males were more sensitive than females (12 males vs 3 females censored in the vehicle group; Table 2)
The mean age at death of the censored mice was very close to the mean survival (153 vs 159 days), the censored mice lived long enough to contribute meaningful data to the survival analysis and the slight gender imbalance does not alter our conclusion that erlotinib fails to prolong SOD1 mouse lifespan
Summary
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease primarily affecting motor neurons. It causes rapid progressive paralysis, with 80% mortality 2–5 years following diagnosis. The SOD1G93A mouse model of ALS is the most widely used animal model for ALS as it phenocopies many aspects of the human disease [2]. In these mice, a familial mutation in the human SOD1 gene (G93A) that causes ALS is expressed transgenically throughout the body under the control of the endogenous mouse SOD1 promoter. The transgene insertion causes a degenerative disease of lower motor neurons leading to progressive paralysis and eventual death, with the number of transgene copies correlating with severity of disease [3]
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