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Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy.

ABSTRACT: Proximal spinal muscular atrophy (SMA), one of the most common genetic causes of infant death, results from the selective loss of motor neurons in the spinal cord. SMA is a consequence of low levels of survival motor neuron (SMN) protein. In humans, the SMN gene is duplicated; SMA results from the loss of SMN1 but SMN2 remains intact. SMA severity is related to the copy number of SMN2. Compounds which increase the expression of SMN2 could, therefore, be potential therapeutics for SMA. Ultrahigh-throughput screening recently identified substituted quinazolines as potent SMN2 inducers. A series of C5-quinazoline derivatives were tested for their ability to increase SMN expression in vivo. Oral administration of three compounds (D152344, D153249 and D156844) to neonatal mice resulted in a dose-dependent increase in Smn promoter activity in the central nervous system. We then examined the effect of these compounds on the progression of disease in SMN lacking exon 7 (SMNDelta7) SMA mice. Oral administration of D156844 significantly increased the mean lifespan of SMNDelta7 SMA mice by approximately 21-30% when given prior to motor neuron loss. In summary, the C5-quinazoline derivative D156844 increases SMN expression in neonatal mouse neural tissues, delays motor neuron loss at PND11 and ameliorates the motor phenotype of SMNDelta7 SMA mice.

SUBMITTER: Butchbach ME

PROVIDER: S-EPMC2798721 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy.

Butchbach Matthew E R ME Singh Jasbir J Thorsteinsdóttir Margrét M Saieva Luciano L Slominski Elzbieta E Thurmond John J Andrésson Thorkell T Zhang Jun J Edwards Jonathan D JD Simard Louise R LR Pellizzoni Livio L Jarecki Jill J Burghes Arthur H M AH Gurney Mark E ME

Human molecular genetics 20091106 3

Proximal spinal muscular atrophy (SMA), one of the most common genetic causes of infant death, results from the selective loss of motor neurons in the spinal cord. SMA is a consequence of low levels of survival motor neuron (SMN) protein. In humans, the SMN gene is duplicated; SMA results from the loss of SMN1 but SMN2 remains intact. SMA severity is related to the copy number of SMN2. Compounds which increase the expression of SMN2 could, therefore, be potential therapeutics for SMA. Ultrahigh- ...[more]

PMID: 19897588

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Project description:BACKGROUND:Significant advances in the development of SMN-restoring therapeutics have occurred since 2010 when very effective biological treatments were reported in mouse models of spinal muscular atrophy. As these treatments are applied in human clinical trials, there is pressing need to define quantitative assessments of disease progression, treatment stratification, and therapeutic efficacy. The electrophysiological measures Compound Muscle Action Potential and Motor Unit Number Estimation are reliable measures of nerve function. In both the SMN?7 mouse and a pig model of spinal muscular atrophy, early SMN restoration results in preservation of electrophysiological measures. Currently, clinical trials are underway in patients at post-symptomatic stages of disease progression. In this study, we present results from both early and delayed SMN restoration using clinically-relevant measures including electrical impedance myography, compound muscle action potential, and motor unit number estimation to quantify the efficacy and time-sensitivity of SMN-restoring therapy. METHODS:SMA?7 mice were treated via intracerebroventricular injection with antisense oligonucleotides targeting ISS-N1 to increase SMN protein from the SMN2 gene on postnatal day 2, 4, or 6 and compared with sham-treated spinal muscular atrophy and control mice. Compound muscle action potential and motor unit number estimation of the triceps surae muscles were performed at day 12, 21, and 30 by a single evaluator blinded to genotype and treatment. Similarly, electrical impedance myography was measured on the biceps femoris muscle at 12days for comparison. RESULTS:Electrophysiological measures and electrical impedance myography detected significant differences at 12days between control and late-treated (4 or 6days) and sham-treated spinal muscular atrophy mice, but not in mice treated at 2days (p<0.01). EIM findings paralleled and correlated with compound muscle action potential and motor unit number estimation (r=0.61 and r=0.50, respectively, p<0.01). Longitudinal measures at 21 and 30days show that symptomatic therapy results in reduced motor unit number estimation associated with delayed normalization of compound muscle action potential. CONCLUSIONS:The incomplete effect of symptomatic treatment is accurately identified by both electrophysiological measures and electrical impedance myography. There is strong correlation between these measures and with weight and righting reflex. This study predicts that measures of compound muscle action potential, motor unit number estimation, and electrical impedance myography are promising biomarkers of treatment stratification and effect for future spinal muscular atrophy trials. The ease of application and simplicity of electrical impedance myography compared with standard electrophysiological measures may be particularly valuable in future pediatric clinical trials.

Dataset Information

Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy.

Publications

Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy.

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