Developing therapies for spinal muscular atrophy

Wertz, Mary H.; Şahin, Mustafa

doi:10.1111/nyas.12813

Cited by 12 publications

(8 citation statements)

References 152 publications

(188 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A number of studies have used Taiwanese SMA model mice for clinical testing, including the use of ASOs. For example, agents aimed at augmentation of SMN2 expression, such as histone deacetylase (HDAC) inhibitor treatment, have been demonstrated to ameliorate motor deficits and increase lifespan in Taiwanese SMA model mice [ 28 , 54 , 55 ]. In the previous study, MO-ASO (10–29) treatment was shown to increase full-length SMN expression, weight gain, and survival time in SMA mice [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Selective Neuromuscular Denervation in Taiwanese Severe SMA Mouse Can Be Reversed by Morpholino Antisense Oligonucleotides

et al. 2016

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by deficiency of the survival of motor neuron (SMN) protein, which leads to synaptic defects and spinal motor neuron death. Neuromuscular junction (NMJ) abnormalities have been found to be involved in SMA pathogenesis in the SMNΔ7 SMA mouse model. However, whether similar NMJ pathological findings present in another commonly used mouse model, the Taiwanese SMA mouse, has not been fully investigated. To examine the NMJs of the Taiwanese severe SMA mouse model (Smn-/-; SMN2tg/0), which is characterized by severe phenotype and death before postnatal day (P) 9, we investigated 25 axial and appendicular muscles from P1 to P9. We labelled the muscles with anti-neurofilament and anti-synaptophysin antibodies for nerve terminals and α-bungarotoxin for acetylcholine receptors (AChRs). We found that severe NMJ denervation (<50% fully innervated endplates) selectively occurred in the flexor digitorum brevis 2 and 3 (FDB-2/3) muscles from P5, and an increased percentage of fully denervated endplates correlated with SMA progression. Furthermore, synaptophysin signals were absent at the endplate compared to control littermate mice, suggesting that vesicle transport might only be affected at the end stage. Subsequently, we treated the Taiwanese severe SMA mice with morpholino (MO) antisense oligonucleotides (80 μg/g) via subcutaneous injection at P0. We found that MO significantly reversed the NMJ denervation in FDB-2/3 muscles and extended the survival of Taiwanese severe SMA mice. We conclude that early NMJ denervation in the FDB-2/3 muscles of Taiwanese severe SMA mice can be reversed by MO treatment. The FDB-2/3 muscles of Taiwanese severe SMA mice provide a very sensitive platform for assessing the effectiveness of drug treatments in SMA preclinical studies.

show abstract

Section: Discussionmentioning

confidence: 99%

Selective Neuromuscular Denervation in Taiwanese Severe SMA Mouse Can Be Reversed by Morpholino Antisense Oligonucleotides

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Histone deacetylase inhibitors (HDACi) increase the expression of the SMN2 gene and ameliorate the SMN2 splicing defects in vitro and in mouse models (Mohseni, Zabidi-Hussin, & Sasongko, 2013;Wertz & Sahin, 2016). The splicing effect of HDACi was attributed to up-regulation of positive regulators of exon 7 splicing (Hofmann, Lorson, Stamm, Androphy, & Wirth, 2000;Hofmann & Wirth, 2002).…”

Section: Introductionmentioning

confidence: 99%

Combined treatment with the histone deacetylase inhibitor LBH589 and a splice‐switch antisense oligonucleotide enhances SMN2 splicing and SMN expression in Spinal Muscular Atrophy cells

Pagliarini

Guerra

Rosa

et al. 2020

Journal of Neurochemistry

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is a motor neuron disease caused by loss of function mutations in the Survival Motor Neuron 1 (SMN1) gene and reduced expression of the SMN protein, leading to spinal motor neuron death, muscle weakness and atrophy. Although humans harbour the highly homologous SMN2 gene, its defective splicing regulation yields a truncated and unstable SMN protein. The first therapy for SMA was recently approved by the Food and Drug Administration and consists of an antisense oligonucleotide (Nusinersen) rendering SMN2 functional and thus improving patients' motor activity and quality of life. Nevertheless, not all patients equally respond to this therapy and the long-term tolerability and safety of Nusinersen are still unknown. Herein, in vivo splicing assays indicated that the HDAC inhibitor LBH589 is particularly efficient in rescuing the SMN2 splicing defect in SMA fibroblasts and SMA type-I mice-derived neural stem cells. Western blot analyses showed that LBH589 also causes a significant increase in SMN protein expression in SMA cells. Moreover chromatin immunoprecipitation analyses revealed that LBH589 treatment induces widespread H4 acetylation of the entire SMN2 locus and selectively favors the inclusion of the disease-linked exon 7in SMN2 mature mRNA. The combined treatment of SMA cells with sub-optimal doses of LBH589 and of an antisense oligonucleotide that mimic Nusinersen (ASO_ISSN1) elicits additive effects on SMN2 splicing and SMN protein expression. These findings suggest that HDAC inhibitors can potentiate the activity of Nusinersen and support the notion that 'SMN-plus' combinatorial therapeutic approaches might represent an enhanced opportunity in the scenario of SMA therapy. K E Y W O R D S LBH589, Nusinersen therapy, SMN2 splicing, spinal muscular atrophy Read the Editorial Highlight for this article on page 146. | 265 PAGLIARINI et AL.

show abstract

“…Thus, SMN2 is considered as an important SMA disease modifier to be a potential target for SMA treatment. However, the correlation between SMN2 copy number and clinical phenotype does not apply to all SMA patients, and medications endeavoring to increase SMN production only slightly attenuate the disease symptoms [ 9 , 10 ]. Other genetic modifiers, plastin 3 (Pls3) , zinc finger protein 1 ( Zpr1 ) and ubiquitin-like modifier activating enzyme 1 ( UBA1 ), have been identified based on their biological functions and genotype-phenotype prevalence in SMA [ 11 – 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, SMA is a multi-system malfunctioned disease with wide spectrum of disease severity [ 16 , 17 ]. Treatments dedicated to motor neuron function have shown some therapeutic effects; however, none has demonstrated substantial curative response in SMA patients due to the disruption of pathologies outside the CNS such as metabolic disorders and dysfunctional autonomic innervation of the heart [ 10 , 18 , 19 ]. Successful development of new SMA therapies requires the identification and characterization of pathological changes that occur across different cell types and tissues affected by SMA [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

An Integrative Transcriptomic Analysis for Identifying Novel Target Genes Corresponding to Severity Spectrum in Spinal Muscular Atrophy

et al. 2016

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is an inherited neuromuscular disease resulting from a recessive mutation in the SMN1 gene. This disease affects multiple organ systems with varying degrees of severity. Exploration of the molecular pathological changes occurring in different cell types in SMA is crucial for developing new therapies. This study collected 39 human microarray datasets from ArrayExpress and GEO databases to build an integrative transcriptomic analysis for recognizing novel SMA targets. The transcriptomic analysis was conducted through combining weighted correlation network analysis (WGCNA) for gene module detection, gene set enrichment analysis (GSEA) for functional categorization and filtration, and Cytoscape (visual interaction gene network analysis) for target gene identification. Seven novel target genes (Bmp4, Serpine1, Gata6, Ptgs2, Bcl2, IL6 and Cntn1) of SMA were revealed, and are all known in the regulation of TNFα for controlling neural, cardiac and bone development. Sequentially, the differentially expressed patterns of these 7 target genes in mouse tissues (e.g., spinal cord, heart, muscles and bone) were validated in SMA mice of different severities (pre-symptomatic, mildly symptomatic, and severely symptomatic). In severely symptomatic SMA mice, TNFα was up-regulated with attenuation of Bmp4 and increase of Serpine1 and Gata6 (a pathway in neural and cardiac development), but not in pre-symptomatic and mildly symptomatic SMA mice. The severely symptomatic SMA mice also had the elevated levels of Ptgs2 and Bcl2 (a pathway in skeletal development) as well as IL6 and Cntn1 (a pathway in nervous system development). Thus, the 7 genes identified in this study might serve as potential target genes for future investigations of disease pathogenesis and SMA therapy.

show abstract

Developing therapies for spinal muscular atrophy

Cited by 12 publications

References 152 publications

Selective Neuromuscular Denervation in Taiwanese Severe SMA Mouse Can Be Reversed by Morpholino Antisense Oligonucleotides

Selective Neuromuscular Denervation in Taiwanese Severe SMA Mouse Can Be Reversed by Morpholino Antisense Oligonucleotides

Combined treatment with the histone deacetylase inhibitor LBH589 and a splice‐switch antisense oligonucleotide enhances SMN2 splicing and SMN expression in Spinal Muscular Atrophy cells

An Integrative Transcriptomic Analysis for Identifying Novel Target Genes Corresponding to Severity Spectrum in Spinal Muscular Atrophy

Contact Info

Product

Resources

About