Splice-switching small molecules: A new therapeutic approach to modulate gene expression

Taladriz-Sender, Andrea; Campbell, Emma; Burley, Glenn A.

doi:10.1016/j.ymeth.2019.06.011

Cited by 10 publications

(5 citation statements)

References 79 publications

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“…Reverting expression to the fetal/neonatal state by encouraging 5N utilization could reduce the excitability of cortical glutamatergic neurons, potentially limiting seizures [ 60 ]. For ASOs, the repeated intrathecal administration would limit such an approach to the most severe cases of epilepsy, however, small molecules can also modify splicing behavior [ 64 ]. It remains to be seen whether this approach could offer therapeutic benefits above and beyond existing antiepileptic drugs.…”

Section: Discussionmentioning

confidence: 99%

Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain

Liang

Darbandi

Pochareddy³

et al. 2021

Genome Med

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Background Genetic variants in the voltage-gated sodium channels SCN1A, SCN2A, SCN3A, and SCN8A are leading causes of epilepsy, developmental delay, and autism spectrum disorder. The mRNA splicing patterns of all four genes vary across development in the rodent brain, including mutually exclusive copies of the fifth protein-coding exon detected in the neonate (5N) and adult (5A). A second pair of mutually exclusive exons is reported in SCN8A only (18N and 18A). We aimed to quantify the expression of individual exons in the developing human brain. Methods RNA-seq data from 783 human brain samples across development were analyzed to estimate exon-level expression. Developmental changes in exon utilization were validated by assessing intron splicing. Exon expression was also estimated in RNA-seq data from 58 developing mouse neocortical samples. Results In the mature human neocortex, exon 5A is consistently expressed at least 4-fold higher than exon 5N in all four genes. For SCN2A, SCN3A, and SCN8A, a brain-wide synchronized 5N to 5A transition occurs between 24 post-conceptual weeks (2nd trimester) and 6 years of age. In mice, the equivalent 5N to 5A transition begins at or before embryonic day 15.5. In SCN8A, over 90% of transcripts in the mature human cortex include exon 18A. Early in fetal development, most transcripts include 18N or skip both 18N and 18A, with a transition to 18A inclusion occurring from 13 post-conceptual weeks to 6 months of age. No other protein-coding exons showed comparably dynamic developmental trajectories. Conclusions Exon usage in SCN1A, SCN2A, SCN3A, and SCN8A changes dramatically during human brain development. These splice isoforms, which alter the biophysical properties of the encoded channels, may account for some of the observed phenotypic differences across development and between specific variants. Manipulation of the proportion of splicing isoforms at appropriate stages of development may act as a therapeutic strategy for specific mutations or even epilepsy in general.

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Section: Discussionmentioning

confidence: 99%

Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain

Liang

Darbandi

Pochareddy³

et al. 2021

Genome Med

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“…Both groups identified small molecules and reported three orally delivered compounds, namely SMN-C1 (isocoumarin), SMN-C2 (coumarin), and SMN-C3 (pyridopyrimidinone derivative); each promoted exon 7 inclusion from SMN2 [ 92 ]. Small molecules can exhibit high selectivity, affecting the modulation of RNA folding of only one or a few genes, among the many thousands of genes expressed in cells [ 93 ]. Most drugs are inhibitors of enzyme proteins or receptors.…”

Section: Small Moleculesmentioning

confidence: 99%

Alternative Splicing Role in New Therapies of Spinal Muscular Atrophy

Lejman

Zieliński

Gawda

et al. 2021

Genes

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It has been estimated that 80% of the pre-mRNA undergoes alternative splicing, which exponentially increases the flow of biological information in cellular processes and can be an attractive therapeutic target. It is a crucial mechanism to increase genetic diversity. Disturbed alternative splicing is observed in many disorders, including neuromuscular diseases and carcinomas. Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease. Homozygous deletion in 5q13 (the region coding for the motor neuron survival gene (SMN1)) is responsible for 95% of SMA cases. The nearly identical SMN2 gene does not compensate for SMN loss caused by SMN1 gene mutation due to different splicing of exon 7. A pathologically low level of survival motor neuron protein (SMN) causes degeneration of the anterior horn cells in the spinal cord with associated destruction of α-motor cells and manifested by muscle weakness and loss. Understanding the regulation of the SMN2 pre-mRNA splicing process has allowed for innovative treatment and the introduction of new medicines for SMA. After describing the concept of splicing modulation, this review will cover the progress achieved in this field, by highlighting the breakthrough accomplished recently for the treatment of SMA using the mechanism of alternative splicing.

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“…These probabilities are largely determined by local features surrounding the splice sites (exon starts/ends) such as the presence of key motifs on the exonic and intronic regions surrounding the splice sites nucleotide. Global contextual regulatory factors such as RNA-binding proteins and small molecular signals [3,34,37] can also influence the transcript probabilities, creating variability for AS outcomes in cells from different tissue types or patients. While exon-skipping is the most common form of AS, there are others such as alternative exon start/end positions and intron retention.…”

Section: Background: Rna Alternative Splicingmentioning

confidence: 99%

RNA alternative splicing prediction with discrete compositional energy network

Chan

Korsakova

Ong

et al. 2021

Proceedings of the Conference on Health, Inference, and Learning

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A single gene can encode for different protein versions through a process called alternative splicing. Since proteins play major roles in cellular functions, aberrant splicing profiles can result in a variety of diseases, including cancers. Alternative splicing is determined by the gene's primary sequence and other regulatory factors such as RNA-binding protein levels. With these as input, we formulate the prediction of RNA splicing as a regression task and build a new training dataset (CAPD) to benchmark learned models. We propose discrete compositional energy network (DCEN) which leverages the hierarchical relationships between splice sites, junctions and transcripts to approach this task. In the case of alternative splicing prediction, DCEN models mRNA transcript probabilities through its constituent splice junctions' energy values. These transcript probabilities are subsequently mapped to relative abundance values of key nucleotides and trained with ground-truth experimental measurements. Through our experiments on CAPD 1 , we show that DCEN outperforms baselines and ablation variants. 2 CCS CONCEPTS• Applied computing → Bioinformatics; Health informatics; • Computing methodologies → Neural networks.

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Splice-switching small molecules: A new therapeutic approach to modulate gene expression

Cited by 10 publications

References 79 publications

Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain

Developmental dynamics of voltage-gated sodium channel isoform expression in the human and mouse brain

Alternative Splicing Role in New Therapies of Spinal Muscular Atrophy

RNA alternative splicing prediction with discrete compositional energy network

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