RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays

Tang, Zhichao; Zhao, Junxing; Pearson, Zachary; Bošković, Žarko; Wang, Jingxin

doi:10.3390/molecules26082263

Cited by 27 publications

(36 citation statements)

References 190 publications

(310 reference statements)

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“…“Masking” ASOs are commonly used as a steric block in the target RNA and, thereby, to modulate RNA splicing and suppress translation. The FDA has approved several ASOs acting through this mechanism to treat a variety of human diseases ( Roberts et al, 2020 ; Tang et al, 2021a ). For example, fomivirsen was the first FDA-approved ASO drug to treat cytomegalovirus (CMV) retinitis (approved in 1998; withdrawn in 2006 for lack of medical need) ( Stein and Castanotto, 2017 ).…”

Section: Viral Rna-targeting Strategiesmentioning

confidence: 99%

“…Fomivirsen binds to the immediate early region 2 in the human CMV mRNA, halting the RNA translation of (IE)-2 protein which is crucial for viral replication ( Geary et al, 2002 ). ASOs are also widely used for modulating RNA splicing in rare genetic diseases, such as Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) ( Tang et al, 2021b ).…”

Section: Viral Rna-targeting Strategiesmentioning

confidence: 99%

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Inhibition of SARS-CoV-2 by Targeting Conserved Viral RNA Structures and Sequences

2021

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The ongoing COVID-19/Severe Acute Respiratory Syndrome CoV-2 (SARS-CoV-2) pandemic has become a significant threat to public health and has hugely impacted societies globally. Targeting conserved SARS-CoV-2 RNA structures and sequences essential for viral genome translation is a novel approach to inhibit viral infection and progression. This new pharmacological modality compasses two classes of RNA-targeting molecules: 1) synthetic small molecules that recognize secondary or tertiary RNA structures and 2) antisense oligonucleotides (ASOs) that recognize the RNA primary sequence. These molecules can also serve as a “bait” fragment in RNA degrading chimeras to eliminate the viral RNA genome. This new type of chimeric RNA degrader is recently named ribonuclease targeting chimera or RIBOTAC. This review paper summarizes the sequence conservation in SARS-CoV-2 and the current development of RNA-targeting molecules to combat this virus. These RNA-binding molecules will also serve as an emerging class of antiviral drug candidates that might pivot to address future viral outbreaks.

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Section: Viral Rna-targeting Strategiesmentioning

confidence: 99%

Section: Viral Rna-targeting Strategiesmentioning

confidence: 99%

Inhibition of SARS-CoV-2 by Targeting Conserved Viral RNA Structures and Sequences

2021

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“…In this study it has not been possible to design PMOs that permit correction of the splicing signalling and furthermore, it was not possible to achieve specificity to target the mutated allele as the same effect was observed in both patient-derived fibroblasts and control fibroblasts. We hypothesize that when the splicing variant is within +/- 13 nucleotides of the acceptor or donor splice site, the PMO could allosterically interfere with the branch point and the U2 snRNA incorporation into the spliceosome [44]. The spatiotemporal localization of the two alleles during splicing could prevent the PMO from specifically targeting the mutated allele and thus it would interfere in the cis-regulation of RNA elements of both alleles equally, resulting in an increased pathogenic effect [45].…”

Section: Discussionmentioning

confidence: 99%

Antisense oligonucleotides targeting exon 11 are able to partially rescue the Neurofibromatosis Type 2 phenotype in vitro

Catasus

Rosas

Bonache

et al. 2022

Preprint

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Neurofibromatosis type 2 (NF2) is an autosomal dominant condition characterized by the development of multiple tumours of the nervous system caused by loss of function variants in the NF2 gene. The clinical presentation of the disease is variable and related to the type of the inherited constitutional mutation. Here, we evaluated the use of antisense oligonucleotides, specifically phosphorodiamidate morpholino oligomers (PMOs), to reduce the severity of the effects of NF2 truncating variants by converting them to milder hypomorphic forms in vitro. Our results showed that the PMOs designed for variants located at +/- 13 from the intron-exon boundary region interfered with the correct splicing signalling of both NF2 wild-type and mutated alleles. On the other hand, we were able to specifically induce the skipping of exons 4, 8 and 11 of both the mutated and the WT allele maintaining the NF2 gene reading frame at cDNA level. Only the skipping of exon 11 produced a hypomorphic Merlin (Merlin-e11) able to partially rescue the phenotype observed in primary fibroblast cultures from NF2 patients harbouring a germline loss of function variant. This encouraging result is an in vitro proof of concept of the use of antisense therapy to develop personalized therapies for NF2

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“…Exon 7 skipping may be caused by increased activity of a regulatory sequence located at the 3′ end of exon 7, called terminal stem loop 2 (TSL2). It exhibits inhibitory activity, probably by competing with U1 snRNP for a binding site [ 57 ]. The inhibitory effect of TSL2 was confirmed by observing the effect of U40G or A54C substitution on exon 7 splicing.…”

Section: Mechanisms Of Smn2 Splicing Regulation Targeted By Therapeuticsmentioning

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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RNA-Targeting Splicing Modifiers: Drug Development and Screening Assays

Cited by 27 publications

References 190 publications

Inhibition of SARS-CoV-2 by Targeting Conserved Viral RNA Structures and Sequences

Inhibition of SARS-CoV-2 by Targeting Conserved Viral RNA Structures and Sequences

Antisense oligonucleotides targeting exon 11 are able to partially rescue the Neurofibromatosis Type 2 phenotype in vitro

Alternative Splicing Role in New Therapies of Spinal Muscular Atrophy

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