Drugging Pre-mRNA Splicing

Woll, Matthew G.; Naryshkin, Nikolai; Karp, Gary M.

doi:10.1007/7355_2017_12

Cited by 3 publications

(5 citation statements)

References 143 publications

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“…78,79 Our evaluation of the geneexpression analysis conservatively restricted interpretation to genes that met an FDR <0.05 and exhibited an absolute R2-fold change (log 2 R1 or %À1). Similar to previously reported splicing modulator compounds, [78][79][80] kinetin treatment had minimal effect transcriptome-wide; only 118 of 18,156 (0.006%) genes were differentially expressed (DE) (Figure 4A and Table S2). We determined splicing alterations by considering the three junctions in triplets of consecutive exons and calculating the c levels of the middle exon, then we considered splicing changes at c R0.2 or %-0.2 and FDR <0.05 (Figure 4B).…”

Section: Kinetin Demonstrates High Selectivity When Assessed By Rna-sequencingsupporting

confidence: 84%

ELP1 Splicing Correction Reverses Proprioceptive Sensory Loss in Familial Dysautonomia

Morini

Gao

Montgomery

et al. 2019

The American Journal of Human Genetics

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Familial dysautonomia (FD) is a recessive neurodegenerative disease caused by a splice mutation in Elongator complex protein 1 (ELP1, also known as IKBKAP); this mutation leads to variable skipping of exon 20 and to a drastic reduction of ELP1 in the nervous system. Clinically, many of the debilitating aspects of the disease are related to a progressive loss of proprioception; this loss leads to severe gait ataxia, spinal deformities, and respiratory insufficiency due to neuromuscular incoordination. There is currently no effective treatment for FD, and the disease is ultimately fatal. The development of a drug that targets the underlying molecular defect provides hope that the drastic peripheral neurodegeneration characteristic of FD can be halted. We demonstrate herein that the FD mouse TgFD9;Ikbkap D20/flox recapitulates the proprioceptive impairment observed in individuals with FD, and we provide the in vivo evidence that postnatal correction, promoted by the small molecule kinetin, of the mutant ELP1 splicing can rescue neurological phenotypes in FD. Daily administration of kinetin starting at birth improves sensory-motor coordination and prevents the onset of spinal abnormalities by stopping the loss of proprioceptive neurons. These phenotypic improvements correlate with increased amounts of full-length ELP1 mRNA and protein in multiple tissues, including in the peripheral nervous system (PNS). Our results show that postnatal correction of the underlying ELP1 splicing defect can rescue devastating disease phenotypes and is therefore a viable therapeutic approach for persons with FD.

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Section: Kinetin Demonstrates High Selectivity When Assessed By Rna-sequencingsupporting

confidence: 84%

ELP1 Splicing Correction Reverses Proprioceptive Sensory Loss in Familial Dysautonomia

Morini

Gao

Montgomery

et al. 2019

The American Journal of Human Genetics

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“…Strategies towards the identification of small molecules which induce a switch in the ratio of mature mRNA isoforms conceptually differs from conventional medicinal chemistry approaches, which are typically focused towards inhibiting a target protein with a small molecule [8]. Examples of therapeutic modulation of alternative splicing include: (a) Point mutations resulting in abnormal exclusion or inclusion of a particular exon leading to the overexpression of an undesirable mature mRNA isoform (Figure 2a).…”

Section: Strategies For the Development Of Splice-switching Small Mol...mentioning

confidence: 99%

“…Small molecules can also induce a switch in alternative splicing indirectly by altering the function of trans-acting factors such as SR proteins [8,23].…”

Section: Protein Kinase Inhibitors As Modulators Of Angiogenesismentioning

confidence: 99%

“…Sitting upstream to translation in the gene expression hierarchy, the processes of transcription and alternative splicing of specific RNA molecules is a highly regulated process [7]. By virtue of the complexity and means of regulation, alternative RNA splicing holds particular promise as a drug target [8]. Approximately 95% of genes are alternatively spliced, resulting in a rich source of protein diversity from a single gene.…”

Section: Introductionmentioning

confidence: 99%

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

Taladriz-Sender

Campbell

Burley

2019

Methods

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“…Previously considered “difficult to drug” on a structural and selectivity basis, considerable efforts in academia and industry are now being focused on targeting RNA as a therapeutic modality. These efforts are driven based on both the biological significance of RNAs, as well as a growing number of studies implicating aberrant RNA biology in many human diseases. − In cells, RNA molecules are essential for cellular information transfer and gene regulation; however, it is now known that, beyond serving as a link between DNA and proteins, RNAs can also play direct effector roles by binding to various ligands, including proteins, DNA, other RNAs, and metabolites. In this manner, RNAs mediate cellular processes such as the regulation of gene transcription, splicing and the enhancement or inhibition of protein activity.…”

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confidence: 99%