Reduction of integrin alpha 4 activity through splice modulating antisense oligonucleotides

May T. Aung-Htut, Iain Comerford, Russell Johnsen, Kerrie Foyle, Sue Fletcher, Steve D. Wilton

Research output: Contribution to journalArticle

Abstract

With recent approvals of antisense oligonucleotides as therapeutics, there is an increasing interest in expanding the application of these compounds to many other diseases. Our laboratory focuses on developing therapeutic splice modulating antisense oligonucleotides to treat diseases potentially amendable to intervention during pre-mRNA processing, and here we report the use of oligomers to down-regulate integrin alpha 4 protein levels. Over one hundred antisense oligonucleotides were designed to induce skipping of individual exons of the ITGA4 transcript and thereby reducing protein expression. Integrin alpha 4-mediated activities were evaluated in human dermal fibroblasts and Jurkat cells, an immortalised human T lymphocyte cell line. Peptide conjugated phosphorodiamidate morpholino antisense oligomers targeting ITGA4 were also assessed for their effect in delaying disease progression in the experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. With the promising results in ameliorating disease progression, we are optimistic that the candidate oligomer may also be applicable to many other diseases associated with integrin alpha 4 mediated inflammation. This highly specific strategy to down-regulate protein expression through interfering with normal exon selection during pre-mRNA processing should be applicable to many other gene targets that undergo splicing during expression.

Original languageEnglish
Number of pages1
JournalScientific Reports
Volume9
Issue number1
DOIs
Publication statusPublished - 10 Sep 2019

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Integrin alpha Chains
Antisense Oligonucleotides
RNA Precursors
Disease Progression
Exons
Down-Regulation
Morpholinos
Proteins
Jurkat Cells
Autoimmune Experimental Encephalomyelitis
Multiple Sclerosis
Fibroblasts
Inflammation
T-Lymphocytes
Cell Line
Skin
Peptides
Therapeutics
Genes

Cite this

Aung-Htut, May T. ; Comerford, Iain ; Johnsen, Russell ; Foyle, Kerrie ; Fletcher, Sue ; Wilton, Steve D. / Reduction of integrin alpha 4 activity through splice modulating antisense oligonucleotides. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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Reduction of integrin alpha 4 activity through splice modulating antisense oligonucleotides. / Aung-Htut, May T.; Comerford, Iain; Johnsen, Russell; Foyle, Kerrie; Fletcher, Sue; Wilton, Steve D.

In: Scientific Reports, Vol. 9, No. 1, 10.09.2019.

Research output: Contribution to journalArticle

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