Sinha, R., Kim, Y. J., Nomakuchi, T., Sahashi, K., Hua, Y., Rigo, F., Bennett, C. F., Krainer, A. R. (June 2018) Antisense oligonucleotides correct the familial dysautonomia splicing defect in IKBKAP transgenic mice. Nucleic Acids Res, 46 (10). pp. 4833-4844. ISSN 0305-1048
Abstract
Familial dysautonomia (FD) is a rare inherited neurodegenerative disorder caused by a point mutation in the IKBKAP gene that results in defective splicing of its pre-mRNA. The mutation weakens the 5' splice site of exon 20, causing this exon to be skipped, thereby introducing a premature termination codon. Though detailed FD pathogenesis mechanisms are not yet clear, correcting the splicing defect in the relevant tissue(s), thus restoring normal expression levels of the full-length IKAP protein, could be therapeutic. Splice-switching antisense oligonucleotides (ASOs) can be effective targeted therapeutics for neurodegenerative diseases, such as nusinersen (Spinraza), an approved drug for spinal muscular atrophy. Using a two-step screen with ASOs targeting IKBKAP exon 20 or the adjoining intronic regions, we identified a lead ASO that fully restored exon 20 splicing in FD patient fibroblasts. We also characterized the corresponding cis-acting regulatory sequences that control exon 20 splicing. When administered into a transgenic FD mouse model, the lead ASO promoted expression of full-length human IKBKAP mRNA and IKAP protein levels in several tissues tested, including the central nervous system. These findings provide insights into the mechanisms of IKBKAP exon 20 recognition, and pre-clinical proof of concept for an ASO-based targeted therapy for FD.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > antisense bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing |
| CSHL Authors: | |
| Communities: | CSHL labs > Krainer lab |
| Depositing User: | Matthew Dunn |
| Date: | 1 June 2018 |
| Date Deposited: | 27 Jul 2018 20:19 |
| Last Modified: | 12 Aug 2019 16:36 |
| PMCID: | PMC6007753 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/37066 |
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