Antisense Oligonucleotide-Based Splice Correction of a Deep-Intronic Mutation in CHM Underlying Choroideremia.

Abstract

Choroideremia is a progressive genetic eye disorder caused by mutations in the CHM gene that encodes the Rab escort protein-1 (REP-1). One of the many CHM mutations described so far is a deep-intronic variant, c.315-4587T>A, that creates a novel splice acceptor site resulting in the insertion of a 98-bp pseudoexon in the CHM transcript. Antisense oligonucleotides (AONs) are a potential therapeutic tool for correcting splice defects, as they have the properties to bind to the pre-mRNA and redirect the splicing process. Previously, we used AONs to correct aberrant splicing events caused by a recurrent intronic mutation in CEP290 underlying Leber congenital amaurosis. Here, we expand the use of these therapeutic molecules for the c.315-4587T>A deep-intronic mutation in CHM by demonstrating splice correction in patient-derived lymphoblast cells.

• Authors: Alejandro Garanto, Saskia D van der Velde-Visser, Frans P M Cremers, Rob W J Collin
• Journal: Advances in experimental medicine and biology (Adv Exp Med Biol) Vol. 1074 Pg. 83-89 ( 2018) ISSN: 0065-2598 [Print] United States
• PMID: 29721931 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• CHM protein, human
• Oligonucleotides, Antisense
• RNA Precursors

Topics

• Adaptor Proteins, Signal Transducing (genetics)
• Cells, Cultured
• Choroideremia (therapy)
• Genetic Therapy (methods)
• Humans
• In Vitro Techniques
• Introns (genetics)
• Male
• Mutation
• Oligonucleotides, Antisense (genetics, metabolism, therapeutic use)
• RNA Precursors (genetics, metabolism)
• RNA Splicing (genetics)
• Transcription, Genetic
• Transfection