Intravitreal Injection of Splice-switching Oligonucleotides to Manipulate Splicing in Retinal Cells

Molecular Therapy. Nucleic Acids
X GérardJean-Michel Rozet

Abstract

Leber congenital amaurosis is a severe hereditary retinal dystrophy responsible for neonatal blindness. The most common disease-causing mutation (c.2991+1655A>G; 10-15%) creates a strong splice donor site that leads to insertion of a cryptic exon encoding a premature stop codon. Recently, we reported that splice-switching oligonucleotides (SSO) allow skipping of the mutant cryptic exon and the restoration of ciliation in fibroblasts of affected patients, supporting the feasibility of a SSO-mediated exon skipping strategy to correct the aberrant splicing. Here, we present data in the wild-type mouse, which demonstrate that intravitreal administration of 2'-OMePS-SSO allows selective alteration of Cep290 splicing in retinal cells, including photoreceptors as shown by successful alteration of Abca4 splicing using the same approach. We show that both SSOs and Cep290 skipped mRNA were detectable for at least 1 month and that intravitreal administration of oligonucleotides did not provoke any serious adverse event. These data suggest that intravitreal injections of SSO should be considered to bypass protein truncation resulting from the c.2991+1655A>G mutation as well as other truncating mutations in genes which like CEP290 or ABCA4 ...Continue Reading

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Citations

Nov 23, 2016·Molecular Therapy. Nucleic Acids·Tobias BonifertBernd Wissinger
Nov 20, 2019·International Journal of Molecular Sciences·Lucia ZiccardiMonica Varano
Oct 17, 2019·International Journal of Molecular Sciences·Marco NassisiIsabelle Audo
Jul 12, 2017·F1000Research·Elisa MolinariSimon A Ramsbottom
Feb 6, 2017·Current Opinion in Ophthalmology·Rob W J Collin, Alejandro Garanto
Jul 1, 2020·Journal of Molecular Neuroscience : MN·Yu ZengYe Song
Jun 20, 2020·Progress in Retinal and Eye Research·Nicole WeisschuhBernd Wissinger
May 20, 2021·Seminars in Ophthalmology·Kevin FerenchakRachel Huckfeldt
Aug 31, 2021·Ophthalmic Genetics·Di HuangFred K Chen

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Methods Mentioned

BETA
gene replacement therapy
transgenic
electrophoresis
antisense oligonucleotides
PCR
confocal microscopy
transfections

Software Mentioned

Oligo Primer Analysis
Excel
BLAST
Biostatgv
geNorm
Primer
ESEfinder
fold

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