Unknown

Dataset Information

0

In vitro and in vivo rescue of aberrant splicing in CEP290-associated LCA by antisense oligonucleotide delivery.


ABSTRACT: Leber congenital amaurosis (LCA) is a severe disorder resulting in visual impairment usually starting in the first year of life. The most frequent genetic cause of LCA is an intronic mutation in CEP290 (c.2991 + 1655A > G) that creates a cryptic splice donor site resulting in the insertion of a pseudoexon (exon X) into CEP290 mRNA. Previously, we showed that naked antisense oligonucleotides (AONs) effectively restored normal CEP290 splicing in patient-derived lymphoblastoid cells. We here explore the therapeutic potential of naked and adeno-associated virus (AAV)-packaged AONs in vitro and in vivo In both cases, AON delivery fully restored CEP290 pre-mRNA splicing, significantly increased CEP290 protein levels and rescued a ciliary phenotype present in patient-derived fibroblast cells. Moreover, administration of naked and AAV-packaged AONs to the retina of a humanized mutant Cep290 mouse model, carrying the intronic mutation, showed a statistically significant reduction of exon X-containing Cep290 transcripts, without compromising the retinal structure. Together, our data highlight the tremendous therapeutic prospective of AONs for the treatment of not only CEP290-associated LCA but potentially many other subtypes of retinal dystrophy caused by splicing mutations.

SUBMITTER: Garanto A 

PROVIDER: S-EPMC6086559 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

altmetric image

Publications

In vitro and in vivo rescue of aberrant splicing in CEP290-associated LCA by antisense oligonucleotide delivery.

Garanto Alejandro A   Chung Daniel C DC   Duijkers Lonneke L   Corral-Serrano Julio C JC   Messchaert Muriël M   Xiao Ru R   Bennett Jean J   Vandenberghe Luk H LH   Collin Rob W J RW  

Human molecular genetics 20160422 12


Leber congenital amaurosis (LCA) is a severe disorder resulting in visual impairment usually starting in the first year of life. The most frequent genetic cause of LCA is an intronic mutation in CEP290 (c.2991 + 1655A > G) that creates a cryptic splice donor site resulting in the insertion of a pseudoexon (exon X) into CEP290 mRNA. Previously, we showed that naked antisense oligonucleotides (AONs) effectively restored normal CEP290 splicing in patient-derived lymphoblastoid cells. We here explor  ...[more]

Similar Datasets

| S-EPMC8124656 | biostudies-literature
| S-EPMC7029474 | biostudies-literature
| S-EPMC7452116 | biostudies-literature
| S-EPMC5415958 | biostudies-literature
| S-EPMC5877614 | biostudies-literature
| S-EPMC8072990 | biostudies-literature
| S-EPMC2862535 | biostudies-literature
| S-EPMC7347940 | biostudies-literature
2023-06-14 | GSE202179 | GEO
2023-06-14 | GSE202178 | GEO