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Antisense oligonucleotide‐induced splice modulation for the treatment of Usher syndrome type 2A
Author(s) -
Wijk Erwin
Publication year - 2019
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/j.1755-3768.2019.8174
Subject(s) - retinitis pigmentosa , biology , genetics , gene , zebrafish , mutation , mutant , rna splicing , retinal degeneration , rna
Mutations in USH2A exon13 are the most frequent cause of both syndromic and non‐syndromic retinitis pigmentosa (RP), for which currently no treatment options exist. It is generally believed that RP due to mutations in this gene is caused by a loss‐of‐function mechanism. In total, over 600 different mutations have been identified in USH2A of which at least three are known to be derived from a common ancestor and are therefore seen more commonly: c.2299delG (p.Glu767fs*21), c.2276G>T (p.Cys759Phe) and c.7595‐2144A>G (p.Lys2532Thrfs*56). The size of the coding sequence (15,606 bp) and the presence of multiple alternatively spliced USH2A transcripts with unknown significance, hamper the development of gene augmentation therapy. Another difficulty in the development of a therapy is the lack of a suitable animal model. The currently available Ush2a mouse model displays only mild retina degeneration with a very late age of onset. Zebrafish ush2a mutant models however, show an early onset retinal dysfunction and are as such provide a unique opportunity to evaluate future therapeutic strategies. Antisense oligonucleotide (AON)‐based splice modulation has been proven to hold great promise as a therapeutic strategy for a number of hereditary conditions, including Usher syndrome. Upon pre‐mRNA binding, AONs will prevent or stimulate binding of the spliceosome thereby modulating splicing events. AONs can be designed and applied for different genes and genetic disorders as the specificity depends on their nucleotide sequence. In this study we explored the therapeutic potential of AON‐induced splice modulation as a therapeutic approach for the future treatment of USH2A ‐associated retinal degeneration.