Antisense oligonucleotide therapeutics in clinical trials for the treatment of inherited retinal diseases

Figures & data

Figure 1. Mechanisms of action of antisense oligonucleotide (ASO) therapies. (a) An ASO hybridizing with a deep-intronic mutation could prevent aberrant splicing which would otherwise lead to the incorporation of a cryptic exon or frameshift. (b) An ASO could be designed to block a splice donor site in order to cause skipping of a mutation-containing exon, so that a shortened but partially functional protein may be produced. (c) ASOs could be designed to knockdown a dominant negative allele by direct binding to the mutant RNA sequence to generate a RNA-DNA hybrid, which would be recognized and degraded by RNase H. Alternatively, knockdown of both alleles may be achieved through ASO binding to the 5ʹ-untranslated region of a target mRNA or ASO-mediated exon skipping with frameshift.

Table 1. Current clinical trials of antisense oligonucleotides (ASOs) in inherited retinal diseases. All three ASOs are by ProQR Therapeutics NV, Leiden, the Netherlands. LCA.

Antisense oligonucleotide	Targeted mutation	Mode of action	Clinicaltrials.gov reference	Clinical trial stage
QR-110 or sepofarsen	c.2991 + 1655A>G mutation in CEP290-associated Leber congenital amaurosis	Splicing modulation	NCT03140969 NCT03913143 NCT03140969	I/II II/III
QR-1123	P23 H mutation in RHO-associated autosomal dominant retinitis pigmentosa	Allele-selective mRNA knockdown	NCT04123626	I/II
QR-421a	c.2299delG mutation in Usher syndrome type 2	Exon skipping	NCT03780257	I/II