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ABSTRACT
Introduction
Antisense oligonucleotides (ASOs) represent a class of drugs which can be rationally designed to complement the coding or non-coding regions of target RNA transcripts. They could modulate pre-messenger RNA splicing, induce mRNA knockdown, or block translation of disease-causing genes, thereby slowing disease progression. The pharmacokinetics of intravitreal delivery may enable ASOs to be effective in the treatment of inherited retinal diseases.
Areas covered
We review the current status of clinical trials of ASO therapies for inherited retinal diseases, which have demonstrated safety, viable durability, and early efficacy. Future applications are discussed in the context of alternative genetic approaches, including gene augmentation and gene editing.
Expert opinion
Early efficacy data suggest that the splicing-modulating ASO, sepofarsen, is a promising treatment for Leber congenital amaurosis associated with the common c.2991+1655A>G mutation in CEP290. However, potential variability in clinical response to ASO-mediated correction of splicing defect on one allele in patients who are compound heterozygotes needs to be assessed. ASOs hold great therapeutic potential for numerous other inherited retinal diseases with common deep-intronic and dominant gain-of-function mutations. These would complement viral vector-mediated gene augmentation which is generally limited by the size of the transgene and to the treatment of recessive diseases.
Article highlights
Therapeutic antisense oligonucleotides are synthetic endonuclease-resistant single-stranded oligodeoxynucleotides or oligoribonucleotides that can be designed to specifically knockdown the level of a disease-causing messenger RNA, alter its pattern of splicing, or block translation.
Phase I/II clinical trial of an intravitreally administered antisense oligonucleotide to correct a splicing defect associated with the common deep-intronic mutation in CEP290-Leber congenital amaurosis has demonstrated safety and early efficacy in terms of improved visual function.
Antisense oligonucleotide therapies are also in early clinical trials for common mutations found in RHO-associated autosomal dominant retinitis pigmentosa and Usher syndrome type 2.
In the future, antisense oligonucleotides may be designed to correct the splicing defects found in a number of other inherited retinal diseases, including Stargardt disease (ABCA4) and retinitis pigmentosa caused by the large EYS gene.
While the therapeutic potential of antisense oligonucleotides is restricted to a select group of genetic mutations, they complement gene augmentation and gene editing approaches, and represent an important modality in the treatment of inherited retinal diseases.
This box summarizes key points contained in the article.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
One reviewer works in an institution that received funding from ProQR.
Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.