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Antisense oligonucleotide (AON) therapy for Stargardt disease type 1 (STGD1) provides a proof of concept with effective restoration of correct ABCA4 transcript splicing. 

Researchers at ProQR Therapeutics, an RNA company based in Leiden, the Netherlands, and with researchers at Radboud University Medical Center in Nijmegen, have reported results from the use of antisense oligonucleotide (AONs) therapies aimed at treating Stargardt disease type 1 (STGD1).  The AON tools (also labelled as “QR-1011”) were targeted at ABCA4 transcripts to correct mutations in the ABCA4 gene which can alter pre-mRNA splicing.  Results of the pre-clinical research suggested a significant increase in correctly spliced transcripts after treatment with the QR-1011 experimental treatment.  Following their study, the treatment may provide “a potent splice-correcting AON and a possible therapeutic intervention for patients harbouring” a severe ABCA4 variant.

Stargardt disease (STGD1) is caused by mutations in the photoreceptor-specific ABCA4 gene which encodes the adenosine triphosphate-binding cassette, subfamily A, member 4. The ABCA4 gene encodes a transporter protein within retinal photoreceptor cells facilitating the active transport of potentially toxic retinoid compounds removing toxic by-products from the visual cycle. A number of pathogenic variants within certain introns of the ABCA4 gene may result aberrant splicing of the gene – including pseudogenes – essentially non-functional segments of DNA. Splicing defects within pseudogenes of ABCA4 can insert aberrant “pseudoexons” (PEs) into the ABCA4 pre-mRNA.  According to the Dutch researchers, a cohort of STGD1 patients have identified over ~2,200 disease-associated variants in ABCA4 gene and the majority of mutations report missense variants that might alter pre-mRNA splicing.  In the current study on the AON research, one of the ABCA4 mutations (c.5461-10T>C) causes the skipping of either exon 39, or exons 39 and 40 together, resulting in an out-of-frame ABCA4 protein that results in the most common severe STGD1-causing variant.  Symptoms of STGD1 disease patients, with homozygous ABCA4 c.5461-10T>C variant, show the disease phenotype within the first decade of life, following an acceleration of deterioration and leading to legal blindness between the ages of 20 and 30 years.

The AON strategy presented a promising therapeutic strategy in their recent report, published in the journal Molecular Therapy: Nucleic Acids (Vol. 31 March 2023), indicating a “validation of target-specific AONs as a possible therapeutic approach to correct the aberrant splicing of ABCA4 caused by the severe STGD1-causing variant”.   AON-mediated process used a re-included skipped exons and correct the disrupted splicing caused by the ABCA4 variant. The results of the study showed a significant increase in correctly spliced transcripts after treatment in a human retinal organoid model, with up to 53% correct transcripts at a 3 mM dose. According to the results from the research team, the AON mechanism of action “ would be sufficient to alleviate the STGD1 phenotype, and therefore QR-1011 shows potential as a therapeutic strategy for the most common severe STGD1-causing variant ABCA4 c.5461-10T>C”.