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Phase 2/3 anti-sense treatment (”QR-421a”) of retinitis pigmentosa (RP) aims to use exon skipping within the USH2A gene to repair the shortened usherin protein.

Dutch researchers at the Radboud University Medical Centre, Nijmegen, and ProQR Therapeutics, a company, based in Leiden, the Netherlands, are enrolling up to 200 patients in a Phase 2/3 study to evaluate a novel anti-sense treatment (termed “QR-421a”) for retinitis pigmentosa (RP).  The treatment is to use an “exon skipping” strategy using an RNA antisense oligonucleotide (AON) for intravitreal injection aiming to produce a shortened usherin protein.  Mutations in the exon 13 of the USH2A consists of a multiplier of three nucleotides and the skipping of the exon does not appear to disturb the open reading frame (ORF) and therefore may potentially result in the production of a viable shortened protein with predicted residual function.


Previous reports in the literature show mutations in USH2A are known among the most common causes of syndromic and non-syndromic retinitis pigmentosa (RP). The USH2A gene, located on chromosome 1q41, has 72 exons and encodes a 1,551-amino acid protein. The two most recurrent mutations in USH2A, c.2299delG and c.2276G > T, both map to exon 13 and patients with USH2A-associated RP often present with night blindness and a primary dysfunction of the rod photoreceptor cells.  According to the researchers, “USH2A gene augmentation therapy is severely hampered by the size of the usherin-encoding sequence (15,606 nucleotides), which exceeds by a significant margin the cargo capacity of the currently used viral vehicles for gene delivery. An RNA therapy approach, for example, using intravitreal (IVT) delivery of synthetic antisense oligonucleotides (AON) to correct aberrant pre-mRNA splicing, could overcome this limitation for a subset of mutations”.


The current randomized Phase 2/3 clinical trials will have two (“Sirius” and “Celeste”) double-masked, interventional RNA therapies, for a 24-month duration. “Sirius” will recruit patients with advanced vision loss, while “Celeste” will recruit patients with early to moderate vision loss.  According to the trial’s sponsor, participants in both of the studies will be randomly assigned to three parallel study arms. In the two treatment arms, participants receive intravitreal injections with QR-421a at different doses (180μg loading dose and 60μg maintenance doses or 60μg loading dose and 60μg maintenance doses). In the third sham control arm, the intravitreal injections are mimicked but no injection or study medication is given. The Sirius study is planned to enroll eighty (~80) participants with advanced vision loss (baseline BCVA of worse than 20/40). The primary endpoint in the study will be the mean change from baseline in BCVA at 18 months in the treated arms compared to the control arm.  Finally, the Celeste study is planned to enroll one-hundred and twenty (~120) participants with early to moderate vision loss (baseline BCVA of equal or better than 20/40). The primary endpoint in the study is the mean change from baseline in static perimetry at 12 months in the treated arms compared to the control arm.  Following the announcement of the milestone on the first patient being dosed,  Aniz Girach, MD, Chief Medical Officer of ProQR stated,  “we are pleased to bring our second RNA therapy into potentially the final stage of clinical testing.  In a previous clinical study, QR-421a appeared to be well tolerated and demonstrated concordant benefit in multiple measures of vision in treated eyes compared to untreated. Our goal is that the Sirius and Celeste studies further validate QR-421a’s ability to stabilize vision loss in people with USH2A mediated retinitis pigmentosa and Usher syndrome.”  QR-421a is intended to be administered through intravitreal injections in the eye and has been granted orphan drug designation in the US and the European Union and received fast-track and rare paediatric disease designations from the FDA.