According to a news release from RNA therapeutics company ProQR Therapeutics N.V. (“ProQR”), the first patients have been dosed in two Phase 2/3 clinical trials evaluating QR-421a for USH2a-mediated retinitis pigmentosa (RP) and Usher syndrome. There are few therapies designed to halt progressive vision loss in patients with these conditions. Thus, if effective, QR-421a has the potential to change the future of treatment.
To begin, what exactly is QR-421a? As ProQR explains, QR-421a:
aims to stop vision loss in people with Usher syndrome and retinitis pigmentosa due to mutation(s) in exon 13 of the USH2A gene. The mutations cause a mistake in the USH2A RNA and therefore the cell cannot use the RNA to produce a working USH2A protein that is essential for vision.
QR-421a is administered intravitreally. It uses exon skipping to produce functional USH2A protein and prevent progressive vision loss. So far, QR-421a earned Orphan Drug, Fast Track, and Rare Pediatric Disease designations within the United States, as well as Orphan Drug status in the E.U. Additionally, prior studies highlighted that QR-421a was generally safe and well-tolerated.
Moving forward, researchers will continue to evaluate QR-421A in the Phase 2/3 Sirius and Celeste trials. Altogether, 81 patients (with advanced vision loss) will enroll in Sirius. 120 patients with less advanced vision loss will enroll in Celeste.
Retinitis Pigmentosa (RP)
Retinitis pigmentosa (RP) comprises of a group of inherited diseases which lead to retinal degeneration. Over 60 gene mutations are associated with RP. Because of this, different forms of RP can be inherited in an autosomal recessive, autosomal dominant, or X-linked pattern. Symptoms depend on whether rods or cones in the retina are involved initially. Usually, rods are affected first, causing loss of peripheral and night vision. Next, patients experience diminished visual acuity, color perception, and central vision. If cones are affected first, symptoms include changes in color and detail perception, as well as decreased central vision. In many cases, patients are legally blind before they turn 40.
MYO7A (USH1B), USH1C, CDH23, PCDH15 (USH1F), SANS (USH1G), USH2A, ADGRV1, WHRN, USH3A, and HARS gene mutations have all been linked to Usher syndrome, a rare genetic disorder characterized by deafness. In many cases, Usher syndrome and retinitis pigmentosa (RP) go hand-in-hand. Usher syndrome has three subtypes, though hearing loss spans all three.
In Usher syndrome type 1, symptoms usually manifest before age 10. These include bilateral deafness, vision problems, and balance difficulties. In type 2, symptom onset usually begins in the late teens to early 20s. These symptoms include moderate-to-severe hearing loss at birth that grows progressively worse, as well as night blindness. Finally, in Usher syndrome type 3, symptoms manifest between ages 20s-40s. These include retinitis pigmentosa (RP), late-onset hearing difficulties, and problems with balance.
Learn more about Usher syndrome here.