Innovative therapy developed for the future treatment of hereditary (deaf)blindness

Mutations in the USH2A gene are the most common cause of Usher syndrome and retinitis pigmentosa, both severely debilitating hereditary conditions resulting in hearing loss and/or progressive loss of vision, affecting approximately 350,000 individuals worldwide. Hearing loss can be partially compensated by providing patients with hearing aids or cochlear implants, whereas currently no treatment options exist for the loss of vision. USH2A mutations are often private and are spread all over the gene. However, two recurrent mutations are known that both reside within the same region of the gene: exon 13. Researchers from the Department of Otorhinolaryngology headed by dr. Erwin van Wijk developed a novel therapeutic strategy to halt the progression or to prevent vision loss in patients as a consequence of USH2A exon 13 mutations. Their results are published in the journal Molecular Therapy, on April 23^rd.

USH2A is among the largest genes that are present within our DNA, with a coding sequence that by far exceeds the cargo capacity of currently used viral vehicles for gene augmentation therapies. As such, the researchers came up with an alternative therapeutic approach named exon-skipping. This method was previously successfully applied as a treatment option for Duchenne Muscular Dystrophy. The principle idea behind this approach is that by using an antisense oligonucleotide, or “genetic patch”, the mutated region of the gene is masked, resulting in a slightly shortened protein with hopefully enough residual function.

Previous research indicated that zebrafish is a highly suitable model organism to study USH2A-associated vision loss. Using this model, the researchers were able to show that skipping of USH2A exon 13 indeed resulted in the production of a slightly shortened, but fully functional USH2A protein. Results were translated towards use in patients, for which the lead genetic patch QR-421a was developed and evaluated. This molecule appeared highly efficient in skipping of human USH2A exon 13, reached the anticipated cells within the mouse retina after a single intraocular delivery, appeared to be very stable and induced no inflammatory responses.

Based on these results, ProQR Therapeutics has launched a phase 1/2 clinical trial (Stellar) for the evaluation of QR-421a. Very recently the highly promising intermediate results were released. As a next step two multi-center phase 2/3 trials (Sirius and Celeste) will be initiated before the end of this year. 

Publication

Dulla K, Slijkerman RW, Van Diepen H, Albert S, Dona M, Chan H, Schulkens I, Beumer W, Vorthoren L, Den Besten C, Buil L, Schmidt I, Turunen J, Miao J, Venselaar H, Zang J, Neuhauss S, Peters TA, Broekman S, Pennings RJE, Kremer H, Adamson P, De Vrieze E, Van Wijk E. Antisense oligonucleotide-based treatment of retinitis pigmentosa caused by USH2A exon 13 mutations. Molecular Therapy. 2021 Apr 22:S1525-0016(21)00212-4. doi: 10.1016/j.ymthe.2021.04.024. Online ahead of print. PMID: 33895329