ProQR announces clearance of Investigational New Drug (IND) to start clinical trial of an RNA-therapy in people with Usher Syndrome Type 2

Earlier this year, Fighting Blindness and patient organisations from Europe, UK and North America joined ProQR to participate in an advisory board and inform the development of a clinical trial study for a novel RNA therapy that has the potential to treat individuals affected by Usher syndrome type 2 and non-syndromic retinitis pigmentosa (RP).

Since then, ProQR have announced that the U.S. Food and Drug Administration (FDA) has cleared the Investigational New Drug (IND) application for this drug to commence with a first in human study.

How does RNA therapy work?

“The central dogma of biology” explains the flow of genetic information in your cells. DNA makes RNA and RNA is the genetic messages that lead to production of proteins. Proteins are the final product and are critical for the health and function of retinal cells, found at the back of your eye.

Many retinal degenerations occur when there are misspellings (or mutations) in your DNA. This can then result in the formation of damaged RNA and ultimately in the development of proteins that do not function properly in the cell. In this case, we refer to mutations in exon 13 of the USH2A gene, which lead to the loss of functional usherin protein and subsequent vision loss as observed in Usher Syndrome type 2 and non-syndromic retinitis pigmentosa (RP).

Whereas gene therapies are a one-time treatment that delivers a replacement gene at the DNA level, RNA therapies are delivered as a kind of drug that works by targeting a very specific part of the damaged RNA. The drug called QR-421a is an anti-sense oligonucleotide (AON), a form of RNA therapy designed to skip disease-causing mutations located in the RNA. By excluding the genetic defect (mutation) from the RNA in the eye, a shortened but functional form of the protein is expressed, potentially modifying the underlying cause of disease. This approach is also known as exon skipping.

QR-421a has received orphan drug designation in the United States and the European Union. This potential therapy has been in development for many years in the laboratory with proof of concept demonstrated in both cell and zebrafish models of disease.

What does the clinical trial involve?

Entitled STELLAR, this is a first-in-human study that will initially include approximately 18 adults that have vision loss due to mutations in exon 13 of the USH2A gene.

The study will be conducted at expert sites in the US and Europe. It will be a double-masked, randomised study exploring several dose levels and a control (sham injection), given as a single intravitreal injection of QR-421a into one eye. The objectives of the trial will include evaluation of safety, tolerability, pharmacokinetics and efficacy, as measured by restoration or improvement of visual function and retinal structure through ophthalmic endpoints such as visual acuity (BCVA), visual field and optical coherence tomography (OCT).

Changes in quality of life in the trial subjects will also be evaluated. ProQR plans to start enrolling patients in this Phase 1/2 trial in the coming months with preliminary data expected in mid-2019.

ProQR and their Ophthalmology Pipeline

ProQR are a Dutch biotechnology company developing RNA therapies for genetic retinal disease. Their research and development pipeline includes programmes focusing on specific forms of Usher syndrome, Leber congenital amaurosis (LCA), Stargardt disease and autosomal dominant retinitis pigmentosa (RP).

In September 2018, ProQR announced vision improvements in a Phase 1/2 clinical trial for QR-110, its emerging AON (also an RNA therapy) for people with Leber congenital amaurosis 10 (LCA10) caused by a mutation in the gene CEP290. The company is planning a Phase 2/3 clinical trial for QR-110 in the first half of 2019.

The trial was conducted at the University of Iowa, the Scheie Eye Institute at the University of Pennsylvania and the Ghent University Hospital, Belgium. You can find more information about the QR-110 ongoing study at

Finally, ProQR have also signed an agreement with Ionis Pharmaceuticals to license QR-1123, an RNA therapy for autosomal dominant retinitis pigmentosa (adRP) caused by the P23H mutation in the rhodopsin (RHO) gene.

ProQR expects to start a Phase 1/2 clinical trial in patients with adRP in 2019, pending submission and clearance of the Investigational New Drug (IND) application by the U.S. Food and Drug Administration (FDA).

Concluding Remarks

There remains a high unmet need for all types of Usher syndrome, and we were delighted to be involved throughout this process, a strong example of public and patient involvement (PPI) in research and development of medicines.

We will be sure to keep you fully informed on any further developments. To learn more about Usher syndrome please visit the toolkit found at Retina International.