The first patient has been dosed in a Phase 1/2 clinical trial of QR-110, a treatment that ProQR Therapeutics is developing to treat a mitochondrial disease that often ends in blindness.
ProQR said in a press release that the trial is aimed at determining the safety and effectiveness of QR-110 as a treatment for a severe form of the eye disease Leber’s congenital amaurosis. The form is called LCA 10.
The company hopes the therapy can stop the progression of the disease and restore lost vision. Mitochondrial diseases stem from problems with mitochondria, the components of cells that generate energy.
Researchers are recruiting six adults and six children with LCA 10 for the open-label, dose-escalating trial (NCT03140969). The study design calls for patients with a disease stemming from a single RNA nucleotide mutation of the CEP290 gene. The mutation is known as p.Cys998X. A nucleotide is a structural component of RNA or DNA.
Trial participants will receive four doses of QR-110, injected into one eye, every three months. In addition to its safety and effectiveness, researchers will be looking at its pharmacokinetics — or how it moves in, through and out of the body — and patients’ ability to tolerate it.
The primary measure of the therapy’s effectiveness will be how many vision problems occur after treatment, and how severe they are. Interim results are expected next year, with one-year treatment data likely in 2019.
Genes code for the messenger RNA, or mRNA, used to produce protein. When mRNA is first produced, it is known as pre-mRNA. Proteins called splicing factors bind to pre-mRNA to splice — or cut out — extraneous parts.
The p.Cys998X mutation leads to an abnormal pre-mRNA molecule. The result is defective pre-mRNA splicing and, later, the production of non-functional CEP290 protein.
Treatment options for patients with LCA 10 are limited. Scientists are looking at gene therapies that can replace the mutant CEP290 gene.
But “we believe most emerging gene replacement technologies do not have the capacity to deliver the large CEP290 gene to the retina,” said Benjamin Yerxa, the chief executive officer of Foundation Fighting Blindness. He welcomes the start of a trial covering “people with devastating vision loss caused by the p.Cys998X mutation.”
QR-110 is an antisense RNA nucleotide. This means it has the ability to recognize pre-mRNA and bind to it. When it binds to a mutant version of pre-mRNA, the splicing factors can no longer incorrectly splice the pre-mRNA. This should lead to the production of normal CEP290.
Animal studies have shown that QR-110 is able to reach the outer nuclear layer of the retina, the part of the eye that detects light. That layer is where the therapy can act.
The results of laboratory and animal studies led to both U.S. and EU regulators designating QR-110 an orphan drug. That designation gives companies incentives for developing therapies for rare diseases. The U.S. Food and Drug Administration has also given the treatment Fast Track status, aimed at speeding up its regulatory approval.
The treatment’s goal is to delay the progression of LCA 10 and, possibly, restore patients’ lost vision. Preclinical-trial studies have shown that QR-110 can almost fully covert mutant pre-mRNA into protein.
ProQR is conducting the trial at the University of Iowa and the Scheie Eye Institute at the University of Pennsylvania and at Belgium’s Ghent University. You can learn how to enroll in the trial and other information about it at the clinical trials.gov page.
QR-110 is ProQR’s lead candidate in its ophthalmology pipeline, which also includes potential treatments for Usher syndrome, Fuchs endothelial corneal dystrophy and Stargardt’s disease.
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