Let’s Chat About…ProQR’s Work in Treatments for Inherited Retinal Disease

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ProQR Therapeutics’ Founder and Chief Executive Officer shared exciting news of the deep pipeline of RNA therapies in development to treat Leber congenital amaurosis (LCA) and other inherited retinal diseases (IRDs), including four major projects, one of which the company hopes will glean significant read-out data in the next few months.

Daniel de Boer told a Hope in Focus webinar audience that his company’s mission is to help patients by creating RNA (ribonucleic acid)  therapies that aim to stop vision loss or even reverse some of the symptoms caused by IRDs.

Daniel de Boer

“We see that there’s a large unmet medical need, as there are more than 5 million people in the world who have a form of an inherited retinal disease and just very few of them have treatments available for them and at ProQR our plan it to change that,” de Boer said in our January session, which can be viewed here.

In the episode called “Let’s Chat About…ProQR’s work in treatments for inherited retinal disease,” he described the company’s projects involving sepofarsen, explained RNA therapy versus DNA therapy, and discussed the method of administering the treatment to patients. The session is part of our free monthly series developed with those living with LCA and IRDs in mind but open to anyone interested in what’s happening in our communities.

After one of de Boer’s children was diagnosed with a rare disease, he started the Dutch biotechnology company to develop RNA therapies for rare diseases. Under his leadership, ProQR developed a platform that yielded a diversified pipeline of potential treatments for rare diseases and raised more than $400 million in funding. Before starting ProQR, he founded several technology companies.

De Boer also is co-founder and strategic advisor to Amylon Therapeutics and Wings Therapeutics, strategic advisor at Frame Therapeutics, Meatable, Algramo, and a member of the advisory board at the Termeer Foundation. He was named “Emerging Entrepreneur of the Year” in 2018 by EY, the multinational professional services network Ernst & Young, and in 2019 was selected for the Young Global Leader program at the World Economic Forum.

Sepofarsen and multiple studies on LCA10 and other IRDs

De Boer said ProQR expects results in the coming months from its Phase 2/3 Illuminate clinical trial of sepofarsen in LCA10 caused by a mutation in the CEP290 gene.

Sepofarsen is an investigational RNA therapy that aims to restore vision in people living with LCA10 due to the p.Cys998X mutation in the CEP290 gene.

Researchers initiated the trial based on data from a Phase 1/2 study that indicated patients treated 12 months with sepofarsen showed improvement in visual acuity measured by best-corrected visual acuity (BCVA).

Earlier this month marked the end of the Phase 2/3 trial, when de Boer said, “The last patient having completed their 12-month visit is an important milestone toward the top-line results from the Phase 2/3 Illuminate trial of our lead program for sepofarsen for LCA10.”

Other major projects underway at ProQR include:

Brighten, a clinical study for children under age 8 living with LCA10;

Sirius and Celeste, two clinical trials of QR-421a in adults and children (age 12 and up) with Usher syndrome and retinitis pigmentosa (RP) due to mutation(s) in exon 13 of the USH2A gene;

Aurora, a clinical trial of QR-1123 in Phase 1/2 for RP, due to the P23H mutation, also known as c.68C>A, in the rhodopsin (RHO) gene;

QR-504a, an investigational RNA therapy that aims to slow down degeneration of the cornea and thereby vision loss in people with Fuchs endothelial corneal dystrophy due to the most common mutation.

You can learn more about ProQR’s studies by visiting the company’s website and/or emailing Andy Bolan, Associate Director of Patient and Community Engagement at patientinfo@proQR.com

RNA therapies repair DNA without changing DNA

De Boer explained in the webinar: “RNA therapy is innovative technology that treats genetic eye conditions such as LCA10 or Usher Syndrome and it is important because the RNA help to carry out the instructions that are in the DNA to make proteins.

“We’re all familiar with genes and DNA that we have in our cells and the RNA is essentially helping to carry out the instructions that are described in the DNA, which is to make certain proteins and these proteins are critical to the healthy functioning of a cell.”

In LCA10 the gene mutation gets copied into the RNA and causes a loss of protein so that the protein is not functioning or missing altogether, leading to a cell unable to work well or even die over time, he said.

ProQR is developing RNA therapies for a range of diseases, including their lead sepofarsen therapy.

“RNA therapies can repair the DNA without altering or changing the DNA, so we don’t have to touch the DNA. We don’t have to change any of the genes, we can leave all of that untouched and we can alter the RNA in between so that cell can make its own functional and healthy proteins.”

Explaining the difference between RNA therapies and DNA therapies, de Boer began with the billions of cells, our DNA, the library of our genes.

“The DNA is copied into the RNA and the RNA is essentially a blueprint that then makes proteins and proteins are expressing in your cells through all kinds of different tasks and essentially that is what makes our bodies function.

“Now, with RNA therapy, what we can do is we can repair the blueprint so we give it an RNA therapy that repairs the blueprint and from this repaired blueprint, the cell can now make its own new functional protein.”

On the other hand, DNA therapy, or gene therapy, replaces the gene into the DNA, which then expresses RNA that makes protein.

Different delivery mechanisms in RNA and gene therapies

De Boer also made the distinction between the delivery systems of RNA therapy and gene therapy and described the advantages of the RNA route.

Gene therapies often require a viral vector, meaning that the therapy is packaged in a virus made in a way that it is no longer harmful to humans. The treatment is delivered through subretinal injection.

“It is used as a delivery system, so this virus is then loaded with the new gene and injected into the back of the eye where it then is entering the cells and expressing the protein.”

RNA therapy is delivered through intravitreal injection (IVT), which entails an injection in the side part of the eye – the wide part of the eye – in a 15-minute procedure.

“Through that route of administration, we have a big advantage that we can treat the entire retina, so only with a small injection in the side of the eye, the RNA therapy will distribute itself throughout the entire eye and will go to all different parts of the retina. That means that we can treat the central retina, as well as the peripheral, which allows us, for example, also to treat early-stage disease, which generally started in the outer part, in the peripheral part of the retina.”

RNA therapies generally need to be administered twice a year in each eye for a sustained benefit over lengthy periods of time.

Lab-grown retinas enhance research process

ProQR is among those biotechnology companies finding new ways to improve efficiency in research, thereby accelerating the process in bringing retinal disease treatments and cures to market.

The company’s researchers grow organoids from skin samples to produce a human retina in the lab.

“From this retina we can then test the activity of our therapeutics so we can administer drugs on these retinal organoids, which then tell us in the lab already if they’re going to be functional, if the drug is going to work once we give it to a person.

“All of this is obviously in a testing phase still, so we can’t have 100 percent certainty that the preclinical model will always be predictive, but so far we have seen that in both sepofarsen and in Usher, the model was spot-on in predicting the activity and also the active dose level that we had to give once we started clinical trials.

“If you think about that I think there is really potential to find more synergies and speed up the development from preclinical to approval once we generate some more data across more of these programs that can help us to validate the correlation with the preclinical models to potentially really accelerate the development timelines.”

ProQR’s beginnings

Daniel de Boer started ProQR about 10 years ago after his son was born with cystic fibrosis (CF). He focused on CF until another company developed a good therapy for the rare disease.

Headquartered in Leiden, Netherlands, with offices in Cambridge, Mass., ProQR reinvented itself over time as a global ophthalmology company.

De Boer developed a partnership with Professor Rob Collin, PhD, from Radboud University in the Netherlands. The molecular geneticist had discovered an LCA10 RNA therapy that evolved into sepofarsen, and clinical trials began in 2017.

By the next year, an interim analysis showed examples of transformational improvements in vision, de Boer said.

One participant began by only being able to perceive light – day or night, no shape, motion, form, or color.

“After a single dose of sepofarsen, this participant then improved his vision such that he could now read, he could recognize people’s faces, and he could essentially navigate the world independently for the first time in decades.

“We saw the hypothesis confirmed that RNA therapy in the eye could potentially make a really meaningful impact. So fast forward to today, we completed our Illuminate Phase 2/3 pivotal trial for sepofarsen recently and are now awaiting the results.”


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