INTERVIEW: How ProQR’s Sirius and Celeste Studies Could Change the Therapeutic Landscape for USH2A-Mediated RP and Usher Syndrome (Pt. 2)

If you would like to read the first part of this interview, please take a look at Part 1 here. In the first part of the interview, I spoke with ProQR Founder Daniel de Boer about the Sirius and Celeste clinical trials, what it means to him to develop therapeutics for genetic eye diseases, and where he hopes to see ProQR going in the future. For Part 2, I spoke with Dr. David Birch of the Retina Foundation of the Southwest, as well as Elle, who is participating in the Sirius clinical trial for USH2A-mediated retinitis pigmentosa (RP) and Usher syndrome.

The Sirius and Celeste Trials: An Overview with Dr. David Birch

Dr. David Birch, Ph.D., has been working with the Retina Foundation of the Southwest since 1982. The Foundation, initially started by local ophthalmologists, has now grown to 35 employees and five labs centered around eye-related research. Dr. Birch explained that he wanted to follow in the tradition of the late Dr. Eliot Bersen, MD, a pioneer within this field.

During his PhD and early work, Dr. Birch was an electrophysiology scientist. He became interested in how the brain functions in relation to the eyes, such as the basic mechanisms behind color vision. In his postdoc work, he became interested in applying this to human conditions. His mission with the Retina Foundation was founded on his desire to learn more about brain mechanisms and retinal degeneration. Dr. Birch shares:

I was working on outcome measures – how to best measure visual fields, responses from the retina, and changes over time in patients with RP. I was also working with people in Houston on gene identification. We had a cohort of around 300 families with dominant RP and went through to identify all known mutations. Then we performed comprehensive exome analysis on patients without a known mutation and identified new mutations in around six or seven families.

One mutation, for example, was found to be common in Hispanic families in Texas and Northern Mexico. However, it does not seem to be very present or common in Mexico City. Because of this, the mutation most likely originated locally in certain areas within the Southwest.

Following natural history studies, Dr. Birch helped develop sensitive tests to monitor RP progression. He focused on optical coherence tomography (OCT), or retinal imaging to determine where photoreceptors were missing. After gaining a reputation as an OCT expert, he shares, it was kind of natural to get involved in some of the earlier clinical trials.

Acting as Investigator

Some of the earlier or additional studies that Dr. Birch has been involved in include:

  • DHA and omega3-rich diets. There have been many considerations about the relationship between omega3 fatty acids and retinal health. While Dr. Birch acknowledges that Mediterranean-type diets could be helpful, this was not the breakthrough patients were looking for.
  • Retinal implants. After identifying a protective growth factor, Dr. Birch and his team questioned whether retinal implants that put out this growth factor could prevent degeneration. However, this did not show significant benefit.
  • Luxterna is a RP65 gene replacement therapy for patients with LCA which has had some early success. However, retinal gene therapy can be very invasive. Because of this, shares Dr. Birch, many researchers and patients are looking for other less invasive but still effective options.

Now, Dr. Birch is the investigator for the Sirius and Celeste trials, which enrolled the first patients in December. He believes that mRNA therapy could confer many benefits:

mRNA therapy seems to be very safe and well-tolerated. The intravitreal injection doesn’t seem to cause inflammation, and the body doesn’t seem to recognize mRNA as foreign. So this could avoid reactions that patients may experience from other treatments. This may not be a permanent correction; the best estimates are six months for each single injection, so part of the trial is finding out what the dose needs to be.

Both trials will have two treatment branches: placebo vs. a high-loading dose of ultevursen and placebo vs. a low-loading dose. As an investigator, Dr. Birch explains that he is responsible for making sure every consent form is understood and signed and that every visit is on time, collecting and evaluating the blinded data, and ensuring that every patient is being followed appropriately. He also relies on his team for help and explains that the research field has evolved to become increasingly collaborative. While research used to feel more competitive, he shares:

We’ve realized that we can only identify these treatments if we work together. We have several sites in these studies and it’s just something where we all need to work together and identify, as a group, the best tests to administer, the best way to follow these patients.

Conducting the Trials

To Dr. Birch, one of the most important parts of conducting the trials is balancing the expectations of the patients. He explains:

I want them to really understand that we don’t know if it’s going to help. We hope to show a benefit or a slowing down of disease progression, but we certainly can’t promise that.

This can be difficult to have to share, he says, as patients with RP and Usher syndrome often deal with a huge psychological burden on top of symptoms like night blindness, loss of peripheral and central vision, changes in visual acuity, and loss of independence.

That being said, he shared that many patients are realistic about their expectations and hope to make a change for future generations – just as Elle does.

Elle’s Story

Elle is the first patient to participate in the Sirius trial for USH2A-mediated retinitis pigmentosa. She explains that her interest in participating in a clinical trial is not only for her own benefit, but to offer hope to others: “that a treatment is in sight.”

Elle has retinitis pigmentosa / Usher syndrome. This is a photo of Elle.
Elle. Photo courtesy of the Retina Foundation of the Southwest

When Elle was younger, she was diagnosed with a hearing impairment. Then, at age 30, she started having trouble sleeping at night, as well as some potential vision issues. After seeing a variety of specialists, Elle was diagnosed with Usher syndrome. She shares:

It was devastating at first. I kept thinking, ‘I’m going to lose my eyesight. I don’t want to lose my eyesight.’

Life with Usher Syndrome 2A

When asked about the experience of living with Usher syndrome, Elle explains:

It’s like having invisible blindsiders on. I used to work with elementary school students and a lot of them would ask, ‘Can you see me?’ Well yes, I can see your face but not your shoulders or the colors in your dress.

In her 30s, Elle had 80% visual acuity, which has gradually gone down over the years. She was declared legally blind in 2012. Currently, she is down to 10% visual acuity and explains that she has good days and bad days, but can still, at this time, use the computer and other technologies, as her progression to blindness has been very slow.

Her Usher syndrome has also since been confirmed via genetic testing. Usher syndrome type 2A is caused by mutations in the USH2A gene, often in a specific area of the gene known as Exon 13. For Elle, her specific and previously unidentified mutation in Exon 13 was identified following testing.

The Research

As she began learning more about her condition over time, Elle also began keeping up with the Foundation Fighting Blindness and taking part with other research. Alongside her mom (her greatest support system), Elle attended conferences, checked in with the local Foundation Fighting Blindness chapters, and kept her eye on the latest research trends.

There were a lot of considerations about whether eating more fish (or omega3 supplements) could prevent retinal degeneration. Dr. Bersen found that Vitamin E benefited macular degeneration but not RP; Vitamin A benefited RP, but not macular degeneration. Despite the push towards newfound research, Elle explains:

For a while, there wasn’t much that I could participate in. I didn’t quite qualify for trials that were strictly RP, and a lot of Usher syndrome trials were looking for patients with Usher type 1.

When Elle discovered that ProQR would need new participants for the Sirius trial, she reached out. Her first appointment in November was to see if she qualified. She then attended another appointment in December, and her next follow-up appointment is in March, consisting of two days of tests and another round of treatment.

Elle explains that she is currently unaware if she is receiving the placebo or ultevursen. However, if she is receiving the placebo, she will be eligible to receive ultevursen following the study. Either way, she shares:

I’m just really grateful that I can help and that it’s not too late for me to stop my eye disease, get out, see some things, and not forget what they look like.

Advocating for Change

Elle also had some advice and thoughts for other people who are newly diagnosed or may be struggling with their diagnosis:

Today, it’s not the end of the world. It may be heartbreaking to hear that you’re losing your eyesight, but there is treatment coming down the wire – not just for my disease, but for many other major eye diseases. We’re just beginning to break into this field and it has changed so much. Genetic testing can narrow down the specifics.

Elle also urges people to:

  • Get out and participate. Meeting others with your condition, or a similar condition, can help you feel less alone and offer lots of support.
  • Advocate for yourself. If you don’t understand something, ask questions – to doctors, researchers, or even other patients. More so, learn how you can best engage and advocate for your needs.
  • Learn new technologies and how to use them. For example, the Magnifier on iPhones can help make reading or seeing details easier. Other burgeoning technologies can also help ease burdens and improve quality-of-life.
  • Register for My Retina Tracker. This registry and research database shares de-identified data with researchers to help accelerate research and treatment development for eye diseases including Usher syndrome, RP, and choroideremia.
Jessica Lynn

Jessica Lynn

Jessica Lynn has an educational background in writing and marketing. She firmly believes in the power of writing in amplifying voices, and looks forward to doing so for the rare disease community.

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