Promising RNA Therapies for LCA10 and USH2A Move Back into Clinical Trials

Moving emerging therapies through clinical trials and across the finish line is often challenging—and in some cases, harrowing. Many treatments never make it.

In early 2022, the future looked bleak for ProQR Therapeutics’ two RNA therapies in clinical trials. The biotech company reported that sepofarsen, its RNA therapy for LCA10 (IVS26 mutation in CEP290), did not meet its primary endpoint of improvement of at least three lines in best-corrected visual acuity or BCVA. (Improvement in BCVA was only on average two lines in the Phase 2/3 trial.) That news came despite vision improvements, some significant, for many patients. But missing the primary endpoint led ProQR to stop development of its ophthalmology assets—sepofarsen and ultevursen (exon 13 mutations in USH2A)—and attempt to find a company to acquire them.

Mike Schwartz, who was then vice president, global project leader, at ProQR, said, “That was devastating for me, the doctors, and the patients.” He noted that one patient with LCA10 in the trial with only light perception gained enough vision after receiving sepofarsen to see letters on an eye chart. Another LCA10 patient in the study returned to his work as a carpenter after treatment.

Fortunately, a year and a half later, the large European eye care company Théa acquired sepofarsen and ultevursen and formed the Sepul Bio business unit to move the therapies back into clinical trials. Many former ProQR staff went to Sepul Bio, including Mr. Schwartz, who is now their chief operating officer.

The global HYPERION Phase 3 clinical trial for sepofarsen and the LUNA Phase 2 trial for ultevursen are now underway. Using what was learned from the ProQR trials, the Sepul Bio team made significant changes to the designs (protocols) for the clinical trials, changes they believe will greatly improve chances for success. Mr. Schwartz thanked the Hope in Focus team for providing input from patients for the sepofarsen clinical development program.

One major change in the new sepofarsen clinical trial protocol has to do with the placebo. In most clinical trials with regulatory authorization, the treatment group is compared to a placebo or control group to ensure that efficacy is indeed a result of the treatment. In the original sepofarsen trial, treated eyes of LCA10 patients were compared to the eyes of untreated LCA10 patients (i.e., the control group). Comparing treated patients to untreated patients was less than ideal because of significant variations in vision loss among LCA10 patients. So, in the new trial, each LCA10 patient will have one eye injected with sepofarsen and the other will get a saline placebo injection. The patient won’t know which eye is getting the treatment. Sepul Bio believes comparing untreated and treated eyes for the same patient will lead to less variation and a stronger efficacy signal.

Keep in mind that sepofarsen injections are made into the vitreous, the soft gel in the middle of the eye. These intravitreal injections are performed routinely (e.g., monthly) and safely in doctors’ offices for treating age-related macular degeneration. In the sepofarsen clinical trial, patients will receive injections every six months.

Sepul Bio’s RNA therapies, known as antisense oligonucleotides (ASOs), are tiny pieces of genetic material that fix mutations in RNA—the genetic messages that cells read to make proteins critical to the cells’ health and function.

Stay tuned. We will report on updates from the trials as soon as we receive them.

For more information on the sepofarsen or ultevursen trials, send an email to: contact@sepulbio.com.

Reports on Gene Therapy Advances: A Highlight from the 2025 Hope in Focus Conference in Minneapolis

Gene therapy is unequivocally the most advanced approach for treating retinal diseases like Leber congenital amaurosis (LCA). Of course, there’s LUXTURNA® which is FDA-approved and has restored significant vision for people with LCA caused by RPE65 mutations. But several other emerging gene therapies are, or will soon be, in clinical trials. Excitingly, some are restoring vision early in human studies.

I had the honor and privilege of moderating an expert research panel at the 2025 Hope in Focus Conference last June in Minneapolis to discuss some of the exciting developments in LCA gene therapies. The three panelists were Kenji Fujita, MD, chief medical officer, at Atsena Therapeutics; Sarah Tuller, JD, chief regulatory officer at Opus Genetics; and Bikash Pattnaik, PhD, a professor at University of Wisconsin-Madison.

Atsena’s LCA1 Gene Therapy Moving into Phase 3

Dr. Fujita delivered the exciting news that Atsena’s LCA1 (GUCY2D) performed very impressively in a Phase 1/2 clinical trial. “We were super-thrilled with the results,” he said. “The gene therapy worked better than we expected.” Thanks to the excellent results, the gene therapy is moving into Phase 3 in a co-development partnership with Nippon Shinyaku which brought a few of their representatives to Minneapolis.

The Phase 1/2 trial enrolled nine adults in Part A (the dose escalation group) to evaluate initial safety and determine the optimal dose. An additional three adults and three pediatric patients were subsequently dosed. Patients receiving the highest dose (all were treated in one eye) had 100-fold improvement in retinal sensitivity, as measured by full-field sensitivity (FST). Some had10,000-fold improvement. Patients were also able to navigate a multi-luminance mobility test (MLMT) in dimmer light (two lux levels lower) after treatment. “This was a transformative difference, on par what we have seen with LUXTURNA,” said Dr. Fujita.

The Phase 3 clinical trial will enroll a larger group of patients and treat both eyes. Some patients will be in a deferred treatment group, serving initially as controls.

The Foundation Fighting Blindness, through its RD Fund, is an original investor in Atsena.

Opus Reports Vision Improvements in LCA5 Gene Therapy Clinical Trial

Opus Genetics, a company established by the Foundation Fighting Blindness in 2021, launched its first clinical trial in 2023 for an LCA5 gene therapy. LCA5 is a severe retinal degeneration diagnosed in a child’s first year. It is also very rare, affecting only about 200 patients in the US.

Opus reported excellent results for the first three patients (adults) in the trial with improvements in FST and virtual maze navigation. The company is now dosing pediatric patients and expects to report on them in the third quarter of 2025. “We are trying to move forward as aggressively as the FDA will allow,” said Ms. Tuller.

She acknowledged the great work of Dr. Tomas Aleman, the principal investigator on the trial, who was also at the meeting and had an engaging discussion with Sarah McCabe, one of the first patients to receive an RPE65 gene therapy.

A CRISPR Therapy is Emerging for LCA 16

Dr. Pattnaik reviewed his team’s emerging CRISPR gene editing approach for correcting the W53X mutation in the gene KCNJ13 which causes LCA16. He explained that the treatment works like molecular scissors to cut out the mutation.

Dr. Pattnaik is using lipid nanoparticles ⎯ which are like microbubbles ⎯ to deliver the treatment into retinal pigment epithelial (RPE) cells. Unlike most other genetic therapies which use engineered viruses to get genetic cargo into cells, nanoparticles have the advantage of being able to deliver therapeutic cargo of any size. Also, they are less likely to cause an immune reaction than viral systems.

Dr. Pattnaik tested the approach in cells and small animal models, and is now evaluating it in a large animal. He said the FDA is very positive about their current development plan.

The CRISPR therapy is currently funded through a grant from the National Institutes of Health (NIH) and was previously supported by the Foundation Fighting Blindness.

Dr. Pattnaik is also a co-founder of Hubble Therapeutics which is advancing a KCNJ13 gene augmentation therapy developed in his lab.

Diverse Emerging Therapies Featured at the 2025 Hope in Focus Conference in Minneapolis

The development of diverse treatment approaches for Leber congenital amaurosis (LCA) is necessary because no single modality will work for everyone affected. While development of gene augmentation therapies (i.e., replacing mutated genes with healthy genes) has much momentum, other approaches also show promise as they move into and through clinical trials. Three of those emerging alternatives were discussed by a panel of experts at the Minneapolis meeting in June. The panel was moderated by Amy Laster, PhD, chief scientific officer, Foundation Fighting Blindness.

Ray Therapeutics’ Optogenetic Approaches

Raj Agrawal, MD, the vice president of clinical development at Ray Therapeutics, presented his company’s emerging optogenetic therapies which are moving into clinical trials for retinitis pigmentosa (RP), choroideremia, Stargardt disease, and age-related macular degeneration. While Ray isn’t currently targeting LCA, optogenetics is an approach which may be applicable to some LCA patients.

Optogenetics is a gene-independent approach for restoring some vision for people with advanced inherited retinal diseases (IRDs) who have lost most or all their photoreceptors (rods and cones), the retinal cells that make vision possible. Ray’s therapies deliver genes that express a light-sensing protein called channelrhodopsin to either bipolar or ganglion cells ⎯ cells that are normally not light sensitive but survive after photoreceptors are lost. In essence, the therapies enable bipolar or ganglion cells to work like a back-up system for photoreceptors. The therapies are delivered by a one-time injection into the vitreous, the soft gel in the middle of the eye. These non-invasive injections are performed thousands of times every day in retinal doctors’ offices for treatment of AMD and diabetic retinopathy.

While Ray’s clinical trials are at an early stage, Dr. Agrawal said early reports for safety and efficacy have been encouraging. Stay tuned.

Sepul Bio’s RNA Therapies for LCA10 and USH2A

In early 2022, the biotech company ProQR reported that sepofarsen, its RNA therapy for LCA10 (IVS26 mutation in CEP290), did not meet its primary endpoint in a Phase 2/3 clinical. That news came despite vision improvements, some significant, for many patients in the trial. The endpoint miss led ProQR to stop development of its ophthalmology assets ⎯ sepofarsen and ultevusen (exon 13 mutations in USH2A) ⎯ and find a company to acquire them.

Mike Schwartz, who was then vice president, global project leader, at ProQR, said, “That was devastating for me, the doctors, and the patients.” He noted that one patient with LCA10 in the trial with only light perception gained enough vision after receiving sepoafarsen to see letters on an eye chart. Another LCA10 patient in the study was able to return to his work as a carpenter after treatment.

Fortunately, a year and a half later, the large European eye care company Théa acquired sepofarsen and ultevursen and formed the Sepul Bio business unit to move the therapies back into clinical trials. Many former ProQR staff went to Sepul Bio including Dr. Schwartz who is now their chief operating officer.

A Phase 2 clinical trial for ultevursen is underway and a global Phase 3 trial for sepofarsen is imminent. Using what was learned from the ProQR trials, the Sepul Bio team made significant changes to designs for the forthcoming trials ⎯ changes they believe will greatly improve chances for success. Mr. Schwartz thanked the Hope in Focus team for providing input from patients for the sepofarsen clinical development program.

Sepul Bio’s RNA therapies, known as antisense oligonucleotides (ASOs), are tiny pieces of genetic material that fix mutations in RNA, the genetic messages that cells read to make protein that’s critical to the cells’ health and function. Both sepofarsen and ultevursen are delivered by intravitreal injections every six months.

BlueRock Therapeutics’ Photoreceptor Replacement Therapy

The development of cell therapies for IRDs has been challenging for numerous reasons. Therapeutic cells haven’t been easy to source and enabling them to survive and integrate when transplanted into patients’ retinas has been difficult.

As a panelist for the session, I had the privilege of discussing a promising photoreceptor replacement therapy from BlueRock Therapeutics which came out of the lab of stem cell pioneer David Gamm, MD, PhD, University of Wisconsin-Madison. Excitingly, BlueRock’s therapy just moved into a clinical trial for people with RP and cone-rod dystrophy. Dr. Gamm said the cells might at some point be relevant to LCA patients.

The photoreceptor precursors used in the trial came from induced pluripotent stem cells (iPSC). The iPSC were derived from a small sample of mature blood or skin cells from a healthy donor. The cells were genetically tweaked to revert back to a stem cell state. The iPSC were then coaxed forward to develop into the photoreceptor precursors. As precursors, they aren’t fully mature. Dr. Gamm research showed that precursors have the best chance at survival and integration after transplantation.

BlueRock has the backing of two prominent companies: Bayer and Fuji Film. The Foundation Fighting Blindness funded Dr. Gamm’s previous iPSC-related lab research.

The BlueRock trial is moving forward methodically so that investigators can ensure safety for patients and best understand which patients and conditions can benefit most from the approach.

Moving Forward: Understanding More about Clinical Trials

The second panel session of the 2025 LCA Family Conference, “Participating in a Clinical Trial,” examined clinical trial development and participation from the researcher and patient perspectives. This session supports a goal of Hope in Focus to educate the Leber congenital amaurosis (LCA) community so members are ready to participate in clinical trials when opportunities occur. For researchers, informed and prepared LCA patient groups are critical to moving a new drug or therapy through the testing pipeline.

Ben Shaberman, vice president of Science Communications at the Foundation Fighting Blindness, was the moderator. The panelists were Tomas Aleman, MD, a researcher with over 30 years of experience in researching genetic therapies related to inherited retinal diseases (IRDs), and Sarah McCabe, a mother and teacher from Iowa, and an LCA individual with the RPE65 gene mutation. Sarah participated in a gene therapy study in 2007, and 14 years later was treated with LUXTURNA®.

Overview of the Research Process

Ben began with an overview of the drug development process, highlighting that it is complex, demanding, and lengthy—often taking 10–15 years, and costing tens of millions of dollars. For retinal diseases like LCA, the development of a drug or therapy begins with identifying and understanding the mutated gene causing the degeneration. Researchers study these genes and their effects on the retina, then create disease models—traditionally in mice, but now also using “mini-retinas” grown in dishes.

Conference attendees listening to the “Participating in a Clinical Trial” panel session.

Transitioning from animal or lab models to human trials is a significant hurdle, requiring higher-quality manufacturing standards, regulatory compliance (e.g., FDA), considerable funding, and specialized expertise. “This phase, called translational research, is often referred to as the ‘valley of death,’ Ben said. “Because many therapies fail to progress to clinical trials.”

For LCA, gene therapies can take 5–8 years to develop. Researchers must determine the right therapy, dosage, and method of administration before progressing to clinical trials, which can last 6–8 years, are extremely expensive, and often pose challenges for researchers and patients. While the process is rigorous and time-consuming, it is critical for developing effective therapies.

LCA Gene Research

Tomas Aleman, MD, co-directs the Center for Hereditary Retinal Degenerations (CHRD) at the Scheie Eye Institute at the Perelman School of Medicine, University of Pennsylvania. Dr. Aleman’s groundbreaking work has transformed the treatment of LCA, becoming the first disease where gene editing techniques were applied and gene therapy successfully restored vision. “Unlike what many people believe, most LCA patients are not completely blind, and their retinas often remain structurally intact,” Dr. Aleman said. “This makes the condition an ideal candidate for experimental therapies.”

Early research focused on RPE65-related LCA and started with animal models, including a dog, that helped pave the way for clinical applications, eventually leading to the first successful human treatments. After a decade of preclinical research, Dr. Aleman’s team moved into human trials, with LCA patients like Sarah McCabe playing a vital role. Dr. Aleman stressed the essential role of patients in clinical trials, saying that “Patient feedback is often critical to recognizing early signs of success.”

Clinical trials present both opportunities and challenges. They require long-term patient commitment and rely heavily on funding from smaller biotech companies. Patient selection for trials is also strategic—those chosen typically have structurally preserved retinas with poor function, maximizing the likelihood of measurable improvement. Dr. Aleman emphasized that exclusion from a trial does not mean the therapy won’t eventually be available for an individual; rather, it reflects the strict criteria needed to answer key safety and efficacy questions.

Looking ahead, Dr. Aleman said the goal is to expand the proportion of treatable LCA forms from roughly 25 percent to 50 percent. The progress made so far demonstrates the transformative potential of gene therapy in restoring vision for patients with inherited retinal diseases.

Doing Gene Therapy

Dr. Aleman gave an in-depth explanation of the gene therapy process for treating inherited retinal diseases, particularly focusing on subretinal delivery techniques. Gene therapy in this context is a meticulous process where the therapy is delivered directly beneath the retina via a subretinal injection.

Performed under general anesthesia, the injection only takes 5–10 minutes. It is done by entering the eye through three small incisions, removing the gel-like vitreous, and using a hair-thin needle to deliver the gene therapy. According to Dr. Aleman, the surgery resembles retinal detachment repair—a well-established procedure.

While there is an alternative delivery method known as intravitreal injection that is less invasive, it has not proven to be as effective or safe for all retinal indications. In particular, immune detection can reduce the efficacy of intravitreal injections, whereas subretinal injections can bypass these mechanisms.

Following surgery, a rigorous monitoring process begins to assess the treatment’s safety and effectiveness. This process includes frequent follow-up visits in the early stages—often at one, three, and six months and a year—during which visual function is tested and retinal imaging is conducted.

Participation in gene therapy trials is entirely voluntary, and patients can choose to withdraw at any time. However, once the gene therapy is delivered, it cannot be undone. The therapeutic genes remain in the eye’s cells indefinitely, making informed consent and long-term commitment critical components of the clinical trial process.

Patients are typically monitored for at least two years, and in many cases, much longer. For example, in the case of one early trial (the RPE65 trial), patients have been followed for over 16 or 17 years. Dr. Aleman emphasized that there is a lifelong partnership between patient and physician, stating that monitoring continues for as long as possible, regardless of whether the formal trial period has ended.

Dr. Aleman hopes to move toward treating very young children, ideally before age two, since the brain’s ability to learn to see develops rapidly in infancy and early childhood. Early treatment is believed to yield better visual and developmental outcomes, supported by early rehabilitation and educational interventions. A grant received two years ago is helping to support research and clinical work toward this goal.

“While gene therapy offers transformative potential, it also requires thoughtful implementation, long-term follow-up, and a commitment to tailoring support beyond the surgical intervention,” said Dr. Aleman. “The mission is not only to restore vision but to improve the quality of life and long-term outcomes for patients, especially children, by intervening as early as possible.”

Sarah’s Story & Clinical Trial Experience

When Sarah was about 10 days old, her mother, an ICU nurse, noticed that she wasn’t following the developmental patterns she’d observed with her son. Concerned, they visited a pediatrician who suspected something was wrong with Sarah’s vision. Further evaluation by a neurologist ruled out any neurological issues, and her parents were assured that Sarah would hit developmental goals right on time.

Regular eye exams ensued, with her parents keeping detailed records of each visit. Eventually, Sarah was referred to the University of Iowa, where tests suggested LCA, but at that time, genetic testing wasn’t available. A definitive LCA genetic diagnosis (RPE65) was finally made when she was in eighth grade.

At age 19, she was recruited for a clinical trial after struggling with vision during college. After going through the initial interviews and assessments, she was approved as a clinical trial participant. Sarah said the doctors clearly explained all the details and risks of the trial and that it was an experimental procedure primarily aimed at testing safety. The decision whether to move forward was left to Sarah and her family. “There wasn’t a whole lot of talking with my parents about it,” she said. “We knew things weren’t going to get any better if I didn’t participate, and I could be a part of helping [research advance].

To facilitate Sarah’s participation in the clinical trial, logistics were carefully arranged around her college schedule. It was toward the end of her senior year that her family drove her from Iowa to the University of Florida, where she underwent her first gene therapy surgery at age 23, describing it as terrifying but perfect.

The pre-operative steps included bloodwork and other standard preparations. During the surgery, Sarah was awake—a protocol that has since changed, with patients now put under general anesthesia. Post-surgery, she had a significant moment when she was able to read a giant letter “A” on a card, confirming that the surgery hadn’t worsened her vision. Over time, she noticed a new visible area in her field of vision, referred to as a “headlight,” which was a significant improvement.

Sarah’s recovery involved staying in Florida for a month with her family, with frequent follow-up visits stretching out from monthly to annually. Her clinical trial team remained in contact with her years after the trial formally ended. Fourteen years later, after LUXTURNA® was FDA-approved, she received the gene therapy at the University of Iowa, which improved her vision. Now in her 40s, Sarah’s primary goal is to maintain the stability of her vision. She summarized her clinical trial and gene therapy experiences, saying, “It was a long time ago now, but it was a very cool experience. All of it!”