LCA10 CEP290 Illuminate Clinical Trial Produces No Observed Benefit

ProQR Therapeutics’ clinical trials of sepofarsen to treat a form of Leber congenital amaurosis (LCA) caused by a mutation in the CEP290 gene did not meet its primary endpoint of improving visual acuity.

Illuminate, the name of the clinical study, aimed to explore whether the investigational medicine sepofarsen was effective and safe for people with LCA10 caused by the CEP290 mutation.

The Phase 2/3 clinical trial produced no observed benefit in visual acuity for participants receiving the treatment versus those in the study not receiving the treatment. Visual acuity is a measure of the ability of the eye to distinguish shapes and details of objects at a given distance.

ProQR Founder and Chief Executive Officer Daniel A. de Boer delivered the news recently and characterized the results as disappointing.

“Given the results observed in earlier studies of sepofarsen, the Illuminate trial results are unexpected and disappointing, especially for people living with LCA10,” de Boer said.

“ProQR was founded with the goal of developing RNA therapies (ribonucleic acid) for patients with high unmet medical need, and we will continue to advance our robust pipeline of therapies for genetic eye disease. We are deeply grateful to all of the participants, their supporters, and investigators who participated in the Illuminate study.

“Since the results in February, ProQR has been conducting additional analyses of Illuminate and will present these findings at a future scientific conference.”

ProQR works on developing RNA therapies to treat LCA and other inherited rare diseases (IRDs). With DNA being the library of our genes and RNA being a blueprint of that collection, RNA therapies help carry out DNA instructions to create certain proteins critical to a healthy cell.

Analyzing Results for More Answers

Hope in Focus Co-Founder and Board Chair Laura Manfre said we will share updates with the LCA community as we learn more from ProQR.

“The results are not what we had hoped for from ProQR on the LCA10 Phase 2/3 trial, but we are resolved to keep hope in focus, knowing that the brilliant minds that got us this far are not giving up.

“It’s important to remember when there are setbacks that only 10 years ago, all we had was hope. Most of the community couldn’t even get a genetic diagnosis, let alone hope for treatment,” she said. “We’ve come a long way in a short period of time, and we’re going to keep advancing.”

Ben Yerxa, PhD, Chief Executive Officer of the Foundation Fighting Blindness, said his organization will work with ProQR to learn more about the data.

“This was not the outcome we had hoped for, and we share in the disappointment many are feeling in the community,” Yerxa said.

“We will continue to work alongside ProQR to learn more from the ongoing analyses and as they work to advance RNA therapies to potentially help children, adults, and families who are affected by rare genetic eye diseases.”

In delivering the results, the biotechnology company gave background about LCA, the most common genetic cause of childhood blindness, affecting about 15,000 people in the Western world. One federally approved gene therapy treatment, LUXTURNA®, exists for people with LCA2 (RPE65), one of the more than 27 forms of LCA.

The rare retinal disease usually appears in the first year of life and is characterized by progressive loss of vision. Other symptoms can include rapid eye movement, known as nystagmus, eye-poking, night blindness, and sensitivity to light, known as photophobia. Depending on the mutation, complete loss of vision can occur during early childhood.

**Specifics of the LCA10 CEP290 Trial**

Illuminate enrolled 36 participants, aged 8 years or older with genetically confirmed LCA10 due to the c.2991+1655A>G (p.Cys998X) mutation in the CEP290 gene.

The study was a randomized, sham-controlled clinical trial that took place in three randomized groups at 14 sites in nine countries.

The first group received a target dose of sepofarsen by intravitreal injection (IVT), the second received a low dose via IVT, and the third underwent a sham procedure that mimicked an injection with no medicine or injection given.

Bart P. Leroy, MD, PhD, one of the study’s key investigators and Director of the Ophthalmic Genetics and Retinal Degenerations clinics in the Division of Ophthalmology and Center for Cellular and Molecular Therapeutics at The Children’s Hospital of Philadelphia (CHOP), said work will continue toward finding therapies.

“LCA10 is devastating, and with no approved therapies, very difficult to treat retinal disease resulting in blindness,” said Dr. Leroy, who also is head of the Ophthalmology Department at Ghent University Hospital and Professor of Ophthalmology and Ophthalmic Genetics at Ghent University in Belgium.

“We will continue to work with ProQR to understand the data as they work for advance therapies for individuals with inherited retinal diseases.”

Andy Bolan, ProQR Director of Medical Affairs, said the team extends its thanks to the study participants, their supporters, the investigators, and their staff for support in developing the trial. He said the biotech remains committed to making a significant and positive impact on the lives of those affected by genetic conditions.

For quarterly news and future study participation opportunities, you can sign up for the ProQR Eye Connect Newsletter or follow them on social media.

People also can contact ProQR with any questions at patientinfo@proqr.com.

Rare Disease Day 2022: Hope in Focus Promotes Rare Disease Advisory Council

Rare Disease Day 2022 kicked off today as people gathered across the country, including us here at Hope in Focus, to raise awareness and generate research for treatments and cures for rare diseases, including Leber congenital amaurosis and other rare inherited retinal diseases.

Hope in Focus joined more than 30 advocates gathered for a virtual celebration of Connecticut’s Rare Disease Day. The day, officially acknowledged annually on the last day of February, is celebrated nationally and globally as a concerted effort to raise awareness, to grant access to medications, therapies, and state services, and to encourage research on the more than 7,000 rare diseases.

The Rare Action Network (RAN) of the National Organization for Rare Disorders (NORD) organized Connecticut’s Rare Disease Day activities, the highlight of which was to inform the state legislature of the vital importance of establishing a Connecticut Rare Disease Advisory Committee (RDAC).

Courtney Assad, Hope in Focus Director of Outreach and Development, presented a statement from our organization in support of and RDAC, telling the group that research and investment paid off immeasurably with the development by Spark Therapeutics of LUXTURNA®.

“LCA patients treated with LUXTURNA® experienced dramatic changes in their lives with greatly improved or restored vision,” she said in the statement. “Five, 6, 7-year-old children treated with LUXTURNA® view life in a new light in big and little ways. They can now see rainbows arcing in the sky and stars shining at night.”

One in 33,000 people are affected by LCA, which represents 5 percent of all retinal dystrophies.

More than 20 states have established such councils and RAN is working toward creating a group for each state. This year, Connecticut’s attempt to establish an RDAC has move farther along than any of the efforts that began in 2015. A task force met a dozen times between 2017 and 2019, but a paper reporting the group’s recommendations never made it to the Public Health Committee of the Connecticut General Assembly.

RAN and NORD drafted legislation referred to as House Bill 5260 and called “An Act Establishing a Rare Disease Council.” We received great news that that the legislation was formally introduced and has been referred to the Joint Committee on Public Health. A public hearing is expected to be scheduled to hear testimony supporting the proposed legislation.

The council would advise and make recommendations to the Department of Public Health and other state agencies, regarding the needs of people in the state living with a rare disease and their caregivers.

It would consult with rare disease experts, develop policy recommendations for improving access to quality medical care, affordable and comprehensive insurance coverage, medications, medically necessary diagnostics, timely treatment, and other necessary services and therapies.

The RDAC also would perform a host of other functions in support of the 250,000 to 300,000 people living with rare disease in Connecticut. You can view the text of the legislation here.*

Rare disease affects more than 25 million Americans. This equates to 1 in 10 Americans, or one on every elevator and four on every bus, according to the National Institutes of Health (NIH). More than 300 million people worldwide live with a rare disease.

Thirteen members would make up the group that includes the commissioners of public health, social services and insurance or their respective designees

A hospital representative and a physician licensed in medical genetics would be appointed by the governor.

Other members would represent patient advocacy groups, family members or caregivers of a pediatric patient living with a rare disease, a caregiver of a child or adult living with a rare disease, an adult living with a rare disease, a rare disease scientist, a rare diseases physician, and a member of the biopharmaceutical industry.

Kristen Angell, NORD Associate Director of Advocacy, and Lesley Bennett, Volunteer State Ambassador for Connecticut’s RAN, organized the event.

Connecticut’s Lt. Gov. Susan Bysiewicz opened the session saying never doubt the power of advocacy and passionate volunteers that have extensively lobbied her and many others in the statehouse to create a RDAC.

“I have a lot of hope. I know my colleagues in the legislature are people of great compassion who will be working for you.”

U.S. Sen. Richard Blumenthal also offered a statement on the event: “This Rare Disease Day, I’m proud to join the National Organization for Rare Disorders as we renew our commitment to supporting patients, families, and essential caregivers. With robust federal investment, we can and will spur innovation of research, treatments, and cures for those living with rare diseases – saving countless lives in Connecticut and across the country.”

More than a dozen people – advocates, caregivers, patients, doctors, and businesspeople – shared their stories. Many of them are parents of children living with rare diseases, such as rare muscle disorders, rare pediatric cancers, rare genetic disorders, and other diseases that often are described as pediatric Alzheimer’s and juvenile ALS (amyotrophic lateral sclerosis, known as Lou Gehrig’s disease.

Connecticut State Rep. Mitch Bolinsky, one of the legislators in on the meeting, said, “WOW! What an incredible group of advocates. You got us to the finish line and now we just have to get ourselves over it.”

BioBonds: Innovative legislation would help fund clinical trials, including those for LCA

A proposed Congressional Act designed to help researchers launch clinical trials for emerging treatments gives hope for getting more treatments across the finish line for people living with a broad range of medical conditions, including rare retinal diseases, such as Leber congenital amaurosis (LCA).

The BioBonds legislation establishes loans up to $25 million to a researcher or company as an innovative way to finance early-stage clinical trials. The program would provide $10 billion annually for three years.

Researchers would be required to repay the low-interest, government-backed loans.

Hope in Focus, along with Foundation Fighting Blindness (FFB) , and more than two dozen other entities, have signed on in support of the legislation.

“Funding for research for all diseases, including rare conditions such as LCA and other rare inherited retinal diseases (IRDs), is always a challenge and was made even more so when COVID hit and so much of biomedicine research was held up,” according to Laura Manfre, President and Co-Founder of Hope in Focus (formerly known as Sofia Sees Hope).

“While we are ever grateful to our funders and grantors, we are excited that the loans provided through this legislation have the capacity to increase momentum and accelerate the development of treatments and cures for blindness and an array of other diseases.”

Biomedical Research Act hopes to bridge chasm between promising research and clinical trials for treatments for LCA and a range of medical conditions

Officially known as the Long-Term Opportunities for Advancing New Studies (LOANS) Biomedical Research Act – H.R. 3437 – the proposed legislation creates a unique way of mobilizing capital of long-term investors to give loans to companies developing treatments and cures for a wide range of disease and disability.

U.S. Representatives Bobby L. Rush (D-IL) and Brian Fitzpatrick (R-PA) introduced the LOANS for Biomedical Research Act to help bridge the financial “valley of death” that separates promising research from clinical trials necessary to delivering federally approved treatments and cures.

Most pharmaceutical and biotechnology companies do not fund early-stage clinical research. By funding early-stage human studies, H.R. 3437 can help move research to the point where it could attract investment from industry for late-stage clinical trials, which often cost hundreds of millions of dollars.

Hope in Focus and FFB, along with other organizations, sent a letter to the representatives in support of this initiative to leverage billions of dollars in private-sector investment to advance early-stage clinical biomedical research.

The letter in part states: “Without H.R. 3437, vital medical research in blindness, cancer, Alzheimer’s, pediatric rare diseases, conditions disproportionately affecting minority communities, and other diseases will take many more years to complete, no matter how promising the progress just a year ago…

“H.R. 3437 would unleash billions of long-term capital for medical cures at little cost to taxpayers – we can think of few national objectives that matter as much as preventing disease, treating disability, and reducing pain and suffering.”

Retinitis Pigmentosa patient and her husband played key role in developing the legislation

FFB plays a key role as a partner in outreach and awareness. Foundation Board Director Karen Petrou and her late husband, Basil, were visionaries for the legislation.

FFB CEO Ben Yerxa, PhD, applauded the introduction of the Act.

As head of the world’s leading organization committed to find treatments and cures for blinding retinal diseases, Yerxa said, “As the remarkable speed of the COVID-19 vaccines development and approval processes have demonstrated, financial capacity – not scientific knowledge – is our biggest hurdle to advancing medical research and delivering the life-saving treatments and cures millions of Americans so desperately await.

“From blindness to cancer to juvenile diabetes, the private sector dollars that this bill will infuse into biomedical research will jumpstart clinical trials stalled by the pandemic,” he said. “These trials are designed to convert basic science into treatments and cures for these diseases and so many more, which is why it’s supported by a growing number of patient advocacy organizations.”

Doctors diagnosed Karen Petrou in her teens with retinitis pigmentosa (RP) and she went blind in her 40s.

A New York Times article describes Petrou’s challenges over four years in developing a new funding model for curing blindness.

Also, Petrou authored an in-depth paper describing the funding model – Generating Billions in Private-Sector Investment Speeding Treatment and Cure.

Please see the Biobonds website for more information about the legislation, including signing on as a supporter, seeing the current sponsor list, reading the legislation, and getting assistance with contacting your U.S. House Representative.

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

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.”

Family Excited About New LCA5-Lebercilin Research Program

John Mills says he would crawl over broken glass if it led to a cure for his daughter’s visual impairment caused by one of the rarest of rare inherited retinal diseases.

Fourteen-year-old Naomi Mills of Virginia lives with one of the rarest forms of Leber congenital amaurosis – LCA5, which encodes the protein lebercilin. Lebercilin is responsible for moving proteins up and down, between the inner and outer segments of the photoreceptor cell so it can operate properly and stay healthy.

While most parents of children diagnosed with a rare inherited retinal disease can identify with John’s feelings toward finding a cure, a new genetics company just might save his hands and knees from harm, as the business plans to prioritize research into this severe form of LCA that affects about one in 1.7 million people.

Opus Genetics based in Raleigh, N.C., plans to file an Investigational New Drug (IND) application this year with the U.S. Food and Drug Administration for an LCA5 research program called OPGx-001.

Naomi on the floor, looking at a Christmas train ornament — Naomi Mills, who lives with a rare form of LCA knowns as LCA5-Lebercilin, loves this Christmas train ornament because it moves and it’s colorful and sparkly.

A pharmaceutical company obtains FDA permission to start human clinical trials and to ship an experimental drug across state lines through an IND application before approving a marketing application for the new drug.

“Kathie (John’s wife) and I pray every day that there’ll be a pathway to improve her vision, that she’ll be able to drive someday.”

The Retinal Degeneration Fund (RD Fund), the venture arm of the Foundation Fighting Blindness led the $19 million in seed financing. The funding will allow Opus to advance the preclinical work of its three scientific founders: Jean Bennett, MD, PhD, the F.M. Kirby Emeritus Professor of Ophthalmology at the Perelman School of Medicine at the University of Pennsylvania; Junwei Sun, Chief Administrator for Penn’s Center for Advanced Retinal Ocular Treatments; and Eric Pierce, MD, PhD, the William F. Chatlos Professor of Ophthalmology at Harvard Medical School and Massachusetts Eye and Ear.

“We’re very excited,” John said. “We know there’s a lot of moving parts here – doctors, advocacy groups, medical research, the FDA. Trying to get all of those aligned for the moon shot is quite an orchestration.”

High Aspirations for Teen with LCA5

Low vision aside, her father said Naomi wants the freedom of mobility in owning a car.

“Naomi was given a suggestion by her wonderful teacher that a best practice is to buy a car, even if you’re blind, so you can ask someone to ‘Please drive me in my own car,’” John said. “She also hopes that she can drive her own car someday.”

The couple’s daughter also loves music, plays piano, and wants to be a filmmaker.

How can a person with visual difficulty make a film? Naomi did on a recent Sunday afternoon, John said, documenting the finishing of the family basement, recording clips of action, inserting music, and editing everything into a film.

“It’s beautiful,” he said. “She’s very good at whipping films together.”

He also said Naomi is her own person.

“She wants to grow up and move out as fast as she can and get her own place and live on her own. That’s a good thing,” John said. “She just loves the thought of being independent. That’s a good thing. We encourage that.”

Naomi and her family vacationed in Germany in 2018 and visited the Dialogue in the Dark exhibition at Frankfurt’s DIALOGMUSEUM, where blind guides lead visitors through settings in absolute darkness. John characterized the experience as a wonderful way to better understand the world of people with visual challenges. He said the Mills family would like to establish a similar exhibit in the United States.

With 20/500-600 vision, Naomi needs bright light, and, while colorblind, she can see contrasts and large black letters on white paper.

“My understanding and interpretation is that Naomi has tunnels of goodness that she can see out of. It’s like looking out of a wiffle ball, tunnels she can see through but not consistently,” he said. “She can read large print and she can write fairly well. She’s also proficient at reading and writing braille.”

Confirmed LCA5-Lebercilin Diagnosis

The couple adopted Naomi in 2010 at age 2 from China, knowing doctors diagnosed her with Retinitis Pigmentosa, and said, “We’re taking her on faith. It doesn’t matter.”

Their son, Michael, now 31, accompanied his parents to China when they adopted their first daughter, Sarah, from an orphanage in 2001. Sarah, now 21, went to China with John and Kathie when they brought Naomi home from foster parents nine years later. Back in the United States, the couple followed up any leads to help Naomi with her vision.

“It was very murky and confusing, trying to connect with resources and groups,” he said.

The family received Naomi’s confirmed genetic diagnosis after a visit to a doctor at the National Institutes of Health. Kathie became highly proficient in braille and initially homeschooled Naomi, who now attends the Virginia School for the Deaf and the Blind.

In the past several years, Naomi made the national finals in the Braille Challenge, the only academic competition of its kind in North America for students who are blind or visually impaired.

“She is so sharp, so smart, and such a blessing,” Naomi’s mom said.

Opus Genetics Launch Brings Cautious Optimism For RDH12 Families

Allison Galloway feels cautiously excited about a new genetics company prioritizing research into her children’s form of Leber congenital amaurosis known as LCA13 (RDH12).

“I would say I’m excited, but I don’t put all my eggs in one basket,” the Colorado mother said of the news to bring a treatment closer to market. Her children, Logan and Zoe, both live with LCA13.

“Many times, we think we made progress and then we had some studies done and invested money, and the researcher never progressed with the research.”

Zoe and Logan on the floor with their hands holding their head — Zoe and Logan Galloway both have LCA13

Now, a new gene therapy company called Opus Genetics plans to target two forms of LCA. The company’s research into LCA13 will focus on restoring protein expression and halting functional deterioration in patients with retinal dystrophy caused by mutations in the retinal dehydrogenase gene RDH12. LCA13 affects one in 288,000 people. Opus also will concentrate on research into LCA5, which encodes the lebercilin protein and affects about one in 1.7 million people.

The Retinal Degeneration Fund (RD Fund) of the Foundation Fighting Blindness led the $19 million in seed financing for Opus, based in Raleigh, N.C.

Motivated Parents

Opus comes amid efforts by the Galloways and a network of motivated parents to raise money, invest in research, and advocate for genetic testing to help drive studies forward to find a treatment for LCA13.

Allison, a nurse practitioner and founder of a women’s health practice, and her husband, Michael, a VP of Finance, are part of a non-profit that parents of LCA13 patients founded more than 11 years ago called RDH12 Fund for Sight.

“We work with scientists around the world to fund research. We support each other even if we live in the U.S., Italy, Australia, or Saudi Arabia. We try to advocate the importance of all children diagnosed with a rare disease to get genetic testing. Without it, we would have never known what our children had, let alone how to cure it.”

A mutation in the RDH12 gene means an inability for the body to create a simple enzyme called retinal dehydrogenase, which helps in the cleaning and health of the eyes. LCA13 is an autosomal recessive gene defect that appears when each parent has a mutation on the same gene in the same place.

Doctors genetically diagnosed Logan at age 3. Now 10, he is a fifth grader who loves everything technology. Logan loves to ski and is fluent in braille. While his vision is fairly stable, he lost some of his field of vision over the years and his night blindness is severe, his mom said.

When Logan was 5 and Zoe was 3, one day at dinner, Allison noticed her daughter’s eye started to

The Galloway family in white shirts — Michael and Allison Galloway with their kids, Zoe and Logan. Both children have low vision due to LCA13, involving the RDH12 gene.

bounce from side to side.

“I immediately knew what it meant,” she said. “A nystagmus means that the eye is weak and sick. I didn’t need the gene results to know that not only did my son have LCA, but my beautiful little girl did too. A 6 percent chance.”

Doctors genetically diagnosed Zoe also at age 3. Now 8, she is a third grader who loves painting, clay modeling, reading, writing, and riding horses. Her vision is much better than Logan’s, and while it has also been fairly stable, she has lost some over the years.

RDH12 Natural History Study

The children took part in an RDH12 Natural History study by Drs. Tomas S. Aleman, Katherine E. Uyhazi, and Jean Bennett, among a host of other researchers, at the Perelman Center for Advanced Medicine at the University of Pennsylvania.

Logan and Zoe were among 21 patients, ages 2 to 17 years old, from 14 families, who underwent exams, imaging, and numerous studies to track details about the gene’s structure and function, and the progression of the disease across a range of patients with the RDH12 mutation. Natural History studies often serve as a critical part in designing clinical trials eventually involving testing on humans.

The journal Retina published results of this segment of the study in an article titled “RDH12 Mutations Cause a Severe Retinal Degeneration with Relatively Spared Rod Function.”

Allison and Michael attended Hope in Focus’ 2019 LCA Family Conference in Philadelphia, where panels of researchers, including Drs. Aleman and Bennett, shared their study results among an audience of patients, care givers, advocates, scientists, and leaders in biotechnology and the regulatory process.

The Galloways and others in the RDH12 group have been disappointed in the past. In one instance, a biotechnology company announced they were moving forward with RDH12 trials.

“Nothing happened. We’re emotionally battered, so we tend to have a little reluctance until it’s actually occurring.”

Regarding Opus’s plans to drive LCA13 research forward to a viable treatment, Allison said, “While we’re excited, we can’t get all our hopes up. As a board member of the RDH12 Fund for Sight, we have other coals in the fire to keep the research going if this doesn’t progress. But we are hopeful that this is our time, and this study is an answer to our hopes and dreams.

“We’re trying to be part of this study financially because we owe it to our kids and affected members to not be left behind like we have in the past,” she said.

“We have fought too hard and for too long to keep watching them lose their sight.”

Big Journey for Little Girl with LCA3

Parvi Gaddam has endured a lot for a little girl genetically diagnosed at 6 months’ old with a form of Leber congenital amaurosis called LCA3 (SPATA7).

Parvi wearing a pink tank top — Parvi Gaddam has a form of Leber congenital amaurosis called LCA3 (SPATA7)

Like most parents discovering their child has a rare inherited disease, the diagnosis of their now 3-year-old took Harini and Suresh Gaddam by surprise because no one in their families experienced vision loss or blindness. LCA, usually inherited as an autosomal recessive genetic condition, means a child inherits two copies of the mutated gene, one from each parent.

The couple, who are software engineers living in Tampa, Fla., hoped Parvi’s mutated gene would be RPE65 associated with LCA2, because vision in some patients with that mutation improves through the federally approved LUXTURNA® gene therapy.

LCA3 Diagnosis Confirmed

She underwent rounds of scans and tests, and at 6-months, Parvi and her family traveled to Pennsylvania’s University of Pittsburgh Medical Center Children’s Hospital, where doctors diagnosed her with a mutation in her SPATA7 gene, associated with LCA3, one of the 27 known forms of LCA. Rare among rare diseases, LCA3 accounts for fewer than 2 percent of all LCA cases. Early-stage research using mice models has shown promising results with gene therapy treatment.

Parvi does have some light perception. Her vision teacher comes to her home because of the COVID-19 pandemic, and helps her by reading storybooks, singing songs, and touching and seeing objects. Parvi also enjoys the company of her older brother, 8-year-old Thanmay, who returned to class in school.

“She’s very smart, does her routine, enjoys reading the books, songs, walking, and playing with her brother,” Suresh said.

Her parents follow studies on the gene and reached out to Hope in Focus and the Foundation for Fighting Blindness for help in their journey.

Parvi in a pink long dress with her brother, Thanmay, besides her wearing blue — Parvi with her brother Thanmay

Harini and Suresh began raising funds for SPATA7 research through GoFundMe and through the Foundation, with a goal of $5 million.

The family is searching for more people living with the SPATA7 mutation to gather patients and bring research forward to clinical trials in humans, with the hope that a treatment or cure will come to fruition.

“We will not give up,” her father said. “And we will continue fighting for my little angel and the SPATA7/LCA3 patient group to bring this treatment to humans.”

Our New Name – FAQs

Why did we change our name?

It’s simple: we’ve grown and matured as an organization. And we’re looking ahead to how we can best position this organization for the future. We were never about one individual – we’ve always been for all of the Sofias – all the individuals, all the families, and all the genetic variants associated with LCA. The new name has simply evolved to reflect that.

Why change the name now?

The pandemic gave us an unintentional break from normal operations, kind of like many of us since early 2020. Unable to plan and go forward with public events, such as our Dinner in the Dark gala fundraiser and our LCA Family Conference, we had time to work on a new name.

Who decided to change the name?

Our President and Co-Founder Laura Manfre has been thinking about changing the name for a long time. Researchers asked her and her family to fundraise when she learned of Sofia’s genetic LCA diagnosis in 2012. She and others founded Sofia Sees Hope in 2014 to advocate and raise funds for all in the LCA and IRD communities, and Sofia came to represent all Sofias. The organization was founded to be inclusive, and we are now updating the name to reflect that inclusivity.

Has anything else about the organization changed?

Nope. Our mission is the same; only our name has changed, and we hope this will better position us to grow and extend the reach of our work and focus.

Why did we work with a branding firm?

We’ve come to know a lot about rare inherited retinal diseases, genetic testing, clinical trials, federal drug approval, 27 different forms of LCA, and tons more about rare inherited retinal diseases, but we needed professional help in the branding department.

We found that help through an old friend, Bonnie Southcott, who has been with us since the beginning and knows our people and our mission. She also is Director of Patient Engagement at Toolhouse, a digital marketing firm in the life sciences sector.

She describes the essence of rebranding or renaming as carefully identifying a brand’s DNA and then capturing it in the new words, look, and feel of the name, the logo, and the tagline. The three-month process involved our founders, board members, staff, donors, and the people we connect with in the LCA and IRD communities. We think she did a great job and hope you do, too!

How was the rebranding funded?

We are very fortunate to have generous supporters who donated their significant talent, and their time to our rebranding initiative. For the expenses we did incur, these were covered with grant funding designated for administrative expenses and capacity building as we position our organization for the future.

It is important to us that contributions received from individual donors are used solely for the benefit of research and genetic testing. Meanwhile, our education, outreach, and advocacy programs, as well as our capacity-building activities and administrative expenses are supported by grants and restricted contributions designated for those activities.

What does Sofia think about the name change?

She is excited for the update! She has always known that the organization’s mission was to serve the broader community, and she looks forward to continuing her involvement, which has included everything from leading a book club for middle schoolers to supporting fundraising to representing the organization at partner events.

Will Dinner in the Dark return?

YES! And here is the date to save: Saturday, October 8, 2022, at the Mystic Marriott in Groton, Connecticut. We cannot wait to gather safely again, for this, and for other in-person events like our LCA Family Conference, A Rare Opportunity, and more.

Sofia Sees Hope Rebrands with an Eye to the Future

Sofia Sees Hope this month unveiled a new name and logo — Hope in Focus — as the organization sets its course for the next decade of work to benefit the Leber congenital amaurosis (LCA) community.

Embracing and encompassing, Hope in Focus is our new name: Embracing because research advancements fuel hope and ease feelings of isolation that often accompany a rare-disease diagnosis, and encompassing because our global advocacy reaches all of those living with LCA and other rare inherited retinal diseases (IRDs).

Our organizational namesake, Sofia, was a little girl with LCA in 2014. She has now come of age, and so have we. Throughout the last seven years, Sofia Sees Hope has transformed from a small NPO into a robust, international organization, and that’s why we’ve taken the exciting step of evolving our name while keeping hope as its centerpiece.

“Hope is built on the bedrock of yearning; not an unrequited yearning, but the yearning for what we know can be,” President and Co-Founder Laura Manfre said. “Hope is fuel, driving us to action. It binds us together and soothes our souls when darkness falls. Hope is our Polaris; the brightest star in the IRD constellation.”

Hope also is empowering and a strong motivator. It is the role of Hope in Focus to make sure we hear those voices of the patients, families, and community, and we help craft compassionate, forward-thinking policy.

“Without hope there is not a chance you’re going to advance treatment,” Manfre said. “We cannot sit back and wait for it like manna from heaven because that’s just not going to work.”

Why The Name Change?

As Sofia Sees Hope grew from its beginnings, so did its reach geographically and genetically with those living with LCA and IRDs. The development and 2017 federal approval of LUXTURNA®, a vision-restoring gene therapy, marked an incredible milestone in the rare retinal disease world. Several factors powered the name change.

Sofia Sees Hope established steady grant funding and strong corporate partnerships over the years to support advocacy programs, such as our LCA Family Conferences, quarterly newsletter, and monthly webinars.

“We are grateful to our grantors and corporate partners, and, for the most part, that funding has remained steady and that’s what we use for outreach and for continuing to build a sustainable organization,” Manfre said.

Our advocacy group forged vital relationships with global organizations like Foundation Fighting Blindness and Retina International and with pharmaceutical and biotechnology companies, resulting in remarkable research advancements. These include improved access to genetic testing and the development of more than 30 clinical trials into retinal disease research.

“We’ve reached this level of organizational maturity where we’re well-known enough that we can manage a name change and continue to provide even better service to the community,” Manfre said. “We are well-positioned for the future and believe this name change will only help us to be more successful.”

Unintentional Opportunity of Time

Manfre said she didn’t necessarily want her daughter’s name attached to the organization because from the beginning it was about so much more than her. After Sofia received her confirmed genetic diagnosis of the gene causing her vision loss — IQCB1 — her family was asked to fundraise.

“Every year I would step back and question it. Is it time to change our name? It was never about Sofia specifically,” she said. “Since our incorporation, we provided funding to support a variety of research initiatives, including My Retina Tracker® Program.”

But then the COVID-19 pandemic set in, giving an unintentional opportunity to press the pause button for time to re-evaluate.

“COVID gave us time, although that’s not how we would have wanted to do it.” The name Sofia Sees Hope served our organization well once we established we were reaching out to people like Manfre’s daughter, Sofia, and people living with any one of the 27 known forms of LCA and a host of IRDs.

Now in the eighth year since our founding, research has advanced exponentially, and we wanted to be clear that we are there for the whole LCA and IRD community” she said.

“We are not changing who we are or what we do. We’re just changing the name.” Manfre said the name change also relieves the pressure on Sofia that comes with having her name be part of the organization. Sofia has supported at fundraisers, educational events, and most recently by leading a book club for middle schoolers with LCA and other visual impairments.

The Process Behind Our New Name

We had amazing help with finding the right name. Bonnie Southcott led the three-month project. Southcott is former Director of Patient Engagement at Toolhouse, a digital marketing firm in the life sciences sector, based in Washington state. Under her guidance, we developed a new name, Hope in Focus, a new tagline, “Seeing a cure for blindness,” and a new logo.

“I think it’s important to know that the organization itself hasn’t changed. The (new) name is more reflective of the greatest audience that they serve and of their vision for the future,” she said. “The other piece of it is that it takes away one of the questions, and that question was ‘Who’s Sofia?’ ”

Sofia represented people with LCA, but some might not get that and think twice before reaching out to our organization, thinking, ‘I don’t know who Sofia is, the organization might not be right for me.’

“That only has to happen once to have an impact,” Southcott said. “To take away that question was key.”

She describes the essence of rebranding or renaming as carefully identifying a brand’s DNA and then capturing it in the new words, look, and feel of the name, the logo, and the tagline. By involving representatives from each stakeholder group and planning a careful rollout, she said, the organization’s supporters, constituents, and staff become champions of the reimagined brand.

“Hope: That was almost like a life raft that people jumped into. You have to focus on hope. It is too central for what this organization stands for.”

The name also reflects the human connection the organization makes with the LCA and IRD communities: “The warm embrace that Hope in Focus stands for.” The name also differentiated our group nicely from others in the field and that’s important for messaging, important for fundraising, and important for growth, she said.

“Some do offer that sense of hope, but you don’t get that from the name. The new name really had to convey that, and it had to underscore that the purpose is not only Sofia, but all the Sofias. “The hope component — that sets us apart.”

Science and research comprised the other piece folding into the mix, thinking about microscopes and getting a clearer focus on treatments and cures, especially with one gene therapy on the market and more developing research in clinical trials.

Southcott and her colleague Chance Martenson began with 40 possibilities for names and narrowed them to 12 after conversations with our founders, board members, staff, donors, and the people we connect with in the LCA and IRD communities. From there, they recommended three for consideration.

The name change or rebrand of our organization stood out among other projects she has done. “It was more an evolution of what existed, as opposed to a revolution or the creation of something brand new, where nothing existed before.”

Finding the right name also meant not disenfranchising people involved with our advocacy group. “There is this real sense of dedication to the organization and a yearning to protect it from anything else, Southcott said. At the end of the day, it had to serve the people that support it and use it.”

Our Future

We at Hope in Focus will expand the reach in our advocacy efforts and continue to grow as a small team doing big things, Manfre said. The vision for Hope in Focus is far reaching, and we are developing exciting ways to engage our community members and bring them together as we support them, and they support one another.

“We’ve been powered by a small team of part-time consultants and volunteers, and we’ve just recently
brought on board a full-time development and outreach director,” Manfre said. “To be able to continue to expand to meet the needs and the demands of the LCA and IRD communities, we need to keep growing. I view this as the first step in that growth.

“We’re checking all the boxes, working to fill unmet needs. This is much bigger than me and much bigger than Sofia. We only began something that is going to continue to grow, and we’re very excited about where it will go.”

Let’s Chat About … CRISPR and Gene Editing

For the first time, early research data shows that a gene editing technique called CRISPR improved vision in people living with a form of Leber congenital amaurosis (LCA), according to Dr. Edmond Chen of Editas Medicine.

“It’s the first time anyone has demonstrated the potential of editing in human eyes,” Dr. Chen said. “We kind of dreamed about this since 2014.”

Researchers administered EDIT-101, an experimental CRISPR gene editing medicine, through a subretinal injection to reach and deliver the gene-editing machinery directly to the retina’s photoreceptor cells.

The research targets LCA10 caused by a mutation in the CEP290 gene, the most common of the more than 27 forms of LCA.

Dr. Edmond Chen

Dr. Chen is the Vice President of Clinical Development at Editas Medicine, a gene editing company based in Cambridge, Mass. The company focuses on developing CRISPR-based treatments.

CRISPR (pronounced “crisper”) is an acronym for Clustered, Regularly Interspaced, Short Palindromic Repeats. It refers to a recently developed gene editing technology that can revise, remove, and replace DNA in a highly targeted manner.

As part of our Hope in Focus webinar series, Dr. Chen described the early, but exciting, data from the ongoing Phase 1/2 Brilliance clinical trial of EDIT-101 in our October episode: “Let’s Chat About…CRISPR and gene-editing technology.” Our Director of Marketing and Communications Elissa Bass moderated the session, which you can view here.

Dr. Chen oversees a portfolio spanning the therapeutic areas of hematology, oncology, ophthalmology, and neuroscience. As a physician executive with more than 20 years of combined clinical and industry experience, he has a track record of success at companies, including Merck and Bayer.

His therapeutic area and drug development expertise is deep and diverse, from rare disease and indications such as bronchiectasis, vasculitis, and pulmonary hypertension, to large cardiovascular areas including congestive heart failure, thrombosis, and therapeutics for primary and secondary cardiovascular prevention.

He earned his medical degree at the University of California, San Francisco School of Medicine, where he trained and practiced in internal medicine and cardiology. He holds a Bachelor of Arts with Honors in Molecular and Cell Biology, Neurobiology, from the University of California, Berkeley.

Exciting early results for CRISPR

Dr. Chen described his passion for innovation and his interest in developing life-saving treatments, including a new aspirin.

Then he thought to himself, “We probably don’t need another aspirin,” and pivoted this passion for innovation to life-altering research, including working with the CRISPR gene-editing treatment.

He has been with Editas since 2020; the company’s work on LCA10 began in 2014.

Dr. Chen said he is excited about the first results of the clinical trial and added that the research is part of an ongoing, current investigation of which “we’re not making any claims.”

Editas recently released early results of the first six patients in the EDIT-101 Brilliance trial at the International Symposium on Retinal Degeneration. Efficacy results were limited to the first five patients treated with the low- to mid-doses and followed for at least three months.

Two of the three patients treated with the mid-dose and followed for up to six months showed improved vision, results that suggest successful editing with EDIT-101. Patients will need to be treated and followed over time to ensure the safety and efficacy of the drug. EDIT-101 is now being assessed at a higher dose and in pediatric patients.

Editas currently is recruiting for children, ages 3 to 17. For recruitment information, contact Editas Medicine’s Clinical Trial Team at 617-401-9007 or patients@editasmed.com. For more information, go to clinicaltrials.gov NCT03872479.

CRISPR is a one-time treatment

Explaining the gene-editing process, Dr. Chen shared some biology basics on DNA, RNA, and proteins, and described the potential of CRISPR gene-editing to restore cellular function.

He described DNA as the building blocks of life, serving as a blueprint, or instructions, for all the proteins in our bodies. When the body reads the DNA, it makes RNA, which then acts like a messenger taking the instructions all over the body to make proteins. Proteins are the tools our cells need to function.

Sometimes, an abnormal change in DNA’s sequence (a mutation) causes disease. These changes can be spontaneous or can be inherited from parents. This is where CRISPR-based medicines come in. Gene editing technology may be able to treat some genetic diseases by intervening at the DNA level.

To demonstrate this process, Dr. Chen, using simple colored Lego® pieces to represent DNA and RNA, explained how CRISPR gene editing medicines contain a nuclease, or a protein that edits DNA, and a guide RNA that can go in and find a specific portion of the gene and make an edit to correct the gene abnormality.

People living with LCA10 have a disease-causing mutation in the CEP290 gene. For EDIT-101, scientists created a specific guide RNA to find the CEP290 gene in the photoreceptor cells and remove the incorrect instructions contained in the patient’s DNA.

The drug is injected one time in one eye under the retina, creating a blister-like pocket of the drug called a bleb for EDIT-101 to treat the target area that allows retina function. Dr. Chen characterized the treatment as an effective and precise process.

“The DNA is actually edited with the genetic defect corrected,” he said. “It’s a very elegant use of science for which the Nobel Prize was given, so this is a big deal.”

Jennifer Doudna, PhD, and Emmanuelle Charpentier, PhD, won the 2020 Nobel Prize in chemistry for their 2012 discovery of CRISPR.

Still a few years to market

One of our webinar viewers asked why the process can’t be used to treat all other forms of LCA.

“It’s a long road,” Dr. Chen said. “For good reasons, the regulatory path is a long one.”

The process can take 15 to 20 years, from molecular research to studying treatment effects in animals and then humans, to undergoing the rigors of earning approval by the U.S. Food and Drug Administration.

In 2017, the FDA approved LUXTURNA,® the first, and so far, only, gene therapy for a form of LCA. Gene therapy is different than gene editing. Gene therapy entails inserting a “healthy” version of the gene to offset the effect of the mutation, while gene editing revises, removes, or replaces a mutated gene at the DNA level.

This study of EDIT-101 centers on one form of LCA and it is in its initial stages, he said.

“Each of the defects, you could add it up and it’s a long, expensive and laborious exercise. It’s a commitment on our part. None of this is easy.”

He estimated that getting the CRISPR treatment to market is still a few years away.

In answer to a question about what keeps him going amid the arduous trial-and-error process that comes with clinical research, he said, some days are very frustrating, but he feels blessed to make a difference in someone’s life.

“It’s all about the patient,” Dr. Chen said. “That makes a world of difference and makes it all worthwhile.”