Category: Science Education

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 headshot
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.”

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 headshot
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.”

Let’s Chat About … the Importance of the Patient Voice in Rare Disease

We hear a lot these days about the necessity of the patient voice in developing treatments, especially for people living with rare disease, such as Leber congenital amaurosis (LCA) or other rare inherited retinal diseases (IRDs).

So, how does the voice of the patient manifest in helping speed up the process of drug development and bringing treatments to market?

In several specific ways, according to Jill Dolgin, PharmD, Head of Patient Advocacy at a clinical-stage biotechnology company. Here they are:

  • Get a confirmed genetic diagnosis through genetic testing to determine the underlying cause of the disease.
  • Add your voice to science by joining a patient registry that gives researchers necessary information for clinical trials.
  • Take part in Natural History studies that glean knowledge and an independent understanding of diseases over time.

People also should tell their stories and bring awareness to as many people as possible to help advance research.

Dr. Dolgin leads Patient and Professional Engagement Strategy at Applied Genetic Technologies Corporation (AGTC), headquartered in Alachua, Fla., with offices in Cambridge, Mass. The company develops transformational genetic therapies for IRDs, and Dr. Dolgin works to drive disease and clinical trial awareness efforts for the AGTC pipeline.

Sofia Sees Hope featured her in its September webinar episode: “Let’s Chat About…the importance of the patient voice.” Director of Marketing and Communications Elissa Bass moderated the monthly series.

Dr. Dolgin has more than 20 years of global pharmaceutical experience in Medical Affairs, Corporate Communications, Patient and Professional Advocacy, and Public Policy. She earned a doctorate in clinical pharmacy from the University of the Sciences in Philadelphia and a Bachelor of Science in pharmacy from The Ohio State University.

At AGTC, she ensures that patient needs are considered and incorporated into every aspect of drug development. Externally, she collaborates with patient advocacy groups, such as Sofia Sees Hope, to educate patients and families about the importance of taking part in clinical trials, gene therapy, and the value of listening to the voices of patients and their families to help the media, healthcare professionals, payors, and policymakers understand the challenges encountered by patients as they live with rare retinal conditions. 

Dr. Dolgin brings patient voices to the corporate table, noting AGTC’s mantra: “No decision about the patient without the patient.”

Genetic Tests, Patient Registries & Natural History Studies

Once a patient receives a clinical diagnosis of LCA, a genetic diagnosis via genetic testing is the next critical step toward advancing research. AGTC and Sofia Sees Hope provide funding to the Foundation Fighting Blindness (FFB) to help patients gain free access to genetic testing. 

More than 100 mutations could cause various forms of eye disease; a confirmed genetic diagnosis narrows the condition to one or more gene mutations. The next steps include finding whether a treatment exists for the condition, whether technology exists to correct the mutation, and/or whether clinical trials are underway for that condition.

That’s when joining My Retina Tracker® registry, a free and secure online registry launched by FFB, comes into play. Dr. Dolgin talked about the necessity of this bank of patient medical information that gives voice to the patient and a role in contributing to science by driving research for LCA and IRD treatment and cures.

With rare disease, where the history and progression of the disease over time is particularly poorly understood and unknown, Natural History studies should be conducted before beginning a clinical trial. 

Researchers gather specific information from patients to better understand a disease’s progression, using the data to assess whether an investigational treatment administered during a trial is affecting that progression. 

Incorporating the patient voice into the development plan goes beyond the clinical trial, she said. Patient and caregiver feedback should be considered throughout the development and commercialization of a product. For example, when developing the formulation of a product given by mouth, researchers need to keep in mind the specific needs of patients, whether they be children, elderly, or anyone with difficulty swallowing, and consider developing a liquid product.

They also should consider ease of use in product packaging. Just trying to open the medicine bottle can be daunting for someone with arthritis. She jokingly said safety caps should be labeled adult-proof, rather than child-proof, because they’re so often difficult to open. 

Becoming Part of a Clinical Trial

Dr. Dolgin’s job also includes discussing clinical trials as a treatment option and finding appropriate participants for clinical trials, a challenging task for developing treatments and cures for rare diseases with smaller pools of potential participants. A rare disease is one that affects fewer than 200,000 people. 

Patients considering taking part in a clinical trial need to understand the process of clinical development, the goals, and the expected outcomes for each stage of development, from pre-clinical animal studies to human studies, she said.

Researchers divide human studies into three phases. In rare disease studies, they combine Phase 1 and Phase 2 studies because of the small number of patients. They design these early-phase trials primarily to assess safety over a wide dosage range and to assess potential biologic activity or efficacy in a small number of patients. 

The final phase before Food and Drug Administration approval is Phase 3, in which researchers enroll a larger number of patients and administer the highest and safest dose given in the Phase 1/2 trial. The goals are to further assess any safety issues and evaluate the potential efficacy of a product in a larger number of participants. In rare disease trials, often fewer than 100 patients take part in each trial phase.

Even when a lot of people initially make up a pool of potential participants, those big numbers shrink fast when people understand the burden of time required to take part in the trial, including multiple scheduled visits in the first year of the trial. 

Most IRD trials last 5 years to determine long-term efficacy and safety. The time commitment can impact childcare, time away from school, work, and family commitments. Time and expense for another person to accompany a clinical trial patient with vision loss is another variable. The trial’s sponsor generally covers travel and lodging costs, but patients should confirm whether that is the case before agreeing to participate.

A potential participant with a clinical and genetic diagnosis may not meet all the inclusion criteria because of the severity of their disease (either too good or too severe), or because they may have other medical conditions that might interfere with medications provided during the trial or the medication under investigation. 

While more than a thousand gene therapy developers are out there, with 50 dealing with ophthalmologic drug development, Dr. Dolgin said, the road to a marketed drug is long and arduous, often taking 10 to 15 years from laboratory and animal studies to final approval for use in humans.

About a hundred trials for various eye diseases are in preclinical stages, with about 60 ongoing clinical trials. It’s a big trial-and-error process, she said, citing trial failure rates of 80 to 90 percent.

She described the two kinds of gene therapies on the market and in development, the first being gene addition, in which doctors insert a functional copy of the gene, and the second, gene editing, by removing the mutating gene and inserting the correct one.

Current AGTC Research Highlights

Along with AGTC’s patient advocacy work, Dr. Dolgin said the company has made exciting progress with three advanced clinical trials: 

The first deals with X-linked Retinitis Pigmentosa (XLRP). Retinitis Pigmentosa (RP) describes a group of rare genetic eye diseases that damage light-sensitive cells in the retina, leading to loss of sight over time. Of the 200,000 RP patients, about 10 percent have X-linked RP, in which a mother passes down the non-working gene to her male children.

AGTC just completed Phase 1/2 of the XLRP clinical trial and is currently  enrolling in a Phase 2 expansion trial and screening for participants for its Phase 3 trial to be initiated soon. 

Achromatopsia (ACHM), an inherited condition caused by mutations in one of several genes, is the subject of two separate Phase 1/2 clinical trials for individuals with a mutation in either the CNGA3 or CNGB3 genes. ACHM is associated with extremely poor visual acuity, extreme light sensitivity, and complete loss of color discrimination. 

AGTC completed Phase 1/2 clinical trial enrollment for both the CNGA3 and CNGB3 trials. 

Let’s Chat About … Patient Registries and My Retina Tracker

Join the My Retina Tracker® registry and you’ll be contributing to science by driving research to help improve your quality of life and to find treatments and cures for Leber congenital amaurosis (LCA) and other rare inherited retinal diseases (IRDs). 

The free and secure online registry launched six years ago by the Foundation Fighting Blindness is being updated and your feedback is needed. The organization currently is conducting a “user-experience” survey of its membership to glean new ideas to make the registry more effective for patients and for researchers, according to the Foundation’s Todd Durham. 

Now, through at least the end of June, you can contribute by taking the survey on the registry’s website and updating your profile. If you’re not already part of the registry, click here to join. The global registry has more than 18,000 members and is open to anyone with an inherited retinal condition and/or adult caregivers of children.

As the Foundation’s Vice President of Clinical & Outcomes Research, Durham is responsible for directing the organization’s Clinical Consortium of retinal experts, developing strategies to enhance product development, partnering with industry, and providing technical input on partnered programs and investment decisions.

The Foundation is the world’s leading private funder of retinal disease research and collaborates with patients, caregivers, researchers, and biopharmaceutical companies. That funding has been a driving force behind the progress toward cures, including the identification of more than 270 genes linked to retinal disease, and the launch of 42 clinical trials for potential treatments.

Durham discussed the patient registry and survey in our May webinar episode: “Let’s Chat About … Patient Registries and My Retina Tracker®.” Sofia Sees Hope Director of Marketing and Communications Elissa Bass moderates the free monthly webinar series. You can watch the webinar here. 

Durham earned a Bachelor of Science in Public Health, a master’s in biostatistics, and a PhD in health policy and management (Decision Science and Outcomes Research) from the University of North Carolina School of Global Public Health. He has more than 25 years of drug-development experience.

Understanding Patients and Retinal Disease Through Data

A patient registry is a planned collection of data around a disease. My Retina Tracker distinguishes itself from others by focusing on inherited retinal degenerations or diseases with the purpose to understand genetics, prevalence of conditions, and impacts of IRDs on individuals’ lives. 

The registry also enables researchers to find people for clinical trials, especially challenging work in the rare disease world of LCA and other IRDs.

Registry subsections include assistive devices, driving, visual symptoms, and the recently added “My Health Today,” a series of questions developed by the National Institutes of Health (NIH) to assess physical and mental health.

To become a member, click on ‘Register Now’ and follow the prompts to establish a username and password and to answer questions to build your personalized retinal health profile. You are then guided through a series of questionnaires developed by retinal clinicians, geneticists, genetic counselors, and rare inherited retinal disease researchers.

The registry becomes your personal retinal health record, updated by you and your doctors. Your history and testing results create a critical resource in tracking the progress of your disease and becoming part of a comprehensive database. It employs state-of-the-art technology to protect privacy and adheres to the highest standards of confidentiality and ethics.

Your disease information is accessible only to you, Foundation registry staff, and researchers who meet a rigorous scientific review application process to use the data for studies and to reach individuals to participate in clinical trials, Natural History studies, or focus groups. Your personal information is never shared with researchers.

It’s important to update your profile because the data unique to those living with LCA and other IRDs gives researchers a trove of opportunities for studies. The more complete the profile, the more likely you are to be contacted about a research opportunity. 

“Many of our research collaborators may approach us with a research idea and a certain criterion they want to apply to their study, and we use as much data in the profile as we can to help find the right target for that study,” Durham said. “As your vision changes, as your life situation changes, we’d like to know the milestones along the way. That’s informative information.”

Enhancing Patient Registries through Survey Feedback

An important improvement to the registry would be the ability to highlight to its members the research emanating from the information given by registrants. Completing the survey and giving specific feedback will help accomplish this.

“The key focus right now is delivering back to the members some information that they find useful, that shows that they are contributing to science.”

The Foundation also wants to engage its registry membership more regularly with information tailored to profiles.

“Speaking with a number of individuals involved with the Foundation, they say ‘it sure would be nice if when I tell you that my gene is, let’s say, EYS that you could tell me more about people like me.’ We’re looking into some ways that we can collect that data, put it in a way that’s understandable, digestible, presentable, and make that available to our membership, the registry.”

Results from the user-experience survey will be central in making the registry more valuable.

“As much as possible we really want folks’ feedback and, in this survey, we ask about their experience not just with the registry itself, but also with our genetic testing program, which many people have been able to take advantage of.

“We’re in a rapidly evolving research field; we’ve got new therapies coming all the time. To me, it’s important to put in mechanisms where we can learn along the way, and we’ll want to get as many indicators as possible.” 

Patient Registries: Making a Difference Through Research

Every month, six or seven researchers contact the Foundation for access to the registry, Durham said. One proposed study would look at patient experience with genetic testing and counseling. 

“How did that counseling session change the way they view their life, what impact did it have on them? This is very promising and interesting research. When we saw this, we thought this is very relevant for our members and for our community in general because we believe genetic testing is hugely important. 

“From my conversations with individuals, that moment when you have the clarity of a genetic diagnosis is kind of a day that you remember. It is now the time where I can at least ask the question, ‘what is the typical progression for folks like me? Are there research opportunities for me? What are the research prospects for people like me?’

“All this research can make a big impact.”

One project using registry data produced an analysis estimating the cost of illness for an IRD – an economic burden of up to $31.7 billion in the United States.

“When you see the paper as to the estimated cost to the U.S. of the IRDs, that study result came because people participated in the My Retina Tracker registry.” 

The Foundation plans to prepare reports or peer-reviewed publications out of the registry over the coming years to show the research community how much can be learned about what life is like with an IRD.

Patient Registries Put People at the Center of Research 

The registry also is an integral part of patient-focused drug development, a national concept organized by the U.S. Food and Drug Administration to put patients at the center of research. 

“This is a unique thing that the Foundation is doing to make sure we don’t lose sight that there are humans, there are people and lives that are impacted by research.” 

In a partnership as part of this patient-focused research, Sofia Sees Hope and the Foundation conducted intensive workshops on the CRB1 and IQCB1 genes that included the voices and perspectives of patients and their families, along with dozens of leading experts.

Another example of patient-centered research is the collaboration between the Foundation and the biopharmaceutical industry to study males with X-linked retinitis pigmentosa (XLRP), an incurable genetic disease that causes blindness in men and affects about one in 15,000 people.

“We’ll be surveying people through our registry and then convening a panel of experts and inviting the FDA to attend a workshop about results of the work and also inviting affected individuals and their caregivers to tell us what life is like with XLRP,” Durham said.

Living in a Time of Hope

Retinal research has come far, with more than 40 clinical trials underway.

“This is an exciting time, and I don’t think it’s an exaggeration to say, which should be a great time of hope, because 10 years ago there were not a whole lot of treatments to talk about,” he said, “and now even as the Foundation stands, we struggle to keep up with all the latest news amongst therapy developers.”

Not all therapies work out, but researchers learn a lot in the process of product development.

Also, conditions once thought to have been impossible to treat now have multiple therapeutic approaches, with even more in the pipeline.

Durham said, for example, neuroprotection, which is the relative preservation of neuronal structure and/or function, and neuroprosthetics,* implantable medical devices that provide some degree of vision to people with blindness.

“If we can just slow down the further degeneration of the photo receptors that could be really helpful, that could add hopefully years to vision. Gene therapy has the potential in many cases to restore vision that was lost. And you have even new technologies for later-stage disease, like (visual) neuroprosthetics.

“It’s pretty amazing technology that’s coming out.”

Let’s Chat About … Why Natural History and Patient Outcome Studies Matter

Amid the intricacies of researching treatments and cures for rare diseases, such as Leber congenital amaurosis (LCA) and other inherited retinal diseases (IRDs), the patient remains the major focus.

Researcher Jonathan Stokes says he takes a holistic approach in developing and evaluating patient-health outcomes in clinical trials that include focusing on signs and symptoms of disease, health-related quality of life for patients, understanding unmet needs, and exploring the burden of disease.

“Patient voices matter,” he said.

Stokes is Director of Patient-Centered Outcomes Research for AbbVie, a Chicago-based biopharmaceutical company. He holds a Master’s in Business Administration from Northeastern University and has a devoted interest in understanding and bringing to light the patient voice and perspective, with more than 16 years of research study design and implementation experience.

He primarily works in health-outcomes research, specifically developing and evaluating clinical outcomes of assessments (COAs) used in clinical trials to substantiate treatment benefit.

Sofia Sees Hope featured Stokes in an April 19 webinar episode of “Let’s Chat About…Why natural history and patient outcome studies are important.” Elissa Bass, Director of Marketing and Communications for Sofia Sees Hope, moderated the session that is part of the organization’s free, monthly webseries. 

We developed the series with the LCA and IRD communities in mind but invite all members of our community, including those in research, industry, and the regulatory communities to join any of the sessions as we look ahead to a common goal of advancing treatments for rare retinal disease.

Objective Versus Subjective Gauges

Patient-centered outcomes are evaluations of a patient’s health status and provide valuable information on how patients feel and function.

Vision measured by navigating a maze renders a tangible, objective result, as do blood tests that reveal cell counts or measures that evaluate tumor size in oncology. 

Certain conditions, or aspects of a given condition, express themselves in ways only known to the patient, such as fatigue with mitochondrial diseases or pain with migraines. These subjective experiences can be assessed in studies and through outcome measures, such as daily diaries or questionnaires. These assessments involve years of qualitative and quantitative research, and they are designed after consulting with patients, their caregivers, doctors, researchers, and literature. 

This information literally is the patient’s voice.

Stokes says, “For me, the question is always the ‘So what?’ What does that mean to the patient?’ ”

He takes an inclusive approach to developing measurements for patient outcomes, considering quality-of-life elements – the effects of a disease emotionally, socially, physically, and in daily activities – to produce valid, reliable results.

“Even if you are not taking part in a clinical trial, these are all steps that need to be done to make sure we’re doing it the right way.”

The information, in turn, is shared back with the patient community. 

“These kinds of things matter to people,” he said. “Their feelings are not just idiosyncratic to themselves.”

This research is critical to the drug approval process and important to all stakeholders – patients, care givers, researchers, regulators, and drug developers – to create what Stokes calls a true partnership.

Health-outcomes research plays an important role in the U.S. Food and Drug Administration’s Center for Drug Evaluation and Research that specifically targets patient involvement through its Patient-Focused Drug Development (PFDD) program.

“PFDD is a systematic approach to help ensure that patients’ experiences, perspectives, needs, and priorities are captured and meaningfully incorporated into drug development and evaluations,” according to the FDA.

The goal is to better incorporate the patient’s voice in drug development and evaluation, which ultimately results in an FDA-published document called “Voice of the Patient.”

Long-term Tracking

Natural History studies also are important to patient outcomes because they reveal the patient experience over time as researchers observe features in the absence of any treatment. These data give knowledge and an independent understanding of the disease, while establishing an essential foundation for building drug development programs. A Natural History study also can be used as a control arm serving as a placebo in a clinical trial.

The studies track the course of a patient’s disease, identifying demographic, genetic, environmental, and other variables that shape the drug development process. They give scientists and researchers a better estimate of the prevalence of the disease, help identify biomarkers, affect clinical outcome assessments, and determine the feasibility of established assessments for clinical trials. 

More than ever, Stokes said, all stakeholders in the drug development process come together and work toward a solution best for the patient.

“Patients are at the center of everything we do.”

Let’s Chat About … Genetics and Inherited Retinal Disease

You or your loved one just received a clinical diagnosis of Leber congenital amaurosis (LCA), a rare inherited retinal disorder caused by a mutated gene. The disease causes severe vision loss at birth and affects the peripheral rod cells that allow night vision and the central cone cells  responsible for fine detail and color vision. What now?

The next most important step is to get a genetic test for a confirmed genetic diagnosis to clarify the underlying genetic explanation of the disease. Finding the specific gene causing the defect is critical for moving forward with research and treatment.

Genetic counselors like Emily Place help navigate the complex world of gene mutations, genetic testing, and genetic diagnoses. She is among the more than 4,700 certified genetic counselors nationwide, and she specializes in counseling families living with inherited retinal diseases (IRDs). 

Place, a Licensed Genetic Counselor and Research Study Coordinator at Massachusetts Eye and Ear (MEE), discussed her role in the ever-evolving world of genetics in our March webinar episode: “Let’s Chat About…the ins and outs of genetic testing.” Sofia Sees Hope Director of Marketing and Communications Elissa Bass moderated the monthly series, which you can watch here. 

Place began her work at MEE’s Ocular Genomics Institute (OGI) in 2011, about the same time the first clinical trials were underway for a vision-improving gene therapy. Six years later, researchers identified, and regulators approved LUXTURNA®, the first gene therapy treatment for an inherited disease, and specifically for LCA2-RPE65, one of the more than 25 gene mutations associated with LCA.

Before OGI, Place worked as a pediatric genetic counselor at Children’s Hospital of Philadelphia, the same place researchers and Spark Therapeutics developed that RPE65 gene therapy.

She earned a Bachelor of Arts in Biology from the University of St. Thomas and her master’s degree in Human Genetics from New York’s Sarah Lawrence College, which in 1969 established the first graduate degree program in genetic counseling. With ever-expanding genetic studies, the profession dramatically increased with more than 50 programs now in the United States.

Basic Genetics

The Human Genome Project (HGP) began in 1990 as an international, collaborative quest to map and understand all the genes of human beings and their roles in health and disease. The project, completed in 2003, revealed there are probably about 20,500 human genes, referred to collectively as our genome, according to the National Human Genome Research Institute.

Scientists have since identified more than 30,000 genes in our body and more genetic causes of inherited conditions, and more research remains to be done to better understand the causes of inherited conditions and to identify more genes.

“Genes are instructions or blueprints that tell us how to grow and function,” Place said.

This genetic information is organized in our chromosomes and can be found in every cell of our body. 

More than 200 genes have been identified as playing a specific role to help retina function.

“These inherited retinal conditions can arise because of a genetic variation or change within a gene that we know is important for retinal function and, what we really mean here, is that this genetic change is changing the genetic code in some sort of way that is causing the gene not to function properly within the retinal cells.”

With a few exceptions, she said, a general eye exam will not reveal the underlying genetic explanation for retinal disease.

“That’s where genetic testing is necessary to rule in or identify which one of these 200-plus genes could be the underlying explanation and thus, more definitively rule in an inherited condition and provide a more definitive specific genetic diagnosis.”

The most common pattern for inherited retinal diseases to occur is a recessively inherited condition, the result of inheriting a genetic variation in two copies of the gene, one of those copies inherited from mom and one from dad.

“In these recessive conditions, generally, there may be no family history of anybody else in the family with similar conditions, and that’s because individuals can be carriers, and they may carry one copy of a variation and one copy of their gene, but they have another that can compensate. 

“Carriers can be asymptomatic and run through multiple generations and not even know that they’re carriers, and it isn’t until two carriers meet that there’s even a chance for both of them to pass on the genetic change.”

Specific Genetic Identification Versus No Clear Explanation

Counselors help in multiple ways as a family or patient is working toward a genetic diagnosis. Place can begin counseling families before testing, gleaning family history details, reviewing complexities of different inheritance patterns, and looking into what can and cannot be learned from testing.

“It’s also exploring with patients and families whether this is the right time for genetic testing. Is this something that the individual is ready to move forward with or is it something that maybe should be discussed or pursued a later time?”

Counselors can work with families after testing, reviewing the result, whether it be that the testing identified a specific gene or that no clear explanation was found, which happens 30 percent of the time, Place said. 

No clear explanation could mean a negative result or an inconclusive result. A negative result can mean no genetic variations were identified. An inconclusive one could be that variants were identified within one to two genes, and the lab does not currently have enough data to classify those variants as disease-causing, but they also cannot be ruled out as not disease causing, she said.

“Sometimes additional testing of other family members may be helpful in resolving the significance of those variants, or that it’s going to take some time and more genetic knowledge is needed to better classify those variants.”

Working with a counselor also helps sort out next steps to take, including the possibility of periodically checking back with your genetic counselor to see if more recent research has updated results or new testing options.

“A True Privilege” To Create Relationships

Long-term relationships can develop between counselors and families after testing. If the test identified a specific gene, they discuss the result, assess the risk of other family members having the mutation, coordinate whether they should get tested, and maintain communications going forward about potential genetic-related treatments and therapies. 

Place said it may not be the case with every counselor, but long-term relationships with families are the norm in her work.

“I think every clinic and counselor’s experience will be a bit different. I have the true pleasure of working within an IRD clinic where we’ve had long-term relations with the families, and I get to see families back over the course of their visits with us, and so it is a true privilege to be able to create these longer relationships with families.”

Her approach to testing is that a patient diagnosed with any type of IRD should undergo a full IRD panel testing so as not to miss a particular gene. 

She also said it’s important for the patients and families to have back-and-forth relationships with their ophthalmologists.

“It’s definitely a two-way relationship, continuing to stay engaged with your providers, but your provider also thinking about being on top of the different testing options that are available.”

Getting Genetically Tested

A person needs a doctor’s order to be genetically tested. Diagnostic testing is done on a patient’s blood or saliva sample at a clinically certified lab that analyzes a specific set of genes identified to be the cause of retinal condition.

Whether you are living in a rural area or a city, you can find genetic counselors and information about testing through the National Society of Genetic Counselors (NSGC) or local genetic providers through the American College of Medical Genetics and Genomics (ACMG).

ACMG is a place to locate a Medical Geneticist (MD/physician), as well as medical genetics clinics. The search ‘Find a Genetic Service’ can be used to locate a genetic professional.

Search engines in both organizations bring up regional options by entering your zip code. Counselors can meet in-person with patients or, depending on the clinic, via telehealth, by phone, video conferencing, and other virtual methods.

Testing resources also can be found through medical or clinical genetics’ departments in your hospital system.

Also, Sofia Sees Hope has donated more than $140,000 to fund free genetic testing for individuals with inherited retinal disease through the My Retina Tracker® program, launched and managed by the Foundation Fighting Blindness. The program is an open access, no-cost genetic testing program for individuals with a clinical diagnosis of an IRD.

“So much has changed in terms of access to genetic testing for inherited retinal diseases over the last several years, and it’s more available to patients than it ever has been in the past. I would say this is really a good time to work toward getting a genetic diagnosis – getting genetic testing if you haven’t had it or re-engaging with your providers if you’ve had testing years ago without a positive result and discuss updated testing options. 

“There are resources out there and available, so there are plenty of individuals like me that are available to help facilitate testing or get you in touch with the right counselor or medical geneticist to help facilitate testing for you.”

“Let’s Chat About …” Webinar Provides Insight Into How the FDA Handles Rare Disease Treatments

Researchers and regulators did not miss a single step in the fast-tracked federal process of developing successful COVID-19 vaccines. And the same goes for fast-tracking gene therapies for rare disease treatments, Dr. Wiley A. Chambers II of the U.S. Food and Drug Administration said during a recent webinar hosted by Sofia Sees Hope.

As the Supervisory Physician in the FDA’s Division of Ophthalmology, Dr. Chambers discussed vaccines and processes necessary for drugs to be approved for human use in our February 16 webinar episode: “Let’s Chat About…What it takes to receive approval for a new treatment for rare disease.” Sofia Sees Hope Director of Marketing and Communications Elissa Bass moderates the free monthly webinar series. You can watch the webinar here.

Dr. Chambers joined the FDA in 1987 as a primary reviewer for ophthalmic drug products and in 1990 became a Supervisory Medical Officer for Ophthalmologic Drug Products. He has supervisory responsibility for the clinical review of ophthalmologic drug products and ophthalmic therapeutic biologic products submitted to the Center for Drug Evaluation and Research.
He has clinically reviewed more than 100 ophthalmology drugs that have received FDA approval, including the first gene therapy, LUXTURNA®, approved in December 2017. The drug – administered through subretinal injection – is a human-engineered virus containing a healthy version of the RPE65 gene that causes blindness in patients with a form of Leber congenital amaurosis (LCA) called LCA2 (RPE65).

Vaccines: “We’ve Got That Down”

Talking about the recently authorized COVID-19 vaccines, Dr. Chambers said it wasn’t a matter of starting from scratch.
“We know how to make vaccines. We’ve been making vaccines for over a hundred years. We make new vaccines every year. The flu shots that come out are a change in the vaccine every year and we put a vaccine out every year that’s specific to different strains of the flu. Every year. So, we’ve got that down.”

The process did differ in two aspects because of the urgency to quell the pandemic.

“What happened with COVID is the federal government said, ‘You companies go make the vaccines. We’re still going to go through the normal process of testing it, having the FDA go and review it, but don’t wait to see if the product works or not before you make up all those doses. Make them now. And we’re going to pay you for them whether it works or not.’

“So, the companies went and did that. We didn’t skip any steps. We know how to make vaccines. We did what we typically know. We made a series of vaccines and at the same time the companies were mass-producing, as everybody would suggest now, not enough, but made a number of doses out so that when the products got approved, they already had doses made. They didn’t have to start manufacturing doses.”

The second distinction is COVID-19 – which has killed more than 550,000 Americans and more than 2.6 million people worldwide – created a public health emergency requiring urgent mitigation.

Rather than getting FDA approval or clearance, COVID-19 vaccines received Emergency Use Authorization (EUA), one of several tools the FDA is using to help make certain medical products available quickly during the pandemic. Under an EUA, the FDA makes a product available to the public based on the best available evidence, without waiting for all the evidence that would be needed for FDA approval or clearance.

EUAs are effective until the emergency declaration ends, and they also can be revised or revoked by the FDA as it continues evaluating available data and patient needs during the public health emergency.

Developing gene therapies to improve vision also meets fast-tracking requirements because vision loss is considered serious. Fast-tracking gene therapy in ophthalmology means extra meetings and FDA communication.
“But you’re not skipping any steps at all,” Dr. Chambers said.

Improving Visual Acuity

The FDA is a gatekeeper requiring that a product be safe and efficacious for its intended population before it can be marketed for human use. Dr. Chambers regularly talks with patients and solicits comments from groups about what is important to them in the search for potential treatments or cures. The information then can be modified into endpoints, or outcomes, measured scientifically through clinical trials.

“We strive to approve products that are going to benefit patients. That’s who’s going to take them. That’s who they’re for, that’s what we’re trying to go and match.”

Dr. Chambers said his personal preference is cures.

“I like diseases to go away. My endpoint, if given the choice, would be to have something go away. But I’ve got to have a product that’s capable of doing that too, so there’s a reality that sets in that I may not get a product that cures, that does everything I would like it to go and do, but we strive for as many of those things as possible and to then try to include them in the trials.”

As an example, he cited visual acuity (clarity of vision) and the ability to drive.

“For better or worse, in the United States, if you want to be independently mobile, as far as living alone in many parts of the country, you have to be able to drive…and every state in the United States has a visual acuity value that if you’re not at the visual acuity or better, you can’t get a driver’s license…

“We think visual acuity is an important thing to be able to improve for patients. Not because they say they want it but because we know if they don’t achieve that level, they’re not going to be able to drive and they’re not going to have the mobility that we know people want.”

Whether someone can see better in some aspect is an important endpoint, even if it means vision is not completely restored.
“I frequently make the comment that my head is going to hurt just as much if I get hit by a ball that I saw or that I didn’t see. If I have a blind spot and I can now not see a ball coming to me and I get hit with that ball, it’s going to hurt. It would have been nice if I had had the full field of vision so that I could see the ball coming and avoid it. So, if I improve my field of vision, even if it’s not dead center, even if it’s not visual acuity, it’s still a benefit to me.

“You’ll see us potentially approve products on things less than fixing the whole thing, but fixing some portion, and again, we’re absolutely open to suggestions by people of things that they think benefit them that we could use as endpoints.”

Research Models

Mice and rats, cats and dogs, rabbits and monkeys – they all play important roles in developing new treatments and drugs. With inherited retinal disease, dogs take the cake.

Researchers use animal models that most resemble humans, and in the case of LCA, studies showed dogs gained improved vision, leading to the federal approval of the groundbreaking drug LUXTURNA®.

Lancelot, a Briard descended from an ancient breed of large herding dogs in France, carried the same RPE65 gene that caused his blindness.

By contrast, rats would not make for good study models in retinal research because they do not have a macula.
“Rats are more interested in going around in the dark. Their eyes are different,” Dr. Chamber said. “You want to pick an animal that has similar receptors in that species.”

Lancelot and his cousins paved the way for FDA approval of the first-ever gene therapy for inherited disease in humans.

Road to Approval through Clinical Trials

The goal of the FDA is to approve a product proven to be safe and efficacious. The product’s potential adverse events are weighed against its benefits in the balancing act of risk versus reward.

The agency regulates interstate commerce, acting as a gatekeeper for any product intended for human use. Because a biotechnology company probably wants to ship the investigational drug to clinical investigators in many states, it first must seek an exemption from that legal requirement. The exemption is granted after the company submits its research for review.
“If we say nothing, they’re allowed to proceed. If we have an objection, we tell them in 30 days.”

The company can move forward with trials after the FDA assigns an Investigational New Drug (IND) number.

Beware of phony trials, Dr. Chambers said. The website clinicaltrials.gov lists both trials that have been issued an IND number and those overseen by the FDA. It also lists trials not reviewed by the FDA.

“First thing: Ask what the IND number is,” he advised. Dr. Chambers noted that clinical trials, for better or for worse, are never conducted for the people in the trial. They are geared to inform what is going to happen in the future with the product.
Rare diseases – such as the more than 25 forms of LCA and other rare inherited retinal diseases (IRDs) – present bigger challenges in finding participants for clinical trials because the rare disease community inherently represents fewer people. The definition of a rare disease in the United States is one affecting fewer than 200,000 Americans.

If only 30 people are studied, you are likely to see adverse events that occur in 10 percent or more of individuals, he said. If you study 300, adverse events can be picked up at a rate of 1 percent or above.

“It’s all about the numbers, numbers, numbers, numbers…It’s a numbers game.”

The process wends its way through more protocols, comparisons, studies, and trials until a company submits a marketing application reviewed by experts at the agency.

The FDA may hold Advisory Committee meetings for public comment from external reviewers, special government employees, patients, consumers, and advocates. In the case of LUXTURNA®, Sofia Sees Hope Co-Founder and Board Chair Laura Manfre testified at an Advisory Committee meeting on behalf of Spark Therapeutic’s application.

FDA oversight does not end after it approves a drug and a biotechnology company begins marketing it for human use.

“We now start monitoring for adverse events that might occur with the product,” Dr. Chambers said.

The process of receiving federal approval of products for human use can be long and expensive: LUXTURNA® research, development, and approval took 12 years and $500 million. The rewards, though, can be priceless, in helping children and adults see the world in a new light.

‘Let’s Chat About …’ Webinar Offers LCA Overview and Updates on Clinical Trials

In the debut of Hope in Focus (formally Sofia Sees Hope) ‘Let’s Chat About …’ monthly webinar series, Ben Shaberman of the Foundation Fighting Blindness, provided his Zoom audience with a plethora of information about Leber congenital amaurosis (LCA), highlighting some of the more than 40 clinical trials underway to find treatments and cures for LCA and other rare inherited retinal diseases (IRDs) and giving updates on promising preclinical research. 

The recorded webinar aired 1 p.m. Wednesday, Jan. 27, 2021, and can be seen here. Elissa Bass, our marketing and communications director, moderated the session.

Shaberman, Senior Director, Scientific Outreach & Community Engagement, stumbled across a science writing position at the Foundation Fighting Blindness 16 years ago without a clue about retinas or blindness. He called his move to the Foundation serendipitous. He knew he made the right choice after hearing retinal researcher Dean Bok, PhD, tell attendees at a 2005 Foundation conference how he was drawn to the field by the seduction of the retina’s myriad complexities and inner workings.

Shaberman, too, felt pulled by the intriguing science of the retina.

As such, so are the 27 forms of LCA that cause varying kinds of visual impairment within each gene mutation and within each affected person. An estimated 8,000 people in the United States have LCA.

The path of retinal research

Shaberman took his audience from the beginnings of identifying the RPE65 gene in 1993 and learning shortly thereafter it could lead to LCA, to using mice models and later studying Briard dogs that had the same gene mutation that caused LCA in humans. A clinical trial at Children’s Hospital of Philadelphia led to the 2017 FDA approval of the breakthrough gene therapy LUXTURNA®, developed by Spark Therapeutics. The drug successfully improved the vision of many of the LCA2-RPE65 patients who received the treatment through subretinal injections.

When children receive an LCA diagnosis, their families should find a good retinal specialist, get regular exams, and ultimately get a confirmed genetic diagnosis to be on the path to more specific information and research into that form of LCA, Shaberman said.

Families also should register with the Foundation’s My Retina Tracker®, a free and secure online registry that facilitates getting a confirmed genetic diagnosis by making registrants eligible for free genetic testing.

The registry becomes your personal retinal health record, updated by you. It employs state-of-the-art database technology to protect privacy and adheres to the highest standards of confidentiality and ethics. 

It also notifies registrants of clinical trials and gives researchers access to their disease data – not their personal information – to advance research and therapy development associated with LCA and IRDs. 

Reading research publications and attending events sponsored by the Foundation and by Sofia Sees Hope also provide opportunities for families to interact and learn the latest research. Shaberman and Bass encouraged people affected by LCA and their families to contact them, respectively, through the Foundation’s website and/or the Sofia Sees Hope website for specific information on clinical trials or other questions and concerns about living with LCA. 

“Yes, it’s work,” Shaberman said. “You have to be your own advocate and your own child’s advocate, but more and more information is becoming available, and that’s the good news.”

More than 40 clinical trials underway

Shaberman also reviewed some of the more than 40 retinal clinical trials in the pipeline for LCA and other IRDs:

Join us Feb. 16

February’s “Lets Chat About …” webinar airs at 3 p.m. ET, Tuesday, Feb. 16. Our guest will be Wiley A. Chambers, MD, Supervisory Medical Officer for the Office of New Drugs, Center for Drug Evaluation and Research at the U.S. Food and Drug Administration. Register here.

Reflecting on the Trajectory of IRD Research

When I joined the Foundation Fighting Blindness as a science writer in 2004, I really didn’t know what I was getting into. I knew nothing about the retina, let alone the complex and diverse world of rare inherited retinal diseases (IRDs) that includes Leber congenital amaurosis (LCA). But the research for treatments was cutting-edge and compelling, so I was excited to dive in and learn.

My early assignments were writing about laboratory studies coming out of academic labs. There were virtually no companies in the IRD space and only one or two clinical trials underway for emerging therapies. But there were a lot of studies of genetically engineered mice and rat models of IRDs for gaining a better understanding of disease pathways and testing potential treatments.

Truth be told, I often wondered if and when rodent-tested therapies were really going to make it into human studies and out to the people losing vision. But the scientists conducting the research were mind-blowingly smart and innovative, so I figured they knew what the heck they were doing. With a master’s degree in poetry, who was I to judge?

Fast forward about four years: I was in my hotel room in Fort Lauderdale – there for the annual Association for Research in Vision and Ophthalmology conference – when my manager called and told me three research groups just reported vision improvements in young adults treated with RPE65 gene therapies in Phase 1/2 clinical trials. That was the breakthrough we’d all been waiting for.

People, rather than animals, with severe vision loss were now seeing significantly better. It was the first time an IRD treatment had worked in humans. I will never forget the headline for the article I immediately wrote: “Now They See.” (Note: One of those RPE65 gene therapies later became LUXTURNA®, the first FDA-approved treatment for the eye or an inherited condition.)

After many years of painstaking work, our hope for treatments and cures had finally begun evolving into promise.

There have been several other aha! moments in the ensuing years, but I distinctly recall cathartic encounters at the 2019 American Society of Retinal Specialists in Chicago. As I perused the snack table during breaks (the accomplished snacking professional that I am), several representatives from biotechs developing IRD therapies – companies I’d never even heard of – came up to introduce themselves to me and tell me about their emerging IRD treatments. They didn’t know me or my role, nor had I previously known them; they were just eager to connect with someone from the Foundation Fighting Blindness to get on our radar screen.

I realized then I couldn’t keep track of all the companies (dozens) focused on IRDs and clinical trials (40-plus) underway for potential IRD treatments. But being overwhelmed felt incredibly good, and it meant more good news likely was on the horizon for saving and restoring vision.

While mouse studies are as critical as ever, I can’t remember the last time I wrote an article about one. That’s because most of my writing is now dedicated to reporting on advances, including encouraging vision improvements, being made in human studies.

Make no mistake: Much more work needs to be done before we eradicate the myriad IRDs affecting millions of people across the globe. And, of course, we cannot get more therapies across the finish line fast enough. But when I look at how incredibly far we’ve come since those early days of mice and rats, I have no doubt we are well on our way to breaking many more ribbons soon.

Clinical Trials and Emerging Research Show Promise for LCA Treatments

Forty clinical trials and a lot of pre-clinical research into LCA treatments show promising pathways to discovering the next LUXTURNA®, according to Shannon Boye, PhD, the opening speaker for the Virtual VISIONS 2020 conference, presented earlier this summer by the Foundation Fighting Blindness. 

The breakthrough drug developed by Spark Therapeutics marked a milestone in the history of genetic research as the first gene therapy in the United States for any inherited disease and as the first to treat one of the more than 25 forms of Leber congenital amaurosis (LCA).

Shannon Boye, PhD in a lab coat
Shannon Boye, PhD

Boye, along with Foundation Chairman of the Board David Brint and Foundation Chief Executive Officer Benjamin Yerxa  PhD, kicked off the three-day, first-time virtual conference, the Foundation’s major annual gathering. Rather than convening in person, the event’s speakers, exhibitors and more than 1,600 attendees participated through an online app, due to concerns surrounding the coronavirus pandemic.

Brint said that the 40 clinical trials and more emerging treatments for various IRDs span the disease profile.

“No matter what your disease is, these hopefully will be able to restore vision,” Brint said. “In the next 10 years, we have an opportunity to bring many more vision-saving treatments into and through the pipeline and across the finish line.”

Yerxa said the topic of genetic therapies would be good to lead off with because of the sheer variety of innovative programs and approaches to each therapeutic challenge.

“There’s essentially a revolution happening right now in personalized medicine and genetic therapies in general,” Yerxa said.

Boye, an assistant professor in the Department of Ophthalmology at the University of Florida, addressed the audience in the beginning session called: “Mission Possible! What’s Next?”

She discussed three major strategies in treating LCA and other IRDs: Gene supplementation or gene replacement therapy, RNA therapeutics and gene editing. 

Boye set up an analogy to better understand the complexities of these strategies, saying we all have little letters in our bodies called DNA. Subunits of those letters – that DNA – are genes. RNA carry the instructions from DNA for making proteins, the building blocks of life.

“They act alone or in concert with a bunch of other proteins to perform essential functions.”

Continuing her letters analogy, Boye said, imagine a friend texts you: ‘Please take out the dog.’ You get that message and perform that function because letters combined correctly to tell you to take the dog out. 

If only the word ‘Please’ appears on your phone screen, you don’t take the dog out.

Or, if the ‘d’ is pushed and an ‘l’ comes out, sending the message, ‘Please take the log out,’ “you then have a mess to clean up,” she quipped.  

In the first strategy of gene supplementation or gene replacement, the right protein needs to be expressed in the patient’s retina. 

The letters need to be correctly sequenced to generate a coherent message, in this case, telling a protein to perform an important function. Any break in that cascade of events can cause visual impairment. 

The gene replacement therapy LUXTURNA is a human-engineered virus containing copies of the corrective gene that doctors deliver through a subretinal injection so the cells can make the originally missing protein.

“You deliver the right letters that make the right message and the right protein,” she said. “That’s a pretty simple concept. That’s LUXTURNA.”

Developed to improve vision in people with LCA2* caused by a mutation in the RPE65 gene, LUXTURNA received Food and Drug Administration approval for  use in humans in December 2017. 

One area of Boye’s research as Associate Division Chief of Cellular and Molecular Therapeutics is entering into a Phase 1/2 clinical trial, applying the same premise for mutations in the GUCY2D gene that causes LCA1. 

“It’s early,” she said. “But this is an example of another perhaps next LUXTURNA being right around the corner.”

She cited similar research moving forward on other IRDs, including Retinitis Pigmentosa (RP), Choroideremia, and Bardet Biedl Syndrome (BBS). 

The second strategy is a form of RNA therapeutics that uses antisense oligonucleotides (AONs) – short, single-stranded DNA  molecules that interact with messenger RNA to correct translation of a targeted gene. Think of an AON as an autocorrect feature that binds to the ‘l’ in log and changes to a ‘d’ for dog.

Promising pre-clinical work now in Phase 2/3 for CEP290 or LCA10 also is coming out of Rob Collin’s research group in The Netherlands, Boye said.

Another AON program underway addresses a form of Usher Syndrome. 

The third strategy – the newest and most exciting – is gene editing. A guide RNA is used to drag a special enzyme to a region in the DNA that contains the mutation, and the enzyme cuts the DNA, like molecular scissors. 

Researchers are exploring a host of gene editing variations, including cutting out a specific area of DNA and replacing it with the right letters to make a coherent message. The lab work has created paths to address a range of IRDs, including CEP290,  Usher Syndrome,  RP, Stargardt Disease and Choroidermia.

“There’s an absolute exponential increase in the therapies that are being developed,” she said.

These strategies are not limited to the disease conditions under discussion and can be more widely applied to a number of genes and conditions.

Addressing those who do not have RPE65 or LCA2 for which a treatment exists, Boye said, with all of this research in progress, “that one day, there’s going to be a LUXTURNA for your inherited retinal disease, too.”