Let’s Chat About … RARE-X with Karmen Trzupek

Through global data sharing and analysis, the nonprofit RARE-X (the research arm of Global Genes) is working to accelerate treatments for rare diseases, including Leber congenital amaurosis (LCA) and other rare inherited retinal diseases (IRDs).

Hope in Focus featured Karmen Trzupek, RARE-X’s Senior Director of Scientific Programs, in its webinar episode “Let’s Chat About…RARE-X.’ Our Director of Outreach and Development Courtney Coates discussed with Karmen RARE-X’s mission and goals, and its recent merger with Global Genes. The March 7, 2023, session can be viewed here.

“Let’s Chat About…” is our free webinar series bringing together researchers, advocates, industry leaders, and people living with LCA and other rare IRDs for conversations important to the rare retinal disease community.

RARE-X and its founding

Nicole Boice founded Global Genes to support patients, families, and patient advocacy groups dedicated to rare diseases. At Global Genes, Nicole and others recognized a tremendous need to solve data collection and sharing problems for patient communities affected by rare diseases, and founded RARE-X to address those critical data issues

Rare disease patients’ data often is collected somewhere and sits privately in a silo where it is inaccessible to others. Or, the patient community actively manages the data in a format precious to a particular researcher, but unhelpful to others. Or, the data doesn’t exist, as is the case with many rare diseases.

RARE-X began addressing these issues through its data collection platform that enables rare disease communities to start gathering data in a highly structured and streamlined way that aligns with existing research philosophies.

“We work very hard at RARE-X to make sure that every single question asked of patients and families is a valid data point,” Karmen said. “Then we also share that data. With patient permission, all the data collected on the platform gets migrated to a data-analysis platform, and any qualified researcher can access that data.”

Collecting the data

“When someone first comes onto the RARE-X platform and starts entering data, it will ask them for their self-reported diagnosis. Do you have a genetic test? It asks about symptoms and the progression of those symptoms over time.

“We have people upload a copy of their genetic test results for the genetic testing data. Then we have a genetic curation team that reviews those, pulls out that data and makes sure that that data is in discrete data points. That’s useful to researchers because a researcher coming onto the platform does not want to pour through a whole bunch of PDFs and sometimes pictures from somebody’s phone of their test results, so we curate all of that data and make sure that that’s available on the research portal.”

Collaborations through RARE-X

Karmen develops programming and strategic collaborations to ensure the company makes the best use of the data that patients and families entrust to them.

In one program, she’s managing an “Open Science Data Challenge” with data from about 30 patient advocacy groups in the pediatric neurodevelopmental space, in collaboration with families of children with disorders causing seizures and global developmental delays.

“We are pulling the data and aligning it with other partner data, and then making it widely available to an extensive research community under a challenging environment, like a hackathon, to try to generate valuable insights and create research proposals for grants.”

Karmen also is looking at how RARE-X develops partnerships for additional data sources and uses of the data that circle back to benefit the patient community. Other groups on the platform include some adult-onset neurodegenerative disorders and some inherited retinal disorders.

“Usher syndrome, for example, that community is actively collecting data on the platform. And then other related inherited ocular conditions that aren’t retinal but share overlapping issues and needs, like Leber hereditary optic neuropathy, are collecting data.”

The company also plans to make digital optical coherence tomography (OCT) data available side-by-side with patient reported data.

“Those images are proprietary to the software and the hardware used. Multiple companies make OCTs, and we’re working with an artificial intelligence group that has developed ways to bring that data together and make it cross-comparative.”

RARE-X plans future LCA community data collection

“The platform has been live for about a year and a half, and we are very much building this plane as we fly it,” she said. “We’re working in the vision consortium to ensure that we’re adding the right kinds of surveys and patient-reported outcome measures to the platform that are most useful to this patient community.

“We’re continuing to talk with Hope in Focus and other groups within the LCA family of diseases. As soon as we start to have some more vision-specific surveys, we’ll begin collecting data pretty actively.”

From genetic counselor to RARE-X’s mission

Karmen’s career began as a genetic counselor in inherited retinal diseases. She worked at the C a sey Eye Institute and then InformedDNA, where she developed ways to share the experience and information received by patients and families seen at a major academic research center with patients and families unable to physically get to a major center. Telemedicine and collaborations and partnerships with local retinal specialists accomplished much of that.

But she realized a much greater need overall for rare disease information sharing and for funding. Through the Usher Syndrome Coalition, Karmen met Nicole and Charlene, the RARE-X founders.

“I loved the mission and that they’re enabling even the smallest patient groups to start becoming very actively involved in clinical research,” she said.

“They are flipping that paradigm where a patient community doesn’t have to wait for a clinical trial or a natural history study for their data to be valuable. But flipping where the patient communities drive the research agenda and begin to say, ‘look, we have the data, and we have started to de-risk this disease as a disease that would be valuable to pharma to invest in.’ I love that paradigm shift. I love getting to be part of that.”

Merger benefits the rare disease community

“Coming together and joining Global Genes helps the entire journey of the patient advocate. If you think about a rare disease patient or parent, you start on your diagnostic journey searching for the diagnosis, right?

“You get that diagnosis, and maybe a patient foundation or community already exists. Maybe not, if it’s an ultra-rare disease. Those patients and families going through that have lots of needs. Those questions might include: Where do I go from here? How do I best support my child in the school system?

“The patient-advocacy journey is something that Global Genes, for a long time, has been very involved in. RARE-X has been developing this platform and developing partnerships to use this data, and now we can provide an extension of that patient advocate journey.

“So much of what both Global Genes and RARE-X have been doing is related to how we educate and support patient advocates in becoming more active participants in research and helping to drive that research agenda. I think there was a lot of overlap that was beginning to develop there. It made sense to merge.”

The future for RARE-X

The U.S. Food and Drug Administration recently approved therapy for a rare neurologic disorder, and for the first time, it accepted

data from an ongoing natural history study as essentially a control arm.

“That brought up a lot of excitement and questions around patient-generated data because the patient community drove that natural history study. RARE-X and Global Genes have an opportunity to be part of this story and its evolution,” Karmen said.

“Now I am not suggesting that clinical data and traditional natural history studies will be replaced. There’s so much value in those studies, but we also know that they only ever capture a small percentage of the patient community who can travel.

“How can we make that kind of research more broadly available to a much larger population of patients and find something that’s a little bit more hybrid? That is a massive part of where I see us going in the next five years.”

Let’s Chat About…Gene-Independent Therapies for Inherited Retinal Diseases with Dr. Daniel C. Chung

We’ve heard a lot about therapies to correct mutations in specific genes causing blindness or low vision, and now research is moving beyond single-gene correction to gene-independent therapies to help delay progression in rare inherited retinal diseases (IRDs) or to restore levels of vision.

We learned about this research from Dr. Daniel C. Chung, Chief Medical Officer of SparingVision, an ocular genomic medicine company focusing on gene-agnostic or gene-independent therapy and gene-editing approaches to combat blinding diseases.

Dr. Daniel C. Chung

Hope in Focus featured Dr. Chung in its June 21, 2022, webinar episode titled “Let’s Chat About…Gene Independent Therapies for Rare Inherited Retinal Diseases.” Courtney Coates, Director of Outreach and Development, moderated the session which can be viewed here. “Let’s Chat About…” is our free webinar series bringing together researchers, advocates, industry leaders, and people living Leber congenital amaurosis (LCA) or other IRDs for conversations important to the rare retinal disease community.

Before his recruitment to SparingVision, Dr. Chung worked with Spark Therapeutics and focused on developing LUXTURNA®. The medicine injected under the retina became the first, and so far, only, gene therapy approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for use in a blinding genetic disease called LCA. The drug targets IRDs due to variants in the RPE65 gene, known as LCA2 (RPE65), which is one of 27 identified forms of LCA, and helped improve vision in people who underwent the procedure that involves a subretinal injection of the medicine into each eye.

Dr. Chung served as the Ophthalmology Therapeutic Leader for Spark, where he led the medical affairs group and contributed to clinical development and operations, marketing, business development, patient advocacy, and preclinical research and development.

With more than 300 genes causing IRDs, and research underway involving myriad programs in academia and the biotech industry, Dr. Chung explained the focus of the company headquartered in Paris with offices in Philadelphia.

“What we are trying to do at SparingVision is to look at some of the ways we could do gene-independent approaches, which means we’re not necessarily correcting the genetic defect, but using other genetic parameters where we can help slow down the degeneration of disease in a gene-independent way.”

Slowing down retinal disease progression

Dr. Chung said one of the company’s preclinical research programs seeks to preserve cone function in people living with rod-cone dystrophies, concentrating on the most common form, retinitis pigmentosa (RP), which is a group of related eye disorders that cause progressive vision loss as the retina’s light-sensing cells deteriorate. The disease affects 2 million people worldwide, or about 1 in 3,500 individuals.

RP affects rod photoreceptors that provide periphery vision, along with night, dim light, and side vision, while cone photoreceptors in the middle of the eye provide the best visual acuity, color vision, and daytime vision.

The question for SparingVision Co-Founders Dr. José-Alain Sahel and Thierry Léveillard, PhD, became: Is there a connection between the death of rod and cone photoreceptors?

The team, which also included Dr. Saddek Mohand-Said, was the first to hypothesize and demonstrate that rod photoreceptors produce a protein that rescues cone photoreceptors, thereby maintaining – and prolonging – light-adapted and high-resolution vision.

They discovered what they call Rod-derived Cone Viability Factor or RDCVF, produced by the NXNL1 gene, which has two forms – a short form and a long form.

“Basically, the short form is a survival factor,” Dr. Chung said, “a factor that occurs naturally in everyone’s eyes, where these rods cells that are on the periphery secrete a protein that attaches to cone cells, and through this long mechanism of metabolic activity helps to protect the cone cells and keeps them functioning and their structure moving forward. So that’s what happens normally.

“But in diseases where you have rod cell death, you don’t have that factor being produced anymore and that’s why it’s gene independent because it really doesn’t matter why your rods are dying. It simply matters that they’re not there to produce that factor and that factor’s necessary to keep your cones functioning, to preserve vision.

“So, by using gene therapy, we’re putting that factor, RDCVF, back into the eye of patients and hopefully we’re able to slow down the degeneration of their cones, and the cones are again for your central vision, your daytime and color vision, and we hope to be able to extend that a significant period of time. As you know, most RP types have a relatively slow degeneration, so if we were able to slow that down by 40 or 50 percent, you would have significantly longer usable vision.”

The gene produces two different factors, the secreted short form and another long form that acts as a powerful antioxidant. We’ve all heard about eating your blueberries and cranberries because they are healthy and high in antioxidants, he said.

“That’s something that works within the retina as well because the retina uses more oxygen than any other organ in the body by gram weight. And because of that, there’s a lot of reactive oxygen species that are produced and so you have to dampen those, and this is what we call the long form of RDCVF.

“The long form works by being a powerful antioxidant, so that coupled with the other property of the secreted form, the two act together to help cone survival.”

Restoring Cone Cell Function

SparingVision’s second research program focuses on another factor. Preclinical research under the guidance of SparingVision Chief Scientific Officer Dr. Deniz Dalkara deals with restoring function to cone cells that have lost the ability to function, but their cell body remains.

These dormant cones are viable cones with diminished outer segments that no longer respond to light, as such that the patients’ light response decreases, and they become unable to see. Since the phototransduction cascade – the process through which photons, or elementary particles of light, are converted into electrical signals, which allows for normal vision – occurs in the outer segment of the cones, these dormant cones are no longer capable of converting light into an electric signal, leaving patients with decreased vision and, as the disease progresses, blindness.

SparingVision research involves an injection that provides dormant cone cell bodies with a channel protein that would allow to restore a short phototransduction cascade within the dormant cone, restoring electric signals, and thereby possibly restoring light sensitivity, visual acuity, and color vision.

“This we believe will actually restore function to cone cells that have lost the ability to function, but their cell body remains. In retinal degeneration, we see that the function is lost, and certain types of structure is lost, but the main cell body stays intact,” he said.

“You can revive those dormant cone cells and thereby restore some level of vision. Again, it doesn’t matter why they degenerated, so it’s not gene dependent because we’re not correcting the gene that caused the degeneration, but we’re adding another factor in that.

Dr. Chung said human trials will start “we hope, very soon.”

He also described the company’s CRISPR gene-editing research, in which the therapy acts as molecular scissors, cutting or editing out gene misspellings that cause dysfunction.

Regarding the company’s research projects, Dr. Chung said, “We’ve gone from one end, where we are gene independent and then we’ve gone all the way to the other side, where CRISPR is not only gene dependent, but it’s also dependent on the misspelling within that gene, and each gene has a lot of misspellings that can cause disease, and so this is a little more targeted.”

Genetic Testing Still Necessary

Dr. Chung said it is still critical that people get a confirmed genetic diagnosis through genetic testing, accompanied by genetic counseling.

“Even though we may be gene independent, I think that the idea is we still want to encourage people to get their genetic diagnosis.”

A definitive diagnosis will help people understand their retinal disease, learn about rates of disease progression, and get connected with patient community organizations, such as Hope in Focus, he said.

On SparingVision, Dr. Chung said the business is not just a gene therapy company.

“We totally think of ourselves as a genomic medicine company, and that’s really using all the genetic tools that are in the toolbox to combat these inherited retinal diseases or ocular diseases in general.”

The company wants to work on many different approaches to have more choices for a tailored therapeutic option.

“We just want to do as many different strategies as we can to try and get more options for patients. I think obviously it would be great to be in a world where it’s not a matter of having one therapeutic option but to have several therapeutic options that are tailored toward where you are in your disease progression and what fits best for you and the inherited retinal disease or ocular disease that you have.”

Let’s Chat About…Advancing Treatments into Clinical Trials with Ben Shaberman

Innovative funding initiatives created by the Foundation Fighting Blindness are accelerating research advances to find treatments for Leber congenital amaurosis (LCA) and other rare inherited retinal diseases (IRDs).

Preclinical research involving animal models often gets stuck in early phases because no funding exists to move into clinical trials where developing treatments can be evaluated on people and advanced toward regulatory approval.

“The science is there; it’s the money that’s needed to fund the clinical trials, especially in later stages,” according to Ben Shaberman, the Foundation’s Senior Director of Scientific Outreach and Community Engagement.

Ben Shaberman

He appeared in a recent webinar episode of our Let’s Chat About online series, in which he detailed strategies driving retinal disease research.

Courtney Coates, our Director of Outreach and Development, moderated the episode, “Let’s Chat About… Advancing Treatments into Clinical Trials: Opportunities and Challenges,” featuring Shaberman, who has been with the Foundation about 17 years. You can view the session here.

Shaberman writes for the Foundation’s electronic and print publications, presents the latest scientific retinal research advancements at local and national events for patients and families, and conducts science training activities for staff and constituents.

He launched a podcast series last year called “Eye on the Cure” and enjoys collaborating with people one-on-one to help them understand their retinal disease and the research underway that could benefit them.

He also leads the company’s outreach to eye care professionals throughout the United States to help educate their patients about resources available to patients with low vision or blindness.

Shaberman earned a Master of Arts degree in writing from Johns Hopkins University, a Master of Science degree in systems management from the University of Maryland, and a Bachelor of Science degree in computer information science from Cleveland State University.

The Foundation is the world’s leading private funder of research on potential treatments and cures for inherited retinal degenerative diseases, including age-related macular degeneration. The nonprofit has raised more than $850 million to find cures for retinal diseases, identify more than 300 genes linked to them, and launch more than 40 clinical trials for potential treatments.

Foundation Funding Programs

Preclinical research or laboratory research done in academic research centers globally is expensive.

“But, when you are moving those emerging therapies from the labs, the cost goes up dramatically and that’s a big barrier for researchers,” Shaberman said. “It costs millions of dollars just to get in that clinical stage.”

That stage brings humans into the research, pulls in the U.S. Food and Drug Administration as a regulator and overseer, and requires submitting to the FDA required applications explaining the research and demonstrating the developing treatment’s safety and efficacy.

“That’s a really intensive process,” he said. “They (these early-stage therapies) may never see the light of day in a clinical trial because of all these issues.”

The Foundation created two programs to help drive projects to clinical stages.

The first, its Translational Research Acceleration Program (TRAP), helps scientists refine preclinical studies and accelerate research toward clinical trials to provide a robust pipeline of potential therapies to fight IRDs.

“TRAP helps researchers do some of that later stage work that will hopefully help them get to the clinical-trial doorstep,” Shaberman explained.

TRAP is funding a study at the Casey Eye Institute focusing on neuro-protective treatments to help reduce inflammation and other symptoms common to retinal diseases. Funding also supports Usher Syndrome Type 3a later-stage lab work.

The second program is the Foundation’s Retinal Degeneration Fund (RD Fund) and marks a step forward from TRAP because it invests in start-up companies. Like a venture capitalist, the investment is looking for a return, which instead of going into investors’ pockets, goes to the RD Fund to help projects in or advancing toward early-stage clinical trials.

“The ultimate goal is once you move something into a clinical trial and help those companies do that, if you can get some early encouraging signals, you can attract tens or hundreds of millions to fund that process.”

The RD Fund led the $19 million in seed financing to create Opus Genetics, the first spin-out company internally conceived and launched by the Fund to further the Foundation’s mission.

The new gene therapy company plans to target two forms of LCA: LCA13 (RDH12), which affects one in 288,000 people, and LCA5, which encodes the lebercilin protein and affects about one in 1.7 million people.

The RD Fund also helped advance ocular gene therapy research by Shannon Boye, PhD, and Sanford Boye, founders of Atsena Therapeutics.

BioBonds Congressional Legislation

Another initiative supported by the RD Fund, Hope in Focus, and two dozen more groups is a proposed Congressional Act designed to help researchers launch clinical trials for emerging treatments and gives hope for getting more treatments across the finish line for people living with a broad range of medical conditions, including rare retinal diseases.

This 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, and researchers would be required to repay the low-interest, government-backed loans.

Shaberman encouraged his webinar audience to go to the BioBonds website for more information and email him about supporting the proposal.

He said he has always been inspired by the courage of patients and families and their success in coping with challenging conditions. They often motivate friends to help with fundraising and get more people involved with advancing research. The stories coming out of the Foundation and Hope in Focus create connections between families and foster positivity and success.

He cited Hope in Focus for its support of the Foundation’s free genetic testing program to get a confirmed genetic diagnosis, a vital step in the journey toward understanding a person’s specific retinal disease caused by a gene mutation.

Fifteen years ago, a handful of trials were underway. Researchers now are working on more than 40 clinical trials.

“A lot has happened. It can never happen quickly enough, but we’re doing everything we can to accelerate the science, and, in the end, science takes time.”

Let’s Chat About … Self-Advocacy and Supporting Your Child’s Education with Beth Borysewicz

Children living with visual impairment become more independent and empowered when parents set high expectations for their kids and challenge them every day.

Just ask Beth Borysewicz. In her role with Connecticut’s Bureau of Education Services for the Blind, she makes a living helping children with visual disabilities realize their potential as strong, self-determined adults. And she’s the first one to say, often with tears in her eyes, that her job is to work herself out of a job.

Beth Borysewicz

She described her work in helping children from birth to 22 years old with visual impairment or blindness become more independent as adults as part of the Hope in Focus “Let’s Chat About …” webinar series. Our March episode, moderated by Courtney Coates, Director of Outreach and Development, featured Borysewicz, an Education Consultant for the Department of Aging and Disabilities, Bureau of Education Services for the Blind.

We developed the series with those living with Leber congenital amaurosis (LCA) and other rare inherited retinal diseases (IRDs) in mind, but we 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. Click here to view this episode.

Borysewicz found her passion working with the blind and low-vision community unexpectedly 16 years ago, when she had a 3-year-old student named Sofia, who was diagnosed with LCA. Yes, that would be the same Sofia as in Sofia Sees Hope, our organization’s original name until a recent rebranding to Hope in Focus. Borysewicz also is Vice Chair of our Board of Directors.

She said parents need to be the biggest advocates for their children.

“If you think your child is not getting what they need, you can ask for it.”

She also encouraged connections with people who have been on this journey before, bringing to mind the Hope in Focus Family Connections program that helps ease feelings of isolation that can arise when a family member is diagnosed with a rare disease.

“It’s the people that have already gone through it who will help you the most, including Hope in Focus. That’s why I’m on the board. What Hope in Focus does for families is immeasurable.”

All the Little Things We Do Every Day

As a Teacher of Students with Visual Impairments (TVI), Borysewicz focuses on teaching students self-advocacy and exploring the Expanded Core Curriculum (E.C.C.), distinguished from a school’s standard core curriculum consisting of courses in math, science, reading, and the like.

E.C.C. comes from the perspective of teaching students with blindness or low-vision and encompasses nine areas: Compensatory Skills, Orientation and Mobility, Social Interaction, Independent Living, Recreation and Leisure, Sensory Efficiency, Assistive Technology, Career Education, and Self-Determination.

The curriculum is more than a checklist or lesson plans for learners with a visual impairment, according to The E.C.C. and Me website. It’s all the little things we do every day, done with intention so children with visual impairments can learn skills they need for a fulfilling life.

“I wish everyone would do what I do,” Borysewicz told her webinar audience. “There is a shortage worldwide of TVIs.”

She advised parents to set expectations high for their children, challenge them every day, and give them a safe place to learn.

“Children can do anything they set their minds to. Do anything you can do to empower them,” she said. “Celebrate everything. Celebrate every little thing.”

She talked about self-determination, saying it’s her favorite part of the curriculum and the most important.

“It’s teaching a child to believe in themselves and just take that leap,” she said. “It’s taking that step off the curb to cross the street with a cane or initiating a conversation at a lunch table that builds self-confidence.”

Making Learning Fun and Exciting

Her work with people from birth to age 22 encompasses figuring out resources for newly diagnosed children, for school-aged students, and for young adults transitioning to the workforce or college.

“I switch hats from appointment to appointment every day,” she said. “As you can tell, I love my job.”

Working with individualized education plans (IEP), she and her team helps students become the best they can be in all the E.C.C. areas.

“It’s so important for the student to say, ‘This is what I need and why I need it,’ and just building those skills will make them successful as adults.”

And a lot of it is fun, especially with Borysewicz who excels in the Recreation and Leisure department. It goes back to when she was growing up and her dad always told her she was good at playing with people and should get a degree in play.

She implements that play degree often by creating board games to make math more fun or putting together programs to help students from prekindergarten through grade 3 explore the nine E.C.C. areas in their daily lives.

In an Expedition to Explore, students in the Young Passport Program worked on accumulating life skills at home over the summer. Each student has a passport consisting of pages designated for each of the nine E.C.C. areas, with a slant toward adventure. For example, “Career Education Caves” focuses on conversational skills, encouraging children to stay connected with their friends over the summer, known in the business world as networking, and holding mock interviews with their siblings or stuffed animals.

In “Self-Determination Safari,” a goal is to get the child to ask for help. A parent asks a child to do an unfamiliar chore, such as taking out the trash or putting toys away but doesn’t give guidance on how to do it or where to put the trash or toys, prompting or encouraging the child to ask for assistance or directions.

“Social Skills Glaciers” encourages children to spread kindness to neighbors and the community and recommends an online guide called “100 Acts of K i ndness for Kids.” Activities include listening, following directions, taking turns, ignoring distractions, cooperating, and showing empathy. (Sounds great for adults, too!)

Resources for People with Blindness or Low Vision

Borysewicz talked about her work from the perspective of Connecticut and said services may differ from state to state.

She authors a blog dedicated to professionals, families, and students called I Love Brl (Braille) and she provided webinar viewers this list of resources:

9 More than Core; The Independent Little Bee; Expanded Core Curriculum Ideas for Preschoolers and Early Elementary; Is My Child Getting a Quality V1 Program?; Integrating E.C.C. Activities into Literacy Instruction; Family Connect; and Wonder Baby.

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 conge n ital 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.