Second Global RDH12 Scientific Conference Brings Clinical Trials Closer to Reality

The community of people living with Leber congenital amaurosis caused by mutations in the RDH12 gene moved closer to realizing the shared goal of establishing a clinical trial to find a treatment for the blinding disease.

More than 40 people gathered for the Second Global RDH12 Scientific Conference in Baltimore. The daylong meeting in November offered perspectives from clinicians, patients, parents, advocates, academia, regulators, and industry.

Silvia Cerolini, founder of Eyes on the Future, one of three organizations under the umbrella of the Global RDH12 Alliance, said the conference made tremendous progress toward a common goal: Designing a successful clinical trial to find a treatment to improve or stabilize vision in people living with RDH12. Current LCA13 RDH12 research is in preclinical stages, with the hope that the first clinical trials may start in 12 to 24 months.

Vicky (L) holding a sparkler and Silvia (R) hugging Vicky. — Silvia Cerolini and her 9-year-old daughter, Vicky

As one woman living with RDH12 voiced during the conference: “Any quantity of vision is everything for us.”

Cerolini, the mother of 9-year-old Vicky who lives with RDH12, submitted a scientific abstract based on the conference to ARVO, the Association for Research in Vision and Ophthalmology, discussing clinical trial designs and outcome measures for inherited retinal dystrophies (IRDs) associated with mutations in the RDH12 gene, one among 27 identified forms of LCA. She recently learned ARVO accepted her abstract as an example of patient-driven collaboration to accelerate research for presentation at the association’s April annual meeting in New Orleans.

In 2019, ARVO published the results of the First Global RDH12 Scientific Conference in its journal – Translational Vision Science & Technology. Families and scientists attending the conference in Columbia, Maryland, discussed therapy development for people with RDH12 mutations. The group developed three priorities: Proceed with a gene therapy clinical trial, assess data through natural history studies, and research the mechanisms of the disease.

This recent conference brought together an international group of scientific, medical, advocacy, and industry experts to identify and prioritize potential elements in designing a clinical trial and its key components: Outcome measures and endpoints.

Outcome measures are used to assess a patient’s vision. Performed at the start of a clinical trial, the measures provide baseline information that can be compared with the same outcome measures done after an intervention or treatment, determining progress and efficacy.

A large group of people posing for picture at the Global RDH12 Scientific Conference — Participants in the Second Global RDH12 Scientific Conference

Endpoints are outcome measures selected as the most relevant and clinically meaningful measurements that can be measured objectively to determine whether the intervention being studied is beneficial.

Selecting the most appropriate and patient-relevant outcome measures as endpoints for each specific IRD is a big challenge for the entire field of inherited retinal dystrophies.

The heterogeneity (diverseness) of IRD phenotypes (characteristics) poses significant challenges to understanding disease pathology, predicting treatment benefit, and selecting outcome measures and endpoints for clinical trials. Challenges in recent clinical trials failing to demonstrate treatment efficacy show the need for innovation in trial design and outcome measures’ selection.

Organizers cited four key challenges unique to treating RDH12 mutations: (1) Severe impairment of retina/vision from early life; (2) Uncertain expectations of stabilization/preservation versus improvement/restoration of vision; (3) Heterogeneity of the RDH12 phenotypes (and IRDs in general); and (4) Slow expected pace of detectable changes after treatment.

Coming Together for RDH12

The RDH12 Global Alliance comprises Eyes on the Future, based in the United Kingdom, RDH12 Fund for Sight in the United States, and Candle in the Dark in Belgium.

Retina International, Foundation Fighting Blindness, and Hope in Focus, partnered with the Alliance to present the conference and served as Patient Representatives. Director of Outreach and Development Courtney Coates attended on behalf of Hope in Focus, joining the Foundation’s CEO Jason Menzo, Todd A. Durham, PhD, and Claire M. Gelfman, PhD, and Retina International’s CEO Avril Daly.

Cerolini and Sue Lacey, PhD, of Astraea Medical Consulting, moderated the meeting.

Conference highlights included stories from people living with the disease and the constructive dialog among industry representatives, clinicians, scientists, and regulators, Coates said.

“Most significant were the RDH12 patients and parents sharing their experiences with progressive vision loss and their hopes for a treatment,” she said. “The day marked a meaningful step toward successful trials and, hopefully, will become a model as other gene-mutation studies progress to trials.”

For Maria Fiore, mother of 17-year-old Bella who lives with RDH12, the day brought hope.

“The input – from the academic side, opinions from the regulatory side, and the competitive nature of having multiple interests on the industry side – gives me a lot of hope that we’re getting closer to an RDH12 clinical trial,” said Fiore, a member of the Board of Directors for RDH12 Fund for Sight.

“We appear to be closer than ever, and events like the conference help to keep the motivation and drive to bring this to the finish line a real possibility.”

Bella and Vicky are part of the global RDH12 community that includes more than 200 families from 20 countries. Children and adults living with the rare inherited retinal disease hail from the United States, Europe, South America, China, India, and Russia.

The families communicate through Facebook and an email newsletter, with some local groups emerging to involve more people and remove language barriers.

The Global RDH12 Alliance organizes twice-yearly virtual community calls to review progress on clinical developments and discuss common challenges. Collectively, the three RDH12 organizations have raised more than $3.5 million since 2011 to advance research and find treatments.

Click here to see a video of people living with RDH12 introducing themselves.

Cerolini said it had been far from easy to wrestle all the participants down for one full day.

“But we came together as one big team to optimize the chances of trial success for our RDH12 community. There is still work to do to give Vicky and all our RDH12 community hope to see the world,” she said.

“It is not easy. But we are as close as ever to the first human clinical trials and we need to keep going. What we are learning about RDH12 can help the entire IRD field.”

Cerolini thanked Sue Lacey for her mastery in moderating the conference, and Francesca Sofia, PhD, and Giorgia Schena, PhD, both with Science Compass, for their preparation help. Consultants and partners also included Karmen Trzupek, MS, of RARE-X; Ebere Igboko, PhD, of Cure RP; Madhu Madhusudhan, PhD, of LifeArc; and Elin Haf Davies, PhD, of Aparito.

Patient Perspectives

The gathering watched a video of children and adults with RDH12 describing difficulties with sight loss and the hope that research will lead to a treatment.

Coates said people from several countries expressed their desires to have a chance to better their vision or at least maintain it.

“The heartfelt presentation reminded everyone in the room why we were there.”

Individuals and their families at the conference comprised a group of nine, sharing worldwide perspectives about trial design and outcome. They said they would accept stabilizing visual function as a “significant win” in the pursuit of a treatment.

Adult patients talked about the importance of keeping whatever light perception they have and shared stories of struggles in knowing where they are in their space, including the perils of bumping and bruising their foreheads when navigating spaces.

As one woman characterized the quest: “Any quantity of vision is everything for us.”

Their comments led to discussions with regulators and clinicians about the complexities of retinal function and the validity of certain endpoints and outcomes.

Along with Cerolini, family patient representatives included Jogin Desai from India, Sumaira Latif from the UK, Sylviane De Vel from Belgium, and Cecilia Vasconcelos from Brazil. The group also included RDH12 Fund for Sight representatives from the US: Mathew Pletcher, PhD, Allison Galloway, Lori Kinney, and Maria Fiore, all of whom are parents of children living with LCA13 RDH12.

Clinical and Academics Perspectives

Clinicians and academics shared unpublished data on RDH12 natural history and thought-provoking perspectives from the latest IRD trials.

Tomas S. Aleman, MD, PhD, presented insight from an RDH12-associated IRD natural history study and the latest expectations for treatment. He talked about differences between the LCA13 RDH12 and LCA2 RPE65 mutations, and the structural and functional relationship in the RDH12 mutation that causes central vision loss resulting in blurring.

Group photo — L-R: Debra A. Thompson, Jean Bennett, Maria Fiore, Allison Galloway, and Tomas S. Aleman

Despite functional and structural degradation of photoreceptors, he said, RDH12 gene therapy may have the potential to improve outcomes, even in adults, once certain toxins can be degraded.

Dr. Aleman is Professor of Ophthalmology and Director of the Hereditary Retinal Degeneration Clinics at the Scheie Eye Institute’s Perelman Center for Advanced Retinal and Ocular Therapeutics (CAROT) at the University of Pennsylvania.

***

Jean Bennett, MD, PhD, discussed outcomes and endpoints from studying the RPE65 gene mutation while developing voretigene neparvovec, known as LUXTURNA®, and whether they can be translated to RDH12 clinical trials.

The U.S. Food & Drug Administration (FDA) in 2017 approved LUXTURNA to help improve vision for people living with RPE65. The therapy remains the first and only approved ocular gene therapy and the only gene therapy treatment for any inherited disease in the United States.

The breakthrough treatment developed at Children’s Hospital of Philadelphia (CHOP) and Spark Therapeutics in Cambridge began with the successful treatment of a special being, Lancelot, the first in a line of Briard herding dogs, who helped drive research to bring the gene therapy to market.

Dr. Bennett told the group the development of a novel patient-relevant endpoint – a multi-luminance mobility test (MLMT) to measure functional vision, or how a person navigates in a vision-related activity across a range of light levels in daily living – was instrumental in demonstrating how voretigene neparvovec could improve vision in RPE65 patients, leading to LUXTURNA’s approval.

The navigational test, though, can be cumbersome and time-consuming, given the elaborate setup with lighting controls, videotaping, analysis, and such. Alternatively, researchers are working on virtual-reality tests, created as time-savers with more versatility. The task would be to design a functional vision test using a virtual-reality obstacle course.

Drs. Bart P. Leroy, Jean Bennett, and Daniel C. Chung, group photo — Drs. Bart P. Leroy, Jean Bennett, and Daniel C. Chung

Dr. Bennett is Professor of Ophthalmology at CAROT and the F.M. Kirby Emeritus Professor of Ophthalmology at the Perelman School of Medicine at UPenn.

***

Dr. Robert E. MacLaren, Professor of Ophthalmology at the University of Oxford, discussed lessons drawn from recent IRD clinical trials and vector delivery. He is working on a trial assessing the effects of retinal gene therapy with an adeno-associated viral (AAV) vector encoding genome particles.

LUXTURNA gene therapy employs a human-engineered AAV vector containing copies of a normal gene injected under the retina to express a protein necessary for vision.

Prof. MacLaren discussed opening the door to a new concept in the IRD space where researchers look for statistically significant improvements that show the vector is working and be more flexible in the immediate argument of whether that has a clinically significant improvement in that patient’s visual function, there and then.

Prof. MacLaren is the Consultant Ophthalmologist at Oxford Eye Hospital and the Consultant Vitreoretinal Surgeon at Moorfields Eye Hospital.

***

Professor Bart P. Leroy, MD, PhD, discussed information learned from recent IRD clinical trials and gene therapies in clinical practice.

He co-authored the PERCEIVE study that analyzed the Year 2 interim research on LUXTURNA, concluding the drug demonstrated safety and effectiveness when used in clinical practice following its regulatory approval. The study also identified a new adverse drug reaction called chorioretinal atrophy, causing inflammation in some patients. So far, the reaction has not affected visual function and will be tracked as the study progresses.

Dr. Leroy discussed the obstacles experienced by ProQR T h erapeutics’ clinical trial of sepofarsen for LCA10 CEP290. Phase 2/3 of the Illuminate trial did not meet its primary endpoint of improving visual acuity. The European Medicines Agency (EMA) recommended an additional trial, prompting ProQR to seek a strategic partner to move the research forward.

He emphasized working toward shared goals and communicating with regulatory agencies on design and outcomes for IRD clinical trials. Saying children are not little adults, Dr. Leroy said questions about specific designs and patient-reported outcomes need to be adapted to the study population.

Dr. Leroy is Professor of Ophthalmology, Ophthalmic Genetics, and Visual Electrophysiology at Ghent University, and Head of the Ophthalmology Department at Ghent University Hospital, Ghent, Belgium.

***

Adam M. Dubis, PhD, Associate Professor, University College of London Institute of Ophthalmology Global Business School for Health, and Advanced Human Retinal Imaging Specialist at Moorfields Eye Hospital, presented information on work planned around data-driven solutions for RDH12 clinical trial support.

The clinician/academia group also included Mariya Moosajee, MD, PhD, Moorfields Eye Hospital; Debra A. Thompson, PhD, University of Michigan; Mark E. Pennesi, MD, PhD, Oregon Health & Science University; Abigail T. Fahim, MD, PhD, University of Michigan; Michel Michaelides, MD, PhD, Meira GTx; and Ramaswamy Subramanian, MD, PhD, Purdue University.

Industry Perspectives

Meira GTx CEO Robert K. Zeldin, MD, PhD, updated the group on the biotech’s RDH12 clinical development. The company is enrolling participants in the US, UK, and Europe for a natural history study and is planning a Phase 1/2 trial to assess safety and tolerability of potential gene therapy treatment.

Opus Genetics’ CEO Ben Yerxa, PhD, discussed capitalizing on key lessons in LUXTURNA’s development. Opus has three LCA-related projects in its pipeline, including one in early stages for RDH12. The company concentrates on preclinical projects in, or advancing toward, early-stage clinical trials to move research forward, with the goal of a successful trial or trials.

The conference’s industry group included: Jennifer Hunt, PhD, Erin C. O’Neil, PhD, and Sarah Tuller, JD, of Opus Genetics; Daniel L. Chao, MD, PhD, and Shannon E. Mullican, PhD, of Janssen Pharmaceutical Companies of Johnson & Johnson; Nicholas Gomm of Meira GTx; Daniel C. Chung, MD, PhD, of SparingVision; Shannon Blalock, PhD, of jCyte; and Aaron Osborne, MD, PhD, of Nanoscope Therapeutics.

Regulatory Perspectives

The FDA’s Dr. Wiley A. Chambers and the EMA’s Jane Moseley discussed trial-design parameters and outcome measures. They articulated their points of view, offering actionable advice on novel endpoints, including structural versus functional measures, virtual-reality mobility mazes, and patient-reported outcomes.

The FDA’s Ekaterini Tsilou, MD, and Jennifer M. Hammer, MD, also participated in the regulatory discussion.

Innovations in IRDs

Todd A. Durham, Foundation Fighting Blindness Sr. VP of Clinical & Outcomes Research, talked about Patient-Reported Outcome Measures (PROMS), questionnaires designed to capture how a patient feels or functions, without input or interpretation from anyone else.

PROMS are developed using qualitative information, such as experiences, priorities, and contextual information from well-defined patient populations. Durham described ways the information could help advance research into treatments for people living with RDH12 and other IRDs, and he recommended steps toward creating a draft PROM strategy to begin conversations with regulators and payors.

Elin Haf Davies, PhD, CEO of Aparito, presented information on patient-centered clinical outcome assessments and the importance of quality of life for people living with rare diseases, such as RDH12.

Attendee Perspectives

The conference, chock-full of experts in myriad aspects of working to find a treatment for people living with RDH12, manifested hope and excitement toward its goal of launching clinical trials. Here are a few reflections from people in attendance:

Vicky wearing red glasses and a black and white shirt. — Vicky, Silvia Cerolini’s daughter

“The level of engagement and willingness to share knowledge, experiences, and perspectives from this multi-stakeholder group was inspiring and motivating,” Astraea’s Sue Lacey said. “And I’m sure this will translate into increased momentum and robust clinical development programs for RDH12.”

From Prof. Bart P. Leroy: “A big thank you for organizing a day that took RDH12-IRD patients considerably closer to gene therapy. The maturity and respect during the day allowed for an open and fruitful discussion.”

Dr. Daniel C. Chung with SparingVision thanked organizers for putting together a great meeting and said, “The free exchange of thoughts and points of view was incredibly enriching. We look forward to continuing this conversation and developing concrete solutions for further development until one day a patient will have the option of a treatment.”

Not Your Typical Monday – Connecticut Car Dealership Embraces Hope in Focus Message

As general manager and vice president of Cardinal Honda in Groton, Conn., Kim Cardinal Piscatelli donates time and money to charities. But when she heard about Hope in Focus and the organization’s advocacy for people living with visual impairment, it struck a personal chord.

Piscatelli was a teenager when she watched her late grandmother slowly lose her vision to glaucoma.

“It was scary to watch her go through that,” Piscatelli recently recalled. “I loved her very much, and I saw her world get smaller and smaller.”

A small group sitting at a table with blindfolds on. — Employees blindfolded

Piscatelli and her family, including her sister, learned how to help her. They closed their eyes and folded laundry. They learned to present meals as if they were on a clock.

“The chicken is at 12 o’clock, and the coleslaw is at 3 o’clock.”

Hope in Focus’ Dinner in the Dark gala fundraiser, an annual culinary adventure that involves wearing a blindfold while eating food from a secret menu, immediately appealed to Piscatelli. She asked her sister to come with her.

“I was so excited,” she said. “As a child, I remember that the empathy I had for my grandmother would lead us to do things to learn to empathize with her.”

Though the concept brought back memories, it wasn’t exactly muscle memory. The two were eager to go, but a bit apprehensive.

“I remember holding hands under the table and being like, ‘I don’t know what is going to happen, but you are right here, right?’” Piscatelli said.

She loved it. Over the years, she’s brought her children, too. But she also has taken the concept back to Cardinal Honda. It started with a morning meeting four years ago. Employees wore blindfolds

“There’s a lot of conversation about diversity and inclusivity,” Piscatelli said. “It seemed like a good way to participate in that conversation.”

That conversation has grown significantly since then, as companies and individuals look to be more inclusive and empathetic to everyone. So, in 2022, the year Dinner in the Dark returned from a two-year pause due to COVID, Piscatelli resurfaced the exercise.

The group blindfolded, sitting at the table and eating. — The group blindfolded.

It was a surprise twist on the typical Monday morning meeting — Piscatelli hadn’t announced her plan. Still, nine of the 10 employees put on blindfolds, while one took photos. When the blindfolds came off, people expressed similar sentiments to those Piscatelli felt during her first Dinner in the Dark.

“They reported they were paying more attention and not worried about what everyone else in the room was doing,” Piscatelli said. “Someone said they felt lonely…because you are not looking around the room making connections or eye contact.”

But even with the uneasiness, people showed interest in trying it again. When Piscatelli asked for six volunteers to put on blindfolds for lunch, the hands shot up.

They tried using tips Piscatelli learned at Dinner in the Dark from Sofia, daughter of Hope in Focus Co-Founder Laura Manfre, and a young woman living with LCA: Bring your food to your face, not your face to your food. Piscatelli announced the clock placement of the meal for the employees, just as she used to do for her grandmother.They huddled up after to discuss.

“Someone said it gave them a whole new perspective,” Piscatelli said. “They didn’t know if they had food on their shirts. They were more aware of what they were eating and how it tasted better, but said it was hard to eat. They lost track of what food was where on the plate.”

Employees sitting in a meeting with blindfolds on

Piscatelli hopes the exercise allows her employees to feel more empathy for people with vision loss and think of strategies to make the world more inclusive for them.

“It forced them to think about different sorts of things,” Piscatelli said. “Instead of changing what was on TV, we had to announce what was going to happen next. It helped people be prepared without visual tools.”

In a home with a person with vision loss, people can announce who they are and why they are coming into the room. For example, “It’s me, Kim, and I am here to do laundry.”

In the end, the staff learned something new and embraced leaving their comfort zones.

“It turned their day…it wasn’t a typical Monday,” Piscatelli said. “Everyone was more aware: What else do I not know?”

Piscatelli hopes other businesspeople feel inspired to learn what they don’t know about vision loss.

“It’s one thing to talk about equity, diversity, and inclusivity.” Piscatelli said. “It’s another thing to immerse everyone in an exercise where they feel empathy for people who have low vision and compassion for other people as they are temporarily trying that on.

Plans in the Works for Connecticut’s New Rare Disease Advisory Council and 2023 Rare Disease Day

Advocates for people living with rare diseases are collaborating with Connecticut Gov. Ned Lamont’s office and leaders of the Connecticut General Assembly’s Public Health Committee to build the state’s new Rare Disease Advisory Council (RDAC) that requires appointees, budgets, and bylaws be in place this summer.

Assistant Director of Advocacy for the National Organization for Rare Disorders (NORD) Kristin Angell joined Co-Ambassadors Katie Gillick and Lesley Bennett of NORD’s Connecticut Rare Action Network (CT-RAN) in hosting a Zoom conference with more than 30 people, including state legislators, patient advocates, doctors, researchers, industry leaders, health care providers, caregivers, and people living with rare disease.

The meeting included two representatives from Connecticut-based Hope in Focus and discussions about the range of needs to be addressed by the new council and the planning of next month’s celebration of Rare Disease Day on Feb. 28.

“We are working on it, and we will get it done,” Bennett said.

A rare disease is defined as one affecting fewer than 200,000 people nationwide. More than 7,000 known rare diseases affect an estimated one in 10 people in the United States, translating to about 30 million people or 10 percent of the country’s population. Globally, 300 million people live with rare diseases.

With the establishment of a permanent Connecticut RDAC, 13 members will be appointed to advise and make recommendations to the Department of Public Health, the Department of Social Services, and other state agencies about the needs of people living in Connecticut with a rare disease and their caregivers. Advisory councils may differ from state to state. Please click here to check whether your state has an RDAC or is working to establish one.

Hope in Focus, in its advocacy for people living with Leber congenital amaurosis (LCA) and other rare inherited retinal diseases (IRDs), helped generate awareness of the need for an RDAC and for the legislation to make it happen.

The cause of many rare diseases is unknown, but about 80 percent are genetic, such as LCA and other IRDs, and about half of all rare diseases affect children.

Getting state agencies to understand the rare disease population is key to the RDAC. Even something as simple as putting links to national rare disease resources on state government departments’ websites would be a big step.

More than 40 people submitted applications to become part of Connecticut’s council, and six have been appointed so far. The names of the new members will be announced when all 13 have been appointed.

The group will include insurance, public health, and social services commissioners, or their designees, and 10 members appointed by the Governor and the Public Health Committee leadership.
Those 10 members will be:

a representative of an association of hospitals or a hospital administrator, and a physician with expertise in medical genetics
a representative of a patient advocacy group in the state representing all rare diseases, and a family member or caregiver of a pediatric patient living with a rare disease
a representative of the biopharmaceutical industry involved in rare disease research and therapy development, and an adult living with a rare disease
a member of the scientific community engaged in rare disease research, and a caregiver of a child or adult living with a rare disease
a physician who treats people living with a rare disease, and a representative, family member, or caregiver of a person living with a rare disease

Planning for Rare Disease Day

Following the midterm elections and changes in some legislative seats at Connecticut’s General Assembly, educating lawmakers is key to finding solutions for people living with rare disease to have the necessary access, resources, and educational tools to enjoy their best quality of life.

One person attending the meeting talked about the need for more doctors and patient advocates in Connecticut because people living with rare disease often must travel to another state for medical care. She also mentioned the potential of patients being charged for sending simple questions to doctors through computer health care portals, and whether lawmakers attending upcoming Rare Disease Day events could help mitigate or eliminate those costs.

Please share any ideas to help raise awareness for Rare Disease Day and your thoughts on bringing Connecticut’s RDAC to fruition by getting in touch with Kristin Angell at kangell@rarediseases.org, Katie Gillick at katie.gillick@rareaction.org, or Lesley Bennett at lesley.bennett@rareaction.org.

NORD and CT-RAN plan another meeting later this month to discuss updates on the RDAC and Rare Disease Day.

Editas Medicine’s EDIT-101 Clinical Trial Update Brings Mixed News on LCA10 (CEP290) Research

The trial update includes safety and efficacy data from all 14 patients treated to date in the study comprised of 12 adults and two pediatric patients. EDIT-101 was tolerated with no serious ocular adverse events or dose-limiting toxicities observed. Most adverse events were mild and expected for subretinal delivery.

Along with showing improvement in BCVA, three of the 14 people demonstrated consistent improvements in two of the following three additional endpoints: Full-field sensitivity test (FST), visual function navigation, which means navigating a mobility course to assess mobility and functional vision in people with an inherited retinal disease such as LCA10, and visual function quality of life, information derived from the patient or caregiver while participating in the study.

Of those three people, two of them each had two identical versions of the genetic marker for the CEP290 IVS26 mutation, meaning they were homozygous for that mutation.

Because LCA10 patients homozygous for CEP290 IVS26 represent an estimated 300 people in the United States, and no other baseline characteristics were identified in the study’s dataset, the Editas statement said, “[T]he company will not progress this program independently and will seek to identify a collaboration partner to continue the development of EDIT-101.

“As a result, Editas Medicine is pausing further enrollment in the BRILLIANCE trial and will continue long-term follow-up of all patients who have been treated to date.”

Stay informed, stay connected

Hope in Focus keeps the LCA community informed of various trials focused on finding cures for any one of the more than 27 forms of LCA, including people living with LCA10 and associated research into developing therapies to correct mutations in the CEP290 gene. LCA10 is the most common form of the rare disease, affecting 20 to 30 percent of all LCA patients. LCA affects about 1 in 33,000 people worldwide.

Hope in Focus Co-Founder and Board Chair Laura Manfre asks anyone interested in learning more about the Editas trial to please send us an email at info@hopeinfocus.org, and we would be happy to facilitate a conversation.

“Science, business, and people are all key to getting a treatment from the lab to the people who need it. The announcement from Editas Medicine is a win for science, most certainly. Being able to go into the back of the eye and safely edit a genetic mutation is nothing short of a historic milestone,” Manfre said.

“The announcement isn’t entirely what we hoped for, however, as Editas has paused its LCA10 trial. More needs to be learned on the science side of things, there are business and regulatory issues to address, and as always, access to the patient community is critical.

“This journey was never going to be a straight line, and setbacks, although disappointing, are just proof we’re still moving. Stay informed, stay connected, and please make sure you’re registered and up-to-date in My Retina Tracker®.”

It will be three years this July when Editas began its CRISPER/Cas9-based trial of EDIT-101, administered through a subretinal injection to reach and deliver the gene-editing machinery directly to photoreceptor cells.

Researchers designed the BRILLANCE Phase 1/2 clinical trial of EDIT-101 to assess the safety, tolerability, and efficacy of the potential treatment. Patients received a single dose of EDIT-101 under the retina in one eye. They are monitored every three months for a year after dosing and less frequently for two more years. More details about the trial can be found at here under the reference NCT#03872479.

Let’s Chat About … Atsena Therapeutics’ LCA Research with Kara Fick and Shannon Boye

Atsena Therapeutics, a clinical-stage gene therapy company focused on reversing and preventing blindness, has an ongoing Phase 1/2 clinical trial evaluating a potential therapy for Leber congenital amaurosis 1 (LCA1) caused by mutations in the GUCY2D gene.

Kara Fick (L) and Shannon Boye (R) on Hope in Focus Let’s Chat About … series

We learned about this research from Kara Fick, head of Patient Advocacy and Medical Affairs at Atsena Therapeutics, and Atsena Founder and Director Shannon E. Boye, PhD, during our Oct. 27, 2022, webinar episode titled “Let’s Chat About…Atsena Therapeutics’ work in LCA.” Courtney Coates, Hope in Focus 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 with Leber congenital amaurosis (LCA) or other rare inherited retinal diseases (IRDs) for conversations important to the rare retinal disease community.

How did Atsena Therapeutics come to be?

Shannon and her husband, Sanford, met in grad school.

“It was a nerd romance,” she said.

Boye’s thesis involved developing viral vectors for retinal disease treatment, specifically for LCA1 (GUCY2D), and she became known for generating gene technology. She has authored more than 60 peer-reviewed manuscripts and multiple textbook chapters. She also has been actively involved in grant and manuscript review, and she has received several major awards.

Over several years, the couple worked with large, medium, and small pharmaceutical companies, but they grew frustrated at how long it took to bring developing therapies to patients.

“It was going very slowly and that was frustrating,” Boye said. “We saw business decisions overriding sound scientific decisions.”

Eventually, she sent a big long vent to Foundation for Fighting Blindness CEO Ben Yerxa, and he helped push her and her husband into starting their own company, Atsena Therapeutics. The couple co-founded the business, with Sanford Boye serving as Chief Technology Officer.

Kara Fick, who has been working as a patient advocate for rare diseases in the biotech world for nearly a decade, is passionate about bringing the patient voice, perspective, and expertise to the table.

“It’s pretty apparent, and you know from Atsena’s founding, that really keeping patients at the center and trying to move research forward so that it can get to patients is super important,” Fick said.

At Atsena, she strives to bridge the gap between the science of innovative therapies and the daily needs of individuals living with rare diseases. She also works to understand more clearly the barriers to diagnosis, treatment, and management of rare diseases and how to better address those hurdles with patients and clinicians.

What is gene therapy?

All of us have genes. They give us blue eyes or brown eyes, for instance. But our genes also make proteins. Proteins are the building blocks of life. They can act alone or in combination with other proteins to perform essential functions in our cells.

A good example of proteins important for vision are the proteins in our photoreceptors and retinas. Those proteins all work together to convert light into an electrochemical signal that is sent to the brain and processed as vision.

Genes make proteins, and proteins perform essential functions. But sometimes, we can have a misspelling in our genes — in other words, a mutation. Because of that misspelling or mutation, in some cases, the protein that gene was supposed to make did not form. In other cases, perhaps, the protein forms, but it’s misshapen and can’t interact properly with the other proteins. When that happens, the normal biological function of the protein is disrupted, for example, in your photoreceptors. As a result, your photoreceptors are unable to transmit light into a signal processed as vision.

The concept of gene therapy involves taking a healthy copy of a gene that lacks that misspelling and delivering that healthy version of the gene to the photoreceptor cells.

How is the LCA gene therapy trial going?

Drug development and gene therapy development take a long time, and there are a lot of processes that companies have to go through to ensure that anything given to patients is safe and effective.

Work to develop this gene therapy began in earnest in 2004 in Boye’s lab at the University of Florida. After pre-clinical studies in chickens and mice, they were ready for clinical trials in humans.

Atsena is working on a combination Phase 1/2 clinical trial for LCA1 (GUCY2D). In this phase of the trial, researchers test different gene therapy doses, find the best dose, and closely monitor the safety of the therapy.

“Because we’re doing a combo Phase 1/2, we’re looking primarily at safety, but we’re also incorporating some tests into the clinical trial that can help to tell us a little bit about the efficacy of the gene therapy,” Boye said.

‘Researchers began with adults aged 18 and up but recently opened it up to ages 6 and up. Fifteen people, all with GUCY2D mutations, are taking part in the trial, ranging in age from 12 to 76 years old.

So far, the trial is going well, with no participants reporting serious side effects related to the gene therapy. They did see two cases of inflammation, but both were mild and resolved after treatment.

Besides safety monitoring, Atsena has conducted several tests, including the Full-field Stimulus Test (FST). The test quantifies visual perception through flashes of varying luminance. Researchers saw significant improvements in the results of that test from individuals who received the highest dose of the gene therapy.

Participants receiving the gene therapy also showed clear improvement in a multi-luminance mobility test (MLMT), in which they navigated a course with obstacles of varying height and under different levels of illumination.

Participants also underwent a third test, called the BCVA or Best Corrected Visual Acuity, which measures everyday vision. (Think of the poster with different letters you’re asked to read at the eye doctor’s.) That test had more mixed results, with some patients seeing improvement and others not seeing much, if any, improvement.

What happens next?

This is still just the preliminary data. Atsena needs all 15 participants in its trial to get through their first full year after being treated with gene therapy. Then, they’ll collect all of the data, analyze it, and summarize it vigorously and thoroughly before moving on to the next phase.

At that point, they’ll need to meet with the Food and Drug Administration (FDA) and other regulatory agencies to get their agreement and permission to move forward with a Phase 3 trial. That trial will focus on efficacy and seeing how well the gene therapy works. It’ll still pay attention to safety, but the primary goal of Phase 3 is to focus on efficacy and use that as supportive data that could be submitted to the FDA and other agencies to get full approval of the gene therapy.

Why genetic testing is essential for clinical trials?

As more trials are starting and more gene-specific research is being done, it’s going to become more important to know precisely which genetic mutation may be causing your LCA.

“Getting genetic testing is essential for figuring out the specific genetic mutation that may be causing your LCA,” says Boye.

If you have not been genetically tested, talk to Hope in Focus. There’s no cost to patients and family members to receive genetic testing.

Boy’s vision improves after undergoing Compassionate Use gene therapy in UK for LCA4 (AIPL1)

DJ and Brendan Broadbin came to our Hope in Focus LCA Family Conference with a lot of questions about their little boy’s blindness, and they left with amazing answers leading to innovative treatment for his type of Leber congenital amaurosis (LCA).

The couple traveled from their southwestern Connecticut home to the July 2019 Philadelphia conference knowing their son Jace had LCA, but not knowing the specific form of the rare disease because their 11-month-old had yet to be tested genetically.

Jace with his red backpack and toy car — Jace ready for the day

Jace’s parents introduced themselves to retinal specialist Prof. Michel Michaelides, one of Britain’s top ophthalmologists, a founding member of MeiraGTx, where he is Head of Clinical Ophthalmology, and a conference panelist.

“At that time,” DJ said, “we hadn’t even met with a geneticist yet, but Michel gave us his contact information ‘just to have.’ We then got to hear the panel discussion at the conference regarding the clinical trials that were taking place across several of the gene variants.

“A few days before we went to Boston to hear Jace’s genetic results (in October 2019, three months after the conference), we received the Sofia Sees Hope (now Hope in Focus) newsletter in the mail, outlining the treatments that were discussed at the conference.

“We brought the newsletter with us to our appointment and almost fell out of our seats when we learned that Jace had the AIPL1 variant, and that MeiraGTx was currently working on treatment through the Compassionate Use case program in the UK – we emailed Michel that same day.”

Compassionate Use treatment

Dr. Michaelides is a Professor of Ophthalmology at University College London Institute of Ophthalmology in the Department of Genetics. He also serves as a Consultant Ophthalmologist at Moorfields Eye Hospital in the departments of Inherited Eye Disease, Medical Retina, and Paediatric Ophthalmology.

The professor has discussed the United Kingdom’s Compassionate Use program in a Hope in Focus webinar series episode called “Let’s Chat About…Gene Therapy for LCA,” describing LCA4 as an exceedingly rare and severe form of the disease in which children have profoundly reduced vision from birth.

A special unlicensed medicine is one manufactured without marketing authorization from the Medicines and Healthcare products Regulatory Agency. The agency only grants a product license once a medicinal product has been proven to be safe and effective. Prescribed products not holding a marketing authorization include those prepared on an individual basis by “special order” manufacturers, according to the National Institutes of Health.

Jace with his face up against the glass of the jellyfish tank — Floating jellyfish capture Jace’s attention

“There is a narrow window of opportunity (for treatment) because the retina degenerates and thins out by the age of 4 years,” Dr. Michaelides said. “Treatment needs to be before 4 years of age. MeiraGTx has manufactured a gene therapy that they are making available under a Specials license in the UK.”

After months of conversations, sharing test results, and talking with the hospital board members and surgeons, Jace received approval for the Compassionate Use treatment in one eye on March 17, 2020.

The family traveled to London, Jace underwent pre-op testing, and the surgery was cancelled: The world had just begun shutting down because of the COVID-19 pandemic.

DJ and Brendan thought the surgery would be cancelled indefinitely, but to their wonderment, they returned in September, quarantined for two weeks, and Jace received the gene therapy in his left eye, which is stronger, on Sept. 30, 2020. He had just turned 2 that August.

Jace in a hospital gown with a bandage on his left eye. He is holding his monkey binkie and Micky Mouse stuffed animal — Jace after undergoing Compassionate Use gene therapy

**Before LCA4 (AIPL1) surgery**

The couple first began to realize when Jace was about 8 weeks old that he was not looking at them or trying to track toys.

“He was smiling from touch, but never in response to one of our smiles. He wasn’t blinking when lights were shown in his eyes and wasn’t shutting his eyes or even squinting in the brightest of sunlight. His eyes never seemed to move out of that ‘newborn’ stage of being all over the place,” DJ said.

“When we brought him to the pediatrician, hoping we were just being paranoid and this was something he’d grow out of, they confirmed that something wasn’t right and within an hour we were meeting with a pediatric ophthalmologist – kicking off a year-long journey for answers.”

Before his surgery, Jace had minimal light perception and not much functional vision.

“Lights had to be very bright for him to react to, and his reaction was at least two seconds delayed. Phone screens and TV screens were not bright enough to elicit a reaction from him and outside he had to always be in sunglasses because the sun was never too strong for him to look away from.

“With his left eye, we felt like he could have some shadow perception or make out very high contrast shapes and objects,” DJ said. “He had some words at the time, and labeled toys by feel and sound, but never by sight.”

Prof. Michel Michaelides in a black suit — Prof. Michel Michaelides

Post surgery

About a year after Jace’s surgery, his parents – now both 33, with mom working as a market researcher and dad as a sourcing manager for a major retailer’s store design team – welcomed another son. Jace’s little brother, Gio, just turned 1 in August.

Gio is sighted and in awe of his big brother – so much so, DJ and Brendan said he always felt like a toddler to them, missing the infant stage, because he’s always trying to keep up with Jace.

He learned how to crawl so he could be closer to his brother and now runs out of bed to meet Jace every morning,” DJ said. “Jace assumed the ‘patient older brother’ role incredibly well. He’s even learned to share his most favorite toys and it’s music to our ears when the boys are both belly-laughing as they rough-house with one another and try out their wrestling moves.”

Jace and Gio sitting in a tent at the beach — Gio loves his big brother

Since the surgery, Jace can identify most of his toys by sight when they’re held three feet or closer to him.

“He is especially good at identifying the ones that are brightly colored and his favorite cars and dinosaurs, of course,” she said.

The couple believe Jace gained valuable functional vision from his surgery.

“Our hope was always that the surgery could protect some of the light perception he did have for a bit longer, never imagining that it could lead to anything more.”

Jace’s mom talked about LUXTURNA®, developed by Spark Therapeutics and the only federally approved treatment for LCA2 caused by a mutation in the RPE65 gene, which has demonstrated improved vision in people who underwent the gene-therapy surgery.

“Someone who received LUXTURNA® described vision improvement as regaining ‘pockets’ of vision in the area where the retina remained intact, and this is exactly how we believe Jace has also regained some vision in his left eye. He will turn his head in certain directions to get a better look at what is in front of him.

The Broadbin Family — Brendan, Jace, Gio, and DJ Broadbin

“In terms of being able to better navigate, Jace now bends down to pick up small objects that might be in his way, noticing them solely based on sight, not feel.”

Jace’s teachers have commented he’ll squat down to look under things when he wants a specific toy in the classroom and stand on tippy toes to find things placed on countertops.

“This makes us laugh to hear.”

Jace, now 4 years old, smiles when he catches a glimpse of his favorite people and things.

“It is heart melting. But he also still flashes that same perfect smile when he feels the sand at beach, hears his favorite country songs, or tastes an ice cream cone – so yes, his vision has changed and it’s amazing to experience, but to us he’s always been amazing to experience.”

P.S. Hope in Focus featured the Broadbin family in its annual Dinner in the Dark video in October 2022. Please click here to view.

Genetic Tests Glean New Diagnoses for People Living with Rare Inherited Retinal Disease

Three people who received diagnoses of Leber congenital amaurosis (LCA) in recent years – but lived most of their lives thinking they had retinitis pigmentosa (RP) – gave us the opportunity to hear their stories at a special session of the VISIONS 2022 conference this summer.

An RP diagnosis is currently given to patients with photoreceptor degeneration but good central vision within the first decade of life; an LCA diagnosis is given to patients who are born blind or who lose vision within a few months after birth.

In the middle of a two-day conference hosted by the Foundation Fighting Blindness, several of us from Hope in Focus in an LCA Mix & Mingle session heard about the sometimes-rocky road to getting a confirmed genetic diagnosis of a rare inherited retinal disease (IRD), especially in the years before access to genetic testing.

Ultimately, though, that difficulty did not hold back these individuals from creating happy and productive lives because they did not allow their blindness to define them.

A college of Linda, Russ, and Emily. — Linda Joy Wirth, Russ Davis, and Emily Townsend Cobb

Linda Joy Wirth

Blind since birth, Linda Joy Wirth, now 75 and living in Lakewood, Colo., was diagnosed with RP in the 1960s. Because she was told from an early age that nothing could be done for her blindness, she stopped thinking about her diagnosis and focused on her education, marriage, and children.

Then she thought: “You can never cure something if you can’t diagnose it.”

In the 1990s, she sought out a highly recommended doctor who treated her with a strong dose of cruel words.

“ ‘You’re blind. What do you want me to tell you?’ ” she recalled the doctor saying. “I was so distraught by the visit; I did not go back to the doctor for years and years and years.”

About 10 years ago, though, she went to a Foundation conference, where she received a referral to a Denver retinal specialist by the name of Dr. Alan Kimura, who changed her life.

“When I finally saw Dr. Kimura, I said I don’t even know why I’m here. I walked out two hours later, and I was walking on cloud nine. It’s so important to have the right retinal doctor.”

Dr. Kimura told her she had LCA. Genetic testing gave her a confirmed genetic diagnosis of LCA10, caused by mutations in the CEP290 gene.

Linda encourages people to get genetically tested to pinpoint the diagnosis, and then, like her, to be aware of the possibility of participating in a clinical trial to advance research into treatments and cures.

People told Linda along the way that because of her blindness, she shouldn’t marry or have children or follow her passion for acting. And, of course, she heard those stinging words from that earlier doctor: “ ‘You’re blind. There’s nothing we can do.’ ”

Linda is a retired clinical social worker in geriatric long-term care, an actor in a theater company, a Foundation volunteer, a mother of four, a grandmother of seven, a motivational speaker, and the author of “Just Because I Am Blind Does Not Mean I Can’t See!”

Russ Davis

Russ Davis, 60, of Jacksonville, Fla., still gets confusing information about the cause of his rare inherited retinal disease.

“One minute I hear it’s probably LCA, or no, that it’s classic RP. I got that at the conference.”

Some retinal experts do consider LCA to be a severe form of RP.

In 2019, Russ received a genetic diagnosis of LCA2, caused by a mutation in the RPE65 gene. Dr. Stephen Russell at the University of Iowa told Russ he could have RP or LCA.

“ ‘It could be either one,’ ” he recalled the doctor saying. “ ‘But at your age with so few retinal cells, we’re not going to know.’ ”

Russ said he’s a little frustrated with the lack of a certain label for the disease, but it’s not going to change his life.

“The blindness part, that’s fine. I am who I am. It doesn’t control my life. But I’d like to have answers.”

These days, Russ is going with LCA.

His vision loss occurred at birth. Growing up he could read a book with a bright light, ride a bike, and he enjoyed long-distance running.

“I could see most everything, except at night when everything disappeared. When the sun went down, I was toast,” he said. “There was nothing there. There was darkness and light bulbs.”

His vision worsened early in his career in his mid-20s working for the State of Florida, looking for people who owed child support and wanted to stay missing. The job was fun for 30 years but about 10 years ago, with his vision getting worse and work getting harder, he retired.

Russ and his partner, Denise Valkema, were like a comedy team at the LCA session, riffing off each other’s words and making the Mix & Mingle group erupt in rounds of laughter.

Denise, who lives with optic nerve hypoplasia, which is an underdevelopment of the optic nerve, met Russ through the National Federation of the Blind. Denise served as NFB’s Florida Affiliate President for seven years.

They both serve on the organization’s board. Their priorities include working with Congress on myriad pieces of legislation to bring about better accessibility to medical care, computer technology, banking, voting, and more.

“The blind community is still not able to participate fully in society because we don’t have access to all the aspects of living that the sighted community has,” Russ said. “Try finding a talking blood pressure cuff.”

Russ advocates for people with diminishing eyesight, reassuring them that that life will go on.

“It’s all about your attitude. I try to tell them, no, that it’s not going to be easy. Lots of times, it’s going to be difficult. There are a lot of things to adjust to. You simply find new ways to do the things you were doing before.

“You can’t let your loss of eyesight define who you are or control you. You have to own it and not let it control you.”

And he lives his words.

“There’s so many times in life, you have the option to laugh or to cry, and I’m going to pick laughter. It would be very easy to pick the other one.”

Emily Townsend Cobb

With a 2½-year-old daughter, another one on the way, and a pediatric physical therapy career, we were lucky we had the chance to talk with Emily Townsend Cobb at the LCA session.

Doctors diagnosed Emily with RP at age 3. Now, 33, she received a confirmed genetic diagnosis in 2019 of LCA13, caused by a mutation in the RDH12 gene.

Emily is in that age group of people misdiagnosed for years before the advent of genetic testing.

“Thirty and over, that’s how it went,” she said.

Getting the confirmed diagnosis didn’t really change her life, especially because LCA13 research is in preliminary stages.

“Now I sit and wait for my number to be called,” Emily said, referring to the possibility of a treatment or cure for her form of LCA. “While we wait for all these things to happen, we have to live life.”

Emily’s husband, and her mom and dad accompanied her at the conference. Her father, Clay, introduced himself, saying, “Oh, I’m the proud father of two girls with RDH12 and I’d do anything to help them.”

As he broke into tears, his wife, Sue, leaned into him, saying, “He’s a crier.”

Without having to say much more, it became clear why Emily credits her family for their loving support and positive approach toward life.

She said she receives 150 percent support from her family.

“That support is so important for anybody, but especially if you have a disability.”

Doctors also diagnosed her 31-year-old sister, Ashley, with RP, and she later received a genetic diagnosis of LCA13 (RDH12).

Emily remembers reading newsprint as a pre-teen and playing soccer, but her vision profoundly worsened as a teen-ager, a tough time for any kid, but especially for her as she was losing her sight.

About the same time, she learned she had LCA but didn’t undergo genetic testing because genetic data was still being mapped out.

We talked with Emily after the session when she returned to her home in Jacksonville, Fla., where early on, she said, her mom set her up with a therapist who had RP, which helped build her confidence as a teen-ager.

She put off using a cane until college and in her sophomore year got her guide dog, a black lab named Fergie, now retired to pet life after 11 years of service.

“She’s currently snuggled up to me on the couch while I fold laundry,” Emily said as her little girl, Elora, napped.

Her second daughter is due in October. And, oh, did we mention she runs half-marathons and is a triathlete?

Emily takes part in triathlons with her husband, Ryan; they are tethered during the running and swimming races and ride a tandem bike for the cycling portion.

“If you ever want to test the strength of a marriage, blindfold one of you and tether to the other,” Emily quipped.

She and Ryan talked about the chances of their children being born with LCA. She recalled her husband saying, “ ‘Emily, if they’re going to end up as awesome as you, I want to.’ ”

They knew their children could be born with LCA, but they also knew the rarity of the disease. Emily said the chances of having a child with LCA are about one in 400.

“I’ll take those odds,” she said. “I’m pretty happy that I’m here.”

Connecticut Legislature Establishes Permanent Rare Disease Advisory Council

Connecticut Gov. Ned Lamont signed into law years-in-the-making legislation establishing a permanent Rare Disease Advisory Council (RDAC), effective July 1, 2022.

Lesley Bennett, Volunteer Ambassador for the Connecticut Rare Action Network of the National Organization for Rare Disorders (NORD), praised the bi-partisan team of the General Assembly’s Public Health Committee, Chair Rep. Jonathan Steinberg and Ranking Member Rep. William Petit, for bringing the legislation to fruition.

“This RDAC will give patients, families, caregivers, health care providers, advocates, researchers, and other stakeholders an opportunity to make formal recommendations to state agencies and our legislature on ways to develop public policy and health care legislation that will improve the lives of those impacted by a rare disease in Connecticut,” Bennett said.

Connecticut-based Hope in Focus advocated over the years with the Rare Action Network for the establishment of the council. The state created a temporary rare disease task force in 2017 that never got off the ground.

This year, in a short legislative session – with lots of input from advocacy organizations, patients, caregivers, doctors, researchers, and advisory council members from other states – Connecticut’s governor signed into law House Bill 5500, now Section 48 of Public Act 22-58, establishing a permanent RDAC.

Laura Manfre, Hope in Focus Co-Founder and Board Chair, commended the action, saying it will bring much-needed awareness to rare diseases.

“Helping people living with rare disease all begins with awareness and Connecticut’s Rare Disease Advisory Council will help with that, and more, for the 7,000 known rare diseases affecting 25-30 million people, about 10 percent of the country’s population,” she said.

“Rare disease by definition needs all the attention it can get and establishing a Rare Disease Advisory Council in Connecticut can only bring more awareness to those living with rare conditions and bring needed support to help improve people’s lives.

“Rare diseases, such as Leber congenital amaurosis (LCA) and other inherited retinal diseases (IRDs), know no geographical boundaries, so it is a terrific step for Connecticut to join the other 22 states that already have established such councils.”

Hope in Focus Gave Supporting Testimony

Hope in Focus representatives testified in the last several years at the capitol in Hartford in support of establishing a permanent council by educating legislators about our organization and LCA to demonstrate in human terms the necessity for such a council.

We told them that LCA is characterized by severe vision loss at birth, and that while some children are born with little or no vision, others may have significant vision loss in the first few years of life, stable vision for a time, and, as the retina deteriorates, eventually blindness.

We let them know that LCA patients living with one form of the rare inherited retinal disease and treated with the gene therapy LUXTURNA® experienced dramatic changes in their lives with improved or restored vision. Five, 6, 7-year-old children treated with the breakthrough drug view life in a new light in big and little ways, and they now can see rainbows arcing in the sky and stars shining at night.

The legislators also needed to know that the optimal window for reversing vision loss is during the early phase of the disease. Current clinical trials and preclinical research give hope to those with one of the 26 other gene mutations identified to cause LCA, as those scientific studies are critical to advancing treatments for LCA and other IRDs.

After the U.S. Food and Drug Administration approved LUXTURNA® in 2017, several states attempted to pass laws denying access to treatment to individuals, saying a certain degree of blindness must be met before they could access treatment. Such restrictions are unacceptable and go against federal health recommendations, which state the earlier the intervention, the better the expected outcome.

Hope in Focus made the point that no one who qualifies according to FDA guidelines should ever have to wait to be “blind enough” to receive access to treatment. We, along with other organizations, were quick to call these states out and urged the Connecticut General Assembly to support patient access to FDA-approved treatments.

Rare Disease Advisory Council Specifics

The new law establishes a 13-member Connecticut RDAC to advise and make recommendations to the Department of Public Health and other state agencies about the needs of people in the state living with a rare disease and their caregivers. Advisory councils may differ from state to state in some ways. Click here to check whether your state has an RDAC or is working to establish one.

Council members will include insurance, public health, and social services commissioners, or their designees, and 10 members appointed by the governor and the Public Health Committee leadership.

The 10 members are:

a representative of an association of hospitals or a hospital administrator, and a physician with expertise in medical genetics.
a representative of a patient advocacy group in the state representing all rare diseases, and a family member or caregiver of a pediatric patient living with a rare disease.
a representative of the biopharmaceutical industry involved in rare disease research and therapy development, and an adult living with a rare disease.
a member of the scientific community engaged in rare disease research, and a caregiver of a child or adult living with a rare disease.
a physician who treats people living with a rare disease, and a representative, family member, or caregiver of a person living with a rare disease.

Initial appointments are required to be made by Oct. 31, 2022. Under the law, five of the first-appointed members serve two-year terms; five members serve three-year terms, and all members serve two-year terms thereafter. Members are not compensated for their services but may be reimbursed for necessary expenses.

The advisory council is required to meet in-person or remotely at least six times between Nov. 30, 2022, and Oct. 31, 2023, and quarterly thereafter. The council also must provide opportunities for the public to make comments, hear council updates, and provide input on council activities.

The council also can hold public hearings to solicit comments from the public to assist with a study or a survey about people living with rare disease, their caregivers, and their health care providers.

The RDAC can consult with experts to develop policy recommendations and conduct research to make recommendations covering treatment, care, safeguards against discrimination, health insurance coverage, drug formularies, and more.

The law also requires the council, starting by Nov. 30, 2023, to annually report to the governor and the Public Health Committee on its findings and recommendations, including council activities, research findings, and legislative recommendations; and potential funding sources for its activities, including grants, donations, sponsorships, or in-kind donations.

The first meeting of the council will be by Nov. 30, 2022.

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.”