Encouraging News for CRB1 Gene Therapy Treatments 

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Early research into a form of Leber congenital amaurosis (LCA) caused by mutations in the CRB1 gene – including the discovery of a new version of a protein expressed by the gene – shows encouraging possibilities toward developing gene therapy treatment.

Amy Laster, PhD, Vice President of Science and Awards programs for the Foundation Fighting Blindness, shared the research news as part of a recent LCA Research Update webinar, summarizing results of an earlier CRB1-associated retinal disease Scientific Advancement Workshop.

“There’s certainly momentum that the research is actively happening, and that the community wants to address outstanding issues,” Laster said.

Laura Manfre, Sofia Sees Hope Co-Founder and President, said more than 40 leading experts in ophthalmology and gene research gathered in one room for more than five hours to share research and patient perspectives on LCA8 (CRB1) and identify the next steps to advance treatment for the patient community. 

Sofia Sees Hope and the Foundation Fighting Blindness created the Scientific Advancement Workshop with the objectives of widening the circle of research awareness into CRB1, building a framework or platform for sharing knowledge, fostering collaboration among stakeholders, identifying gaps, and setting priorities for action.

The route to approved LCA treatments consists of multiple, winding paths rather than one direct straightaway: No quick, easy solutions.

“For CRB1, in particular, the biology here is very, very complex,” said Manfre, who is also a member of the Foundation’s Board of Directors.

Referencing results of the workshop, Manfre displayed what she called a “celebration photo” of a smiling young girl hitting a piñata bursting forth with sprays of candy.

“What I want to communicate here is just how much of a celebration it is that we had this workshop. There are no simple, straightforward answers, but the really good news, or the celebration, is that this was one more step ahead in bringing the right people and all the very smart people together,” Manfre said.

CRB1 Preclinical Research

Laster described the gene therapy development path from research to treatment or cure. The path begins with basic knowledge of the gene and its functions and understanding the biology of the disease, which includes designing non-human research models and conducting Natural History studies. 

Preclinical CRB1 research currently centers on understanding the biology of the mutation and working toward conducting a Natural History study. 

Natural History study researchers observe clinical features in the absence of any treatment, gaining an understanding of myriad features, including the retina’s architecture and the patient’s visual function, sensitivity to light, and peripheral vision. The data provide knowledge and an independent understanding of the disease, while establishing an essential foundation for building drug development programs.

Later stages on the way to treatments and cures include designing clinical trials, selecting patients, predicting outcomes, setting measures for endpoints and outcomes, and conducting Phase I, II and III human clinical trials. The goal is U.S. Food and Drug Administration approval of a safe and effective treatment. 

Laster shared news from the workshop that Jeremy Kay, PhD, found a new version, or isoform, of CRB1 called CRB1b.

Kay, Associate Professor of Neurobiology and of Ophthalmology at Duke University, found that the CRB1b protein is more abundant in human and mouse retinas than the first identified version, CRB1a.

“Unlike CRB1a,” Laster said, “the removal of the CRB1b causes a retinal degeneration in mice and this has not been shown before with the first identified isoform.”

The research gives rise to new questions as to whether CRB1a or CRB1b protein expression or both should be the target for a gene therapy, she said.

Duke University research news characterized Kay’s findings published in Natural Communications as “a game-changer in light of the critical progress, over the past few years, in the treatment of inherited retinal diseases …”

Laster referenced CRB1 research models and gene augmentation therapy studies by Jan Wijnholds, PhD, Principal Investigator in the Department of Ophthalmology at Leiden University Medical Center, Leiden, Netherlands. The findings by him and his team can be found here in Frontiers in Neuroscience

She also discussed the work of Dr. Jacque Duncan, Professor of Clinical Ophthalmology at the University of California, San Francisco. Dr. Duncan is in talks with the Foundation about her interest in understanding the relationship between CRB1’s genotype and phenotype, or its genetic characteristics and physical characteristics. 

“On the clinical side, in terms of actually conducting a Natural History study, there was a lot of enthusiasm about that,” she said. “The Foundation is in touch with Dr. Jacque Duncan about potentially moving forward with that.”

The Foundation, the largest private funder of research for treatments and cures of blinding retinal diseases, has raised nearly $800 million since its inception and funds more than 80 research projects globally. Laster oversees the organization’s preclinical research portfolio consisting of research awards in funding programs that support career development, laboratory-based science research, translational research, and multi-investigator program projects.

CRB1 Patient and Caregiver Survey

Todd Durham, PhD, also an organizer of the Scientific Advancement Workshop, said sharing CRB1 patient perspectives through survey answers marked one of the highlights of the workshop because it gave researchers insight to help focus their studies for treatments or cures.

In the survey developed by the Foundation Fighting Blindness and Sofia Sees Hope, 85 percent of the respondents have a profile on My Retina Tracker® registry, a free online registry that enables people with inherited retinal degenerative diseases, their doctors, and researchers to actively collaborate in the research process. 

Durham, the Foundation’s Vice President of Clinical and Outcomes Research, said the CRB1 survey also showed patients received a clinical diagnosis at an average age of 13, while 24 was the average age for getting genetically diagnosed, showing a significant gap between the diagnoses.

The most reported worries were progression to blindness and concerns about employment. Most of the survey takers said they would participate in clinical trials, while many were concerned about the safety of the trials, the risks to remaining vision, and the potential for benefit.

People also were asked to describe their motivation for taking part in a clinical trial. A common thread to the responses, Durham said, was to help themselves see better and help others through research. 

In a sampling of comments, one person wrote: “1. Cure the disease. 2. Have a more comfortable life. 3. Not feel different from the rest because of your visual impairment.” 

Under the section “Anything Else to Share with Researchers,” a respondent wrote: “I feel the mental health impacts of a disability are overlooked a lot of the time.”

An Engaged CRB1 Community

In the question-and-answer session, an audience member asked where to go for information about CRB1, noting that his doctor had no idea about it. He said he felt lucky to live near a teaching hospital and could reach out for help but thought others may not be as fortunate.

Ben Shaberman, the Foundation’s Senior Director of Scientific Outreach and Community Engagement, said he understands that difficulty and he is part of a team educating eye-care professionals around the country. He encouraged people to email the Foundation at info@fightingblindness.org for contacts in the academic and medical world of retinal specialists and researchers.

Manfre said the CRB1 community is highly active and suggested that people join the new CRB1 Network on Facebook and check out the Resources page on the Sofia Sees Hope website that has a link to a CRB1 group called Curing Retinal Blindness Foundation. She said people can also find a strong Spanish-speaking community at Grupo CRB1 España y Latinoamérica

She advised people to update their profiles on My Retina Tracker to help advance research and to follow the Foundation and Sofia Sees Hope websites for information and research news. You can email questions or concerns to Sofia Sees Hope at info@sofiaseeshope.org

Advocating for treatment and cures for rare diseases such as CRB1 takes a grassroots effort, Manfre said, requiring people to inform, support, and educate one another, and to continue sharing stories and reaching out on social media.

Gathering in groups such as this webinar, she said, also helps connect people and generate awareness that, in turn, advances research. 

“All of this makes a huge difference.”