Advancing hope

When their 5-year-old boy was diagnosed with Stargardt disease, that family's world changed in an instant. As fear and uncertainty took over, they were left wondering how much longer their child would be able to see their faces and the world around him. The rare ophthalmologic disorder ultimately robs people of sight, but exactly when that happens remains unknown.

"They are stressed by the unknowns accompanying this disease," said Esther Biswas-Fiss, professor and chair of UD's Department of Medical and Molecular Sciences (MMSC). "Others feel like they're sitting on a ticking time bomb because they know their genotype but haven't had any symptoms yet."

At the VISIONS 2024 conference in Chicago, hosted by Foundation Fighting Blindness, Biswas-Fiss, who has dedicated her life to vision research, presented the latest cutting-edge research and emerging therapies that could help those impacted by vision loss. There, she also heard the distress in the voices of that young boy's family. That urgency continues to drive her research.

Recently, she received a $2.3 million grant from the National Institutes of Health's National Eye Institute (NIH/NEI) to further study the ABCA4 gene and its thousands of variants. Her research could lead to breakthroughs in understanding inherited retinal diseases like Stargardt, which is caused by changes in the ABCA4 gene. The rare genetic eye disease affects 30,000 people in the U.S., according to Foundation Fighting Blindness.

"A person is born with a variant in this gene, and depending on the severity or magnitude of the impact of the variant, they could have visual impairment as early as late teens or early adulthood and become blind shortly after that," said Biswas-Fiss. "It could also slowly manifest over time. So, every patient is different and doesn't present the same clinically. That makes understanding the genetic drivers of a person's inherited blindness critical."

Nearly 40% of the ABCA4's genetic variants remain unclassified in pathogenicity, posing significant challenges for accurate diagnosis and treatment.

Using artificial intelligence

Biswas-Fiss is leading an interdisciplinary research team consisting of Sam Biswas, professor of MMSC, Shawn Polson, associate director of UD's Center for Bioinformatics and Computational Biology, and Barry Bodt, a senior biostatistician in the Epidemiology program. Together, they're developing a machine-learning model that could revolutionize understanding these genetic variants.

"Through this NIH grant, we will develop a model that looks at all variants that have been unequivocally classified as pathogenic and benign to create a data set that can use algorithms to make predictions," she said, "From there, we'll use the variants of unknown significance to test the model."

The team will leverage 3D computational modeling to analyze the protein structures of these variants.

"We'll also integrate clinical data, such as the frequency of these variants in the population," she added. "For instance, a frequently appearing variant is less likely to be pathogenic, while a rare variant might be more concerning."

This kind of genetic testing and the discoveries by Biswas-Fiss' team will lead to more personalized medicine.

"The goal of our research is for people to understand the nature of the variant and whether it is pathogenic," said Biswas-Fiss. "This can help determine what clinical trials or precision therapies might be appropriate. It would also help patients gain eligibility into clinical trials and assist them with life-planning decisions."

The NIH/NEI grant comes on the heels of $300,000 in funding Biswas-Fiss received from Foundation Fighting Blindness for her vision research earlier this year.

Opportunity beyond scientific impact

The ongoing research also offers Biswas-Fiss an opportunity to create opportunities for underrepresented students in science. Among them, medical sciences doctoral candidate Senem Cevik, a first-generation college student, recently accepted a faculty position in her native Turkey. She's worked alongside Biswas-Fiss on this research for several years.