Retinitis pigmentosa (RP) is a degenerative eye disease that causes the progressive loss of photoreceptors—the light-sensitive cells in the retina—leading to vision loss and, eventually, blindness. Autosomal recessive RP is a form of the disease caused by genetic mutations, most commonly in the USH2A gene. This gene encodes Usherin, a protein that helps keep photoreceptors functional and healthy.
Until now, there was no reliable human disease lab model to study how USH2A-associated RP begins and progresses, which has slowed the development of new treatments. To address this gap, Dr. Brian Ballios and his team from UHN’s Donald K. Johnson Eye Institute (DKJEI) developed a retinal organoid model that more closely reflects USH2A-associated RP in the mature human retina. Organoids are 3D lab-grown models of a tissue or organ that capture the complex structure and function of real tissue.
To create these organoids, the team used induced pluripotent stem cells (iPSCs)—lab-made stem cells created by turning mature cells back into a state where they can become any type of cell again—using blood cells from patients with USH2A-associated retinitis pigmentosa. To compare to patient-derived organoids, the team also created organoids from healthy iPSCs that they genetically engineered to lack the gene. Throughout the organoids’ development, Dr. Ballios and the DKJEI team analyzed their genetic, molecular, cellular, and structural characteristics.
The findings show that retinal organoids with USH2A mutations are a good model, as they closely resemble what is seen in the clinic in individuals with RP. This includes the pattern of photoreceptor loss and changes to the retina’s structural and molecular characteristics that accompany the loss.
In addition, the study sheds light on how USH2A mutations drive changes in the development of the retina, contributing to photoreceptor loss in RP. For example, these models showed that fewer photoreceptors form in retinas with USH2A mutations, resulting in a smaller pool of photoreceptors that is lost more quickly. The research further highlighted the role of USH2A in early retinal development, which was previously unexplored. These changes happen long before symptoms appear, making them impossible to study without organoid models or in patients directly.
This work is an important step toward understanding retinitis pigmentosa. By offering a reliable model that can be manipulated in the lab, these findings could improve future research into new therapies. By beginning to understand the developmental underpinnings of USH2A-associated RP, this work may also introduce new avenues for early intervention aimed at slowing or preventing retinal degeneration. For patients, this progress moves us closer to a future where blindness is not inevitable in those living with retinitis pigmentosa.
Kristen Ashworth, Jiajie (Jackson) Zhang, and Cassandra D’Amata are co-first authors of this study. Kristen is a research trainee at UHN’s Donald K. Johnson Eye Institute (DKJEI) and a PhD candidate at the University of Toronto. Jiajie completed his MSc at the University of Toronto and is now a research technician in the Ballios Lab at DKJEI. Cassandra is a research technician and the lab manager of the Ballios Lab at DKJEI.
Dr. Brian Ballios, the senior author of this study, is a Scientist and a Retina Specialist at UHN’s Donald K. Johnson Eye Institute and an Assistant Professor at the University of Toronto’s Temerty Faculty of Medicine.
This work was supported by the Foundation Fighting Blindness, the University of Toronto, and UHN Foundation.
The authors report no competing interests.
Ashworth KE, Zhang J, D'Amata C, Héon E, Ballios BG. USH2A-Mutated Human Retinal Organoids Model Rod-Cone Dystrophy. Invest Ophthalmol Vis Sci. 2025 Nov 3;66(14):2. doi: 10.1167/iovs.66.14.2.