Stem Cell Models Offer New Insight into Childhood Genetic Blindness

Researchers at the Eye Genetics Research Unit at the Children's Medical Research Institute (CMRI) have become the first in the world to use stem cells to study one of the genetic causes of Leber Congenital Amaurosis (LCA), a rare inherited condition that causes severe vision loss in infants and young children. Findings published in Stem Cell Reports indicate that gene therapy may soon provide a potential pathway to prevent blindness in affected patients.

Modeling RPGRIP1-Related Retinal Disease

The study, led by Dr. To Ha Loi and colleagues, investigated RPGRIP1, a gene essential for the development and maintenance of photoreceptor cells, the light-sensitive cells that enable vision. Mutations in RPGRIP1 can lead to severe, currently untreatable retinal disease in children.

Many RPGRIP1 variants are still difficult to interpret. Nearly half of the known mutations are listed in the ClinVar database as having uncertain significance, limiting the ability of families and clinicians to confirm diagnoses or determine eligibility for clinical trials and future gene therapy programs.

Using Stem Cell–Derived Retinal Organoids

To address this challenge, the CMRI team developed 3D retinal organoids from stem cells, lab-grown mini retinas that replicate the structure and function of the human eye. These organoids allowed the researchers to study how RPGRIP1-related retinal disease develops and progresses at the cellular level.

This study marks the first use of retinal organoids to model RPGRIP1-related disease using both patient-derived and genetically engineered cells. The team found that even in early-onset cases, the overall structure of the retina appeared preserved, indicating that gene therapy may still have potential to restore vision in affected children.

Implications for Future Gene Therapy

Previous research into RPGRIP1-related disease relied primarily on animal models, such as mice. In contrast, the new human retinal organoids provide a more precise and scalable platform for studying inherited retinal disorders.

The findings highlight the potential for gene therapy to address early vision loss caused by LCA, supporting continued research into treatment options for children with inherited retinal conditions.

Reference:

Connecting cilium, stress response and proteostasis abnormalities inform variant and therapy assessment in RPGRIP1 retinal organoids, Stem Cell Reports (2025). DOI: 10.1016/j.stemcr.2025.102717