Leber Congenital Amaurosis (LCA) is a rare inherited eye disorder that causes severe vision loss in infants, affecting between 2 and 3 out of every 100,000 newborns. The condition results from mutations in more than 20 different genes, each of which can have hundreds of possible genetic variants. Some of these variants do not impact vision, while others cause the disease. There are also many variants whose effects are unknown; these are called variants of uncertain significance (VUS).
A research team led by Robyn Jamieson at the Children's Medical Research Institute, University of Sydney, has developed a laboratory platform to help classify these VUS using retinal organoids. Retinal organoids are small three-dimensional structures grown from stem cells that resemble the human retina.
The researchers published their findings in Stem Cell Reports. They created retinal organoids from stem cells taken from an LCA patient with known harmful changes in the RPGRIP1 gene and another patient with a VUS in the same gene. Both sets of organoids showed abnormalities such as fewer photoreceptors and altered gene expression.
Jamieson's team then introduced the RPGRIP1 VUS into healthy retinal organoids. The engineered organoids developed similar disease features as those seen in patients, showing that this particular VUS was pathogenic. When they reintroduced a healthy version of the RPGRIP1 gene into these organoids, the disease signs were reversed.
"This new platform can be used to classify new VUS in RPGRIP1 and other LCA genes, enabling clinical genetic diagnosis. Ultimately, the gained knowledge may help to develop targeted therapies for LCA patients and will inform decision-making and genetic counselling for at-risk populations," according to Jamieson's team.
This approach could improve how doctors diagnose LCA caused by unclear genetic changes and may support future efforts to create specific treatments for affected individuals.
