CLN3, the protein missing in people with juvenile Batten disease, is required for a normally occurring cellular process in the retina that functions to maintain specialized cells needed for sight, a study has found.
According to its researchers, these findings help to understand the cellular and molecular mechanisms responsible for vision loss in children with this form of Batten disease and support work on new treatment pathways, including gene or cell therapy.
“Understanding how vision loss is triggered in this disease, what is primary and what is secondary, is important and will allow us to develop new therapeutic strategies,” Ruchira Singh, PhD, associate professor at the Center for Visual Science at the University of Rochester, and the study’s lead author, said in a university press release.
The study, “A human model of Batten disease shows the role of CLN3 in phagocytosis at the photoreceptor-RPE interface», published in the journal Communications Biology.
Juvenile Batten disease, also known as CLN3 disease or juvenile neuronal ceroid lipofuscinosis (JNCL), is caused by mutations in the CLN3 gene that decreases the amounts of functional CLN3 protein available.
It is characterized by an early and progressive loss of vision, which can appear in children as young as 4 years old.
In many cases, vision problems precede the serious neurological and developmental problems also associated with this disease, making it difficult to diagnose correctly.
Vision loss and blindness in patients with CLN3 disease are known to result directly from retinal damage. But the exact cellular and molecular mechanisms underlying this damage are still unknown. (The retina is made up of layers of light-sensitive photoreceptor cells that line the back of the eye and send signals to the brain, enabling sight.)
“This is partly due to limited and conflicting data on CLN3 localization and function in the retina, and the lack of a suitable model system that recapitulates the human disease phenotype. [symptoms]“, wrote the researchers.
The Rochester researchers and their colleagues developed a new human cell model capable of mimicking what happens in patients and found evidence that CLN3 is required to maintain specialized cells in the retina that play a key role in vision.
The team started by isolating skin cells from patients and people without the disease, both family members and unrelated people. These cells were then reprogrammed to give rise to human-induced pluripotent stem cells, which can grow into almost any type of cell.
The researchers then used these stem cells to create retinal pigment epithelium (RPE) cells – those that make up the pigmented layer of the retina and whose main function is to support the photoreceptor cells in the retina. These RPE cells carried the same mutations known to cause CLN3 disease.
With this model, the researchers found that CLN3 is required for RPE cells to maintain their normal structure, as well as to engulf and degrade the outer segment of photoreceptor cells in a process known as phagocytosis. This process of periodically shedding the older outer segments of photoreceptors is part of a natural maintenance mechanism, put in place to ensure that these photosensitive cells survive and continue to function as they should.
In their experiments, the researchers demonstrated that RPE cells derived from patients were less able to bind to the outer segments of photoreceptors and engulf them. They also showed that this process could be restored by supplying the cells with a healthy copy of the CLN3 embarrassed.
“Taken together, these results illustrate a novel role for CLN3 in the regulation of POS. [photoreceptor outer segment] phagocytosis, and suggest a contribution of primary RPE dysfunction for photoreceptor cell loss in CLN3 disease that can be targeted by gene therapy,” the researchers wrote.
