Vision Loss in Juvenile Batten May Be Due to ‘Maintenance’ Failure

CLN3, the protein missing in people with juvenile Batten disease, is needed for a cellular process normally taking place in the retina that works to maintain the specialized cells needed for sight, a study reports.

According to its researchers, these findings aid in understanding the cellular and molecular mechanisms responsible for vision loss in children with this form of Batten disease, and support work into new ways of treatment, including gene or cell therapy.

“It is important to understand how vision loss is triggered in this disease, what is primary and what is secondary, and this will allow us to develop new therapeutic strategies,” Ruchira Singh, PhD, an associate professor in 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 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 lower the amounts of functional CLN3 protein available.

It is characterized by early and progressive vision loss, which can appear in children as young as age 4.

In many cases, vision problems precede the severe neurological and developmental issues also associated with this disease, making it hard to properly diagnose.

Vision loss and blindness in patients with CLN3 disease is known to directly result from damage to the retina. But the exact cellular and molecular mechanisms underlying this damage are still unknown. (The retina consists of  layers of light-sensitive photoreceptor cells that line the back of the eye and send signals to the brain, allowing for sight.)

“This is partly due to limited and conflicting data on CLN3 localization and function in the retina, and lack of a suitable model system that recapitulates the human disease phenotype [symptoms],” the researchers wrote.

Rochester researchers and their colleagues developed a new human cell model able to mimic what happens in patients, and found evidence that CLN3 is needed for the maintenance of 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 individuals. These cells were then reprogrammed to give rise to human-induced pluripotent stem cells, which can grow into almost any cell type.

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 photoreceptor cells in the retina. These RPE cells harbored the same mutations known to cause CLN3 disease.

With this model, investigators discovered that CLN3 is needed 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 removing photoreceptors’ older outer segments is part of a natural maintenance mechanism, in place to ensure these light-sensitive cells survive and continue to work as they should.

In their experiments, the researchers demonstrated that patient-derived RPE cells were less able to bind to and engulf photoreceptors’ outer segments. They also showed this process could be restored by providing the cells with a healthy copy of the CLN3 gene.

“Altogether, these results illustrate a novel role of CLN3 in regulating 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.