3D retina model reveals how vision loss may begin in juvenile Batten disease

A new 3D model of the retina, the light-sensitive tissue at the back of the eye, is helping researchers uncover how vision loss may begin in juvenile Batten disease, also known as CLN3 disease, while pointing to a potential therapeutic approach to protect vision.

Using the model, researchers at the University of Rochester Medicine found that dysfunction in retinal pigment epithelium (RPE) cells — which support the eye’s light-sensing photoreceptors — can drive photoreceptor degeneration. The findings suggest that vision loss in CLN3 disease may stem partly from problems in these support cells, rather than solely from problems within photoreceptors themselves.

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The researchers also linked photoreceptor degeneration to reduced levels of acid ceramidase, an enzyme that helps process fatty molecules inside cells. Treating the 3D model and an animal model of CLN3 disease with a lab-made version of the enzyme eased photoreceptor degeneration.

“Our data shows that primary RPE dysfunction is sufficient to instigate photoreceptor degeneration,” Ruchira Singh, PhD, an associate professor at the University of Rochester Medicine Flaum Eye Institute and lead author of the study, said in a university news story. “This may help explain why vision loss is one of the earliest symptoms in CLN3-Batten disease.”

The study, “A 3D human retina model reveals a non-cell-autonomous and non-neuronal mechanism of photoreceptor loss in a lysosomal storage disorder,” was published in Science Translational Medicine.

CLN3 disease, the most common form of Batten disease, is caused by mutations in the CLN3 gene that disrupt the function of lysosomes, structures inside cells that break down and recycle waste. As waste builds up, nerve cells become progressively damaged, leading to neurological decline.

Vision loss is often one of the earliest signs of the disease, usually emerging during childhood and often years before other Batten symptoms occur. As the disease progresses, people can develop cognitive decline, seizures, and worsening motor problems.

Despite its early onset, exactly how CLN3 mutations lead to retinal degeneration remains poorly understood.

3D model recreates key photoreceptor-RPE interaction

Photoreceptors — nerve cells in the retina that detect light — depend on neighboring RPE cells for support. But studying this relationship has been difficult because existing lab models do not preserve how the two cell types are normally organized and interact in the human retina.

To overcome this, the researchers developed a 3D human retina model from pluripotent stem cells, which can develop into many different cell types. The model combined retinal organoids — miniature retina-like tissues — with RPE cells, allowing the researchers to study how the two cell types interact.

“Although molecular and cellular changes associated with the disease have been shown in other models, this retina model captures the earliest and most consistent pathology seen in patients, including photoreceptor outer segment loss and degeneration,” Singh said. Photoreceptor outer segments are specialized structures that capture light and are essential for vision.

Using the 3D model, the researchers studied the effects of the most common CLN3 disease-causing mutation, called CLN3^Δex7-8, in which exons 7 and 8 of the gene are missing.

The mutation led to loss of photoreceptor outer segments, reproducing an important feature of retinal degeneration seen in CLN3 disease. It was also associated with reduced levels of acid ceramidase and sphingosine-1-phosphate, a fatty signaling molecule.

Acid ceramidase is an enzyme that helps break down sphingolipids, a group of fatty molecules important for cell function. By studying RPE cells both on their own and in the 3D model, the researchers found that problems in the RPE cells themselves could promote photoreceptor outer-segment loss and retinal degeneration.

The findings suggest that problems in these support cells can damage neighboring photoreceptors, rather than photoreceptor degeneration arising solely from problems within the photoreceptors themselves.

Findings extend to miniswine and donated human eyes

Molecular and structural changes seen in the 3D model were also validated in a miniswine (animal) model of the disease and in donated eyes from two people with CLN3 disease.

The team next investigated whether restoring acid ceramidase could protect photoreceptors. Treating the 3D model with recombinant human acid ceramidase (rhAC), a lab-made version of the enzyme, eased photoreceptor degeneration. Similar benefits were seen in the miniswine model, supporting further study of the approach.

“rhAC is a strong therapeutic candidate because it restores enzyme activity in diseased cells without affecting healthy ones,” Singh said.

More research will be needed before the approach can be tested as a treatment for people with CLN3 disease. Still, the study offers new insight into how vision loss may develop and suggests “that rhAC could be a therapeutic approach for retinal degeneration in CLN3 disease,” the researchers wrote.