Key Takeaways

• A human stem cell-derived 3D retina model showed that primary RPE dysfunction can initiate photoreceptor degeneration in CLN3-Batten disease
• Reduced acid ceramidase levels and associated lipid abnormalities emerged as a potential mechanism contributing to retinal damage
• Recombinant human acid ceramidase improved cellular health and reduced retinal degeneration in preclinical models, supporting further investigation as a potential therapy

Researchers at University of Rochester Medicine have developed a 3D human stem cell-derived retina model that sheds new light on the mechanisms underlying early vision loss in CLN3-Batten disease and identifies recombinant human acid ceramidase as a potential therapeutic approach.

The study, published in Science Translational Medicine, suggests that dysfunction of the retinal pigment epithelium (RPE) may be sufficient to initiate photoreceptor degeneration in CLN3-Batten disease.¹ The findings challenge the view that retinal degeneration in the inherited disorder is driven primarily by abnormalities within neurons and photoreceptors.

CLN3-Batten disease is a rare inherited neurodegenerative disorder in which vision loss frequently occurs before progressive neurological decline. For affected children, declining vision can interfere with reading, learning, mobility, and independence years before other neurological manifestations emerge.

Studying the earliest stages of retinal degeneration has been difficult because the disease affects interactions between photoreceptors and supporting cells within the retina. To better reproduce those interactions, investigators created a 3D human stem cell-derived model designed to mimic the relationship between photoreceptors and the RPE.

“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,” Ruchira Singh, PhD, associate professor in the University of Rochester Medicine Flaum Eye Institute and lead author of the study, said in a University of Rochester Medicine article. 

Using the model, investigators found that disease-related abnormalities confined to RPE cells could lead to photoreceptor degeneration. The observation points to the RPE as an important contributor to the retinal manifestations of CLN3-Batten disease and could help explain why visual impairment occurs early in the disease course.

“Our data shows that primary RPE dysfunction is sufficient to instigate photoreceptor degeneration,” Dr. Singh said. “This may help explain why vision loss is one of the earliest symptoms in CLN3-Batten disease.”

The findings could also influence therapeutic development by indicating that preservation of vision may require targeting the broader photoreceptor-RPE unit rather than photoreceptors alone.

Investigators also identified reduced levels of acid ceramidase, an enzyme involved in cellular lipid regulation, in CLN3-Batten disease cells. Reduced enzyme activity was associated with lipid abnormalities that may contribute to retinal degeneration.

The team subsequently evaluated recombinant human acid ceramidase (rhAC) as a potential treatment in laboratory-grown retinal tissue and a large-animal model of CLN3-Batten disease. Treatment improved measures of cellular health and reduced signs of retinal degeneration, according to the researchers.

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

The results add a potential enzyme-based strategy to a therapeutic landscape that already includes investigational gene therapies and approaches targeting lipid metabolism. The researchers indicated that recognizing the role of RPE dysfunction could help inform these efforts by emphasizing the need to address both photoreceptors and their supporting cells.

Beyond its therapeutic implications, the 3D retina model could provide investigators with a human-relevant platform for studying disease mechanisms and screening candidate treatments. The approach may also have applications in other retinal disorders involving dysfunction of the photoreceptor-RPE interface.

Additional studies will be needed to establish the long-term safety and efficacy of rhAC before clinical testing and to determine whether the strategy could affect manifestations of CLN3-Batten disease beyond retinal degeneration.

The study included collaborators from the University of Rochester, University of Tasmania, Cleveland Clinic, and Icahn School of Medicine. Funding was provided by the National Eye Institute, ForeBatten Foundation, and Mangurian Foundation.

Reference

1. Han J, Foley N, Dalvi S, et al. A 3D human retina model reveals a non-cell-autonomous and non-neuronal mechanism of photoreceptor loss in a lysosomal storage disorder. Sci Transl Med. 2026;18(864):eady7616. doi:10.1126/scitranslmed.ady7616