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Human Organoids and organ-on-chip open new paths for gene therapy for blindness in childhood dementia

Successful efficacy test in human retinal model paves the way for clinical trial

Researchers have succeeded in demonstrating the efficacy of gene therapy against a symptom of the rare childhood dementia “CLN2 Batten disease” in a human retinal model – without animal testing. The therapy, being developed by the US company Tern Therapeutics, was able to reduce disease-related processes in retinal organoids and retina-on-chip models and has the potential to prevent the progression of blindness in patients. The results have already paved the way for a clinical trial in the UK.

Disease mechanisms recreated in the laboratory

Neuronal ceroid lipofuscinosis type 2 (CLN2) is an uncommon genetic condition that leads to childhood dementia and blindness due to mutations in the TPP1 gene. These mutations result in reduced levels of a lysosomal enzyme called TPP1 and development of symptoms. Brain and retinal degeneration can start in infancy. The photoreceptors, which are sensory cells responsible for vision, are especially impacted. Affected children go blind in a few years and, if untreated, typically only reach the age of eight to twelve. Available therapy can slow progression of some symptoms of disease, but there is no treatment for vision loss.

A research team from Tuebingen's Institute of Neuroanatomy & Developmental Biology and the Institute of Biomedical Engineering has achieved a realistic simulation of the disease using a complex model of the human retina: combining stem cell-derived retina organoids with a “retina-on-chip” model. The model replicates the structures and functions of the human retina in a plastic chip about the size of a one-euro coin so realistically that the toxic lipofuscin deposits typical of CLN2 disease could be precisely detected. The chip replicates the natural microenvironment of retinal cells in detail and enables a kind of artificial blood flow that dynamically supplies the cells with nutrients and oxygen, just as in the body. 

Gene therapy stops deposits in model

A new gene therapy being developed by Tern Therapeutics (TTX-381) has been tested using a laboratory model of the disease. To deliver the therapy, researchers use a modified virus as a transport vehicle. This virus acts like a small shuttle: it carries a working copy of the missing TPP1 gene directly into the retinal cells so that they can make the missing enzyme TPP1. The vector used belongs to the group of adeno-associated viruses. It does not cause illness; in this therapy it serves only as an “empty shell” to safely carry the gene into the cells.

The results are promising: the treated cells were once again able to produce the missing enzyme, and harmful deposits of lipofuscin either decreased or failed to appear. “Our retinal organoids show that we can reproduce eye diseases in the lab in a realistic way and use them to test whether gene therapy can work. This allows us to gain insights relevant for humans – without having to use animal experiments,” explains Dr. Kevin Achberger, head of the research group.

On the basis of these findings, a clinical trial has now been approved in the UK for children with vision problems caused by CLN2 disease – without prior testing of the gene therapy's efficacy in animal models. Traditional animal models are not suitable in context of efficacy testing for CLN2 disease, because they simply do not reflect the clinical picture as well as the retina organoid in combination with the retina-on-chip model has done. First interim results of the clinical trial of TTX-381 in humans are encouraging: there are early signs that this gene therapy can stabilize vision and may even improve it.

New approaches in gene therapy

In parallel with retinal therapy, Tern Therapeutics is working on a second gene therapy, TTX-181, that is designed to act directly in the brain of those affected. The aim is not only to prevent blindness, but also to slow down or even halt the neurological course of the disease and significantly extend life expectancy. "Families living with CLN2 have told us that one of their biggest fears is that their children will quickly go blind.  This is why it was so important for us to first focus on treating vision loss in CLN2. Preserving vision offers these children better quality of life and hope for a brighter future. However, we’re aware of the many other challenges these children and their families face, and therefore, we’re also developing gene therapies to treat other aspects of CLN2 disease" explains Alex M. Bailey, CEO of Tern Therapeutics. 

Significance for research

The collaboration is considered one of the first examples in which clinical trials for gene therapy could be conducted without the use of animal testing to test efficacy. Retina organoids in combination with organ-on-chip technology open up new approaches for drug development: they can replicate human diseases so realistically that they are increasingly being used as an integral part of testing new therapies before clinical trials. They have the potential to shorten the time between drug development and patient treatment, which is particularly crucial for patients with rare diseases. Although individual diseases may be rare, a total of around 400 million people worldwide suffer from a rare disease. 

About Tern Therapeutics
 Tern Therapeutics (Tern) is a privately-held biotechnology company founded in 2023 with a new vision to accelerate the development of transformative, one-time genetic therapies for rare diseases. Tern is committed to integrity, empathy, urgency, innovation, and determination as they collaborate with patient communities at every stage of development to bring therapies to people with rare diseases around the world. The first-in-human clinical trial to evaluate TTX-381 is active and recruiting patients. Learn more at www.clinicaltrials.gov (NCT05791864). For more information about Tern Therapeutics, please visit WWW.TERNTX.COM 

Image caption: The image on the left shows the retinal organoid with the toxic lipofuscin deposits (green) typical of CLN2 disease, which impair the photoreceptors (pink). On the right, almost no deposits are visible after gene therapy.

Image: © Kevin Achberger

Publication title: Corti, S., Kim, K., Cheng, T.. et al. Recreating pathophysiology of CLN2 disease and demonstrating reversion by TPP1 gene therapy in hiPSC-derived retinal organoids and retina-on-chip. CELL Reports Medicine (2025).

DOI: https://doi.org/10.1016/j.xcrm.2025.102244