Successful efficacy test in a human retinal model enables clinical trial
Researchers from the MicroOrganoLab and the Institute of Neuroanatomy from the University of Tuebingen have succeeded in demonstrating the efficacy of a gene therapy against a symptom of the rare childhood dementia “CLN2 – Batten disease” in a human retinal model – without using animal experiments. The therapy, 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. These results have now been published and paved the way for a clinical trial in the United Kingdom.
Recreating disease mechanisms in the laboratory
Neuronal ceroid lipofuscinosis type 2 (CLN2) is a very rare hereditary childhood dementia caused by mutations in the so-called TPP1 gene. From early childhood onward, the disease leads to progressive degeneration of the brain and retina. The photoreceptors—sensory cells responsible for vision—are particularly affected. Children lose their eyesight within a few years and, without treatment, typically reach only eight to twelve years of age. Existing therapies can slow the progression of some disease symptoms, but there is no treatment for vision loss.
The researchers have now succeeded in realistically simulating the disease in a complex model of the human retina: so-called retinal organoids derived from stem cells in combination with a “retina-on-chip” model. The model replicates the structures and functions of the human retina so realistically—on a plastic chip about the size of a one-euro coin—that the CLN2-typical lipofuscin accumulation could be precisely detected.
Gene therapy stops deposits in the model
In this in-vitro disease model, a gene therapy developed by Tern Therapeutics (TTX-381) was tested. A modified virus serves as a transport vehicle. Like a small shuttle, it transfers a functional copy of the missing TPP1 gene directly into the retinal cells.
The so-called adeno-associated viral vector is not a disease-causing agent and is used merely as an empty shell to deliver the missing gene into the cells. The results show that production of the missing enzyme could be restored. The harmful lipofuscin deposits decreased through the treatment or did not occur at all. “Our retinal organoids demonstrate that we can realistically recreate eye diseases in the lab and successfully test the efficacy of gene-therapeutic approaches in a human-relevant way without having to rely on animal testing,” explains research group leader Dr. Kevin Achberger.
Thanks to these preclinical results, a clinical trial for children with CLN2-related retinal damage has been approved in England—without any prior efficacy testing of the gene therapy in animal models. Early interim results from the TTX-381 clinical trial offer additional hope: there are already indications that the gene therapy may stabilize or even improve vision in patients.
New pathways in gene therapy
In parallel with the retinal therapy, Tern Therapeutics is working on a second gene therapy (TTX-181) that is designed to act directly in the brain. The goal is not only to prevent blindness but also to slow or even halt the neurological progression of the disease and significantly extend life expectancy. “One of the greatest fears of families whose children have CLN2 is the loss of vision. It was therefore essential that we first focus on treating vision loss in CLN2. Our therapy has the potential to significantly improve the quality of life for these young patients. However, we are acutely aware of the many other challenges these children and their families face, and are therefore also developing gene therapies to treat other aspects of CLN2,” explains Alex M. Bailey, CEO of Tern Therapeutics.
Significance for research
The collaboration is considered one of the first examples in which the path to clinical testing of gene therapies was possible without using animal experiments to demonstrate efficacy. Retinal organoids in combination with organ-on-chip technology offer new opportunities for drug development: they can model human diseases so realistically that they are increasingly becoming a fixed part of the methodological toolkit. Moreover, they have the potential to shorten the time between drug development and patient treatment—especially important for rare diseases. Despite their name, rare diseases are not so rare: a total of around 400 million people worldwide are affected.
About Tern Therapeutics
Tern Therapeutics (Tern) is a private biotechnology company based in Washington (USA), founded in 2023 with a new vision to accelerate the development of transformative, one-time gene therapies for rare diseases. Tern stands for integrity, empathy, drive, innovation, and determination, and collaborates with patient groups at every stage of development to make therapies accessible to people with rare diseases worldwide. The first human clinical trial evaluating TTX-381 is ongoing and currently recruiting patients. More information can be found at www.clinicaltrials.gov
