Systematic Drug Screening Against Childhood Dementia

A research project funded by the NCL Foundation is testing around 10,000 already known compounds to determine whether they can correct disease-related changes in the childhood dementia NCL. The aim of the project is to identify promising drug candidates and accelerate their progression into clinical development.

Neuronal ceroid lipofuscinoses (NCL), a form of childhood dementia, are rare inherited neurodegenerative diseases. Approximately 70,000 children worldwide are affected. The disease leads to progressive loss of vision and motor function, cognitive decline, and epilepsy. There is currently no cure. Life expectancy is significantly reduced, and most patients only reach the age of about 20 to 30 years.

To identify potential therapeutic approaches more quickly, Prof. Diego Medina from the University of Naples and the Telethon Institute of Genetics and Medicine (TIGEM), a research institute founded by the non-profit organization Fondazione Telethon whose mission is to advance research toward the cure of rare genetic diseases, plans to test around 10,000 already known or approved compounds. The goal is to find substances that could also be effective in NCL. The NCL Foundation is funding the research project in Italy with €300,000 over a period of three years.

"This generous support from the NCL Foundation comes at a critical time for families affected by Batten disease”, says Prof. Diego Medina. “It will allow us to systematically screen 10,000 compounds, bringing hope for the rapid identification of promising candidates and accelerating their path toward clinical development. For families living with this devastating disease, this support represents not just funding, but a real chance for progress and hope.”

Disruptions in the Cell’s “Recycling Centers”

NCL is caused by genetic mutations. These mutations lead to the absence or malfunction of important proteins in lysosomes. Lysosomes are the “recycling centers” of the cell. When their function is impaired, metabolic by-products accumulate, particularly in the brain and retina, leading to the death of nerve cells.

Previous work by other research groups has identified two classes of molecules that change significantly in the lysosome in CLN3 disease: GPDs (glycerophosphodiesters) accumulate, while BMPs (bis(monoacylglycero)phosphate) are strongly reduced. Because GPDs inhibit degradation processes in the lysosome and BMPs are an essential component of these processes, it is assumed that reducing GPD levels and/or normalizing BMP concentrations could significantly improve disease progression.

Research-Team of the High Content Screening Facility at TIGEM, L to R: Dr. Sandro Montefusco, Dr. Claudia La Vecchia, Dr. Antonella Capuozzo (all three Postdocs, High Content Screening Facility, TIGEM) and Prof. Dr. Diego Medina

Automated Search for Promising Substances

In the newly funded project, Prof. Medina’s team is using high-throughput methods to search for substances capable of correcting pathological changes in BMP and GPD metabolism. To do this, the researchers combine modern cell biology with an automated imaging-analysis approach.

Previous work by the research group has also shown that the lipid molecule Gb3 accumulates in the lysosomes of NCL laboratory models. This accumulation can be measured automatically across many samples simultaneously using a specialized method known as high-content imaging.

Using this method, the team will test approximately 10,000 compounds in cell cultures that model NCL cells. In the next step, the researchers will examine whether the most promising substances can also normalize BMP and GPD metabolism. The most effective candidates will then be tested in animal models to evaluate their effects in a living organism.

The tested substances include both drugs already approved for other diseases and molecules whose safety has already been evaluated in clinical trials. If suitable candidates are identified, they could potentially be moved into clinical studies relatively quickly.

The researchers hope to identify new drug candidates that can eventually be further developed in clinical trials. At the same time, the project establishes a platform that will allow additional substances to be systematically tested for their potential in NCL in the future.

Webinar Series

In the webinar series “Advances in NCL Research: Global Perspectives After 200 Years” by the NCL Foundation, Prof. Diego Medina provides insights into the methods he has developed to study NCL and potential drug candidates and presents results from his previous research.

Click here for the video!