DEM-CHILD

A Treatment-Oriented Research Project of NCL Disorders as a Major Cause of Dementia in Childhood

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 Obiettivo del progetto (Objective)

'The DEM-CHILD project focusses on the main cause for childhood dementia in Europe, the neuronal ceroid lipofuscinoses (NCLs). The NCLs are neurodegenerative diseases characterized by dementia, blindness, epilepsy and physical decline leading to an early death of the patients. Since no cure is currently available, these disorders represent a serious social, medical, and economic challenge. To date, eight NCL genes have been characterised. There is evidence suggesting that further gene loci remain to be identified. NCLs are under-diagnosed in many countries around the world as there is an overall lack of research, early diagnosis, treatment and expert availability. Furthermore, due to their broad genetic heterogeneity it is difficult to collect large numbers of genetically similar patients. As such, large therapeutic studies required for advances in treatment are difficult to initiate. The DEM-CHILD project will combine the expertise of (i) recognized European research teams with (ii) high-technology SMEs, and will (iii) collaborate with Indian experts on the following objectives: (1) High-technology SMEs will develop innovative cost- and time-effective testing and screening methods for all NCLs in order to ensure early diagnosis and thereby prevention. (2) DEM-CHILD will collect the world’s largest, clinically and genetically best characterised set of NCL patients in order to study disease prevalence and precisely describe the natural history of the NCLs leading to the development of an evaluation tool for experimental therapy studies. (3) Novel biomarkers and modifiers of NCL will be identified to support the development of innovative therapies. (4) Focussing on the development of therapies for NCLs caused by mutations in intracellular transmembrane proteins, two complementary therapeutic strategies will be used and compared in eye and brain of mouse models: a) viral-mediated gene transfer and b) neural stem cell-mediated delivery of neuroprotective factors.'

Introduzione (Teaser)

Neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative disorders that have no cure and are the leading cause for childhood dementia in Europe. NCLs cause visual loss, dementia, epilepsy and progressive physical decline, resulting in the death of the patient.

Descrizione progetto (Article)

The EU-backed project 'A treatment-oriented research project of NCL disorders as a major cause of dementia in childhood' (DEM-CHILD) was initiated to develop innovative treatment options to combat NCL. The DEM-CHILD consortium consists of expert scientists, clinicians and ethicists, high-technology small and medium-sized enterprises (SMEs), and NCL patient and family associations.

An online DEM-CHILD patient database consortium has been developed with members from 10 countries, and patient recruitment as well as data collection is continuing. A major accomplishment to date is the development of the NCL diagnostic algorithm, the focus of two peer-reviewed journal publications.

NCLs have been associated with gene mutations such as CLN1, CLN2 and CLN3. An automated enzyme activity testing method based on mass spectrometry has been successfully developed to detect CLN1 and CLN2 gene mutations from dry blood spots. Researchers have also developed a cost-effective, rapid genetic diagnostic tool to detect all NCL forms through comprehensive analysis. Work is ongoing to adapt this for high-throughput applications.

Additionally, scientists identified a novel signalling pathway associated with CLN3 disease that could be a potential target for therapy. Animal models have been used to study proteomic changes due to CLN mutations and certain biochemical changes specific to CLN1 have been identified. Researchers also identified a to-date unknown NCL disease gene called ATP13A2/CLN12.

Pre-clinical testing of therapeutic options is ongoing. Adeno-associated virus constructs carrying the CLN3 or CLN6 gene for mice deficient in CLN3 or CLN6 transmembrane proteins were developed and testing is being carried out. Neural stem cell lines that over-express proteins responsible for the growth, survival and maintenance of neurons have also been established. These cell lines will be used in intra-vitreal transplants to test vision recovery in mice.

Project outcomes have been disseminated through DEM-CHILD teaching seminars, the http://www.dem-child.eu (project website) , workshops, conferences, a diagnostic hand-out and a teaching video. Early detection of NCL in a family could facilitate prenatal testing for NCL in future offspring and prevent more NCL cases. Validation of experimental therapies and palliative care with the DEM-CHILD patient database should improve patient quality of life and hopefully their outcomes.