Back to "Research and Funding" - Fundings

Completed Fundings

In recent years, quite a few projects funded by the NCL Foundation have been successfully completed. We would like to present these projects in the following pages. In addition, you will find a list of all publications that we have launched.


Development of a Cell-based Bioassay (Rehovot, 2014)


The PhD student Osnat Zontag-Cohen was working on the development of an assay method for NCL. She was supported by Prof. Jeffrey Gerst of the Weizmann Institute of Science in Rehovot and promoted by us, the BDSRA and the BDFA. Her research was based on baker’s yeast as a model organism and aimed at understanding molecular mechanisms in diseased NCL cells. Osnat was able to measure differences, in for example shape and distribution of cell organelles, between wild type and CLN3-deficient cells. She tried to make use of the measurability of differences between normal and diseased cells by establishing a functioning testing procedure, which could be used as a basis for screening potential therapeutic molecules.

 

Characterisation of a Cell Signalling Pathway in NCL (Rehovot, 2014)


The financial support from the 1st NCL Research Award helped Niv Dobzinski boost his research on yaest as a model organism to find out how protein accumulations arise in the vacuole. Niv was supported by Prof. Jeffrey Gerst of the Weizmann Institute of Science in Rehovot and financed by the BILD-metropress-Golf-Cup and our Charity Dinner amongst others. He found out that a lack of nutrients leads to inactivation of a certain signaling pathway and subsequently to protein mislocalisation. Furthermore, he characterized the protein modification (ubiquintination), some enzymes and a regulatory protein, which are all involved in the process. Such a miss-localisation is caused by a deletion in the BTN1 gene of yeast, which corresponds to the human CLN3 gene. Niv’s results could therefore be applicable to the protein accumulations in the lysosomes of NCL patients and could help to understand cellular processes in NCL diseases.

 

The Golgi apparatus of NCL cells (London, 2014)


The reward money from the 3rd NCL Research Award, won by Dr. Sara Mole from the University College London, enabled Davide Marotta to analyze the Golgi apparatus of JNCL-cells. This organelle plays a crucial role in final packaging and delivery of all proteins synthesized in the cell. The PhD student found a morphological modification of the Golgi apparatus of NCL patients, which could be connected to cellular disease symptoms and thus be considered a possible approach for new therapies.


 

 

 

The interaction between CLN3 and SorCS1 - a connection to Alzheimer ? (Hamburg, 2014)


Funded by AstraZeneca, the Olympus Europe Foundation and Hamburger Sparkasse, Sandra Oetjen researched in the laboratory of PD Dr. Guido Hermey of the University Clinic Hamburg (ZMNH). Aiming at understanding more about the function of CLN3, she identified and investigated potential interaction partners in the cell. These interactions could be connected with the strong impact JNCL has on the brain. Sandra detected an interaction of the NCL protein CLN3 with another membrane protein which is part of a complex that cleaves certain proteins. This cleavage process is necessary for several cell functions and is associated with other neurodegenerative diseases. CLN3 or a defective CLN3 might therefore also influence those diseases.

Since the results of this work are very promising, the project will be continued by an additional doctoral scholarship.

 

Proteome composition of pathological aggregations of ceroid (Düsseldorf, 2014)


In the research group of Prof. Carsten Korth of the University Clinic Düsseldorf Philipp Ottis investigated the composition of proteins of ceroid lipofuscin. It aggregates in cells of the central nervous system of JNCL patients. Funded by the NCL Foundation the PhD student isolated proteins of the storage material from brain cells of patients and mice affected with NCL as well. He compared the pathological proteomes among each other and to non-pathological lipofuscin storage linked to aging. The aim was to identify protein components characteristic to pathological ceroid lipofuscin and their associated molecular mechanisms. They could serve as approaches for symptom treatments.

 

 

 

"Modifier genes" - new therapy approaches in NCL-yeast-model (London, 2014)


In the laboratory of Dr. Sara Mole of the University College London, the biologist Mariana Vieira worked on NCL yeast cells. The BTN1 gene in the yeast Saccharomyces pombe is a homologue to CLN3 in human. Mariana identified potential modifier genes, which might influence the disease progression. Furthermore, the PhD student investigated, if those genes alleviated the disease pattern in the yeast cells by suppression or over-expression. In collaboration with the Auerbach Foundation, the NCL Foundation supported her work to find new therapy approaches for JNCL and establish an assay for screening purposes.


 

 

Immune activation in the retina at NCL (Cologne 2013)


The Canadian-born Myriam Mirza researched in Prof. Thomas Langmann’s corporation (teaching hospital of Cologne - Experimental Immunology of the eye). This project has been promoted from 01/11/2009 to 31/10/2011 by the NCL-Foundation in cooperation with the Auerbach Foundation.

In the research project a possible malfunction of the microglia, especially in visual disturbances, was studied as a symptom of juvenile neuronal ceroid lipofuscinosis. In addition, the effect of immunotherapy on the treatment of retina degeneration in NCL was examined in mouse subjects. With a curcumin, luteolin or omega-3 fatty acid-containing diet, the mice (CLN-6 mouse model) showed improved vision. The anti-inflammatory agents inhibit the immune response and thereforeprotect the retina from further damage. These results were published in October 2013 in the journal PLoS One.

 

Establishment of induced pluripotent stem cells as a new model for NCL (Dresden, 2013) 


Xenia Lojewski researched in the laboratory of Prof. Alexander Storch at the TU Dresden. In cooperation with the Max Plank Institute in Münster (Prof. Dr. Hans Schöler), it has become successful in producing induced pluripotent stem cells (iPS cells) from skin cells from JNCL patients. Later on, the first patient cells were reprogrammed into pluripotent stem cells (iPS cells) at the Teaching Hospital in Dresden, the project in Boston could be continued at the Massachusetts General Hospital. Together with Dr. Cotman’s research group, she succeeded in investigating iPS cells from a total of 5 patients studied. After a thorough biochemical investigation, cell lines of the brain were prepared from the iPS cells. The mature neurons as well as their predecessors, the neural precursor cells, were then analysed phenotypically. The cells were examined and it was determined whether there are abnormalities in the patient's cells compared to control cells using the most modern biochemical technology. It was found that the nerve cells derived from patient's cells, in fact, showed abnormalities. This phenotype can now be used for further studies in basic research. It has therefore succeeded in establishing iPS cells based on human cell models of juvenile neuronal ceroid lipofuscinosis, which will hopefully soon provide the researchers with further information about the disease. Furthermore, the developed cell model is suitable for drug screening.

 

What are the effects from immune cells in the brain of NCL mice? (London/ Würzburg, 2013)


The project of Thomas Kühl (King's College London) should be promoted due to the generous support of the British Day BCCG and of the NCL research group of Prof. Jonathan Cooper. His doctorate was entitled "Pathogenic impact of immune-related cells in two models of neuronal ceroid lipofuscinosis (Batten disease)" and was a joint project with the laboratory of Prof. Rudolf Martini (Würzburg). Thomas Kühl has found that NCL occurs in T cells in the brain of the mouse subjects. He has generated a new NCL mouse model, which no longer has these cells. "Both in clinical as well as in neurobiological terms, the condition of the mice has greatly improved," says Rudolf Martini.

 


In Würzburg Janos Groh has been working on a joint project in the Experimental Developmental Neurobiology department of Prof. Rudolf Martini. The PhD position by Janos Groth has been jointly set up with the R + W Foundation from November 08 '. Janos showed that cytotoxic T Zellenim brain of mice affect disease-reinforcing. Click here to read more about this project (german).


 

The data have been published in the learned journal Brain (2013).

 

 

Action Drugs that are used in autoimmune diseases, possibly with NCL (Würzburg, 2013)


Irene Spahn tested immune regulators for their effect on NCL. Due to the fact that it has been found that immune cells in phases have a negative impact on NCL disease progression, agents that modulate the immune response may be a potential therapeutic approach. The project of Prof. Rudolf Martini’s (Würzburg) laboratoryis expected to obtain the first results soon. However, the grant has been completely funded by us for this project.

 

 

 

 

Does the cell's own digestive process play a role with NCL? (New York, 2013)


This project was funded by the 2nd NCL Research Award. In his doctoral thesis Matthew Micsenyi has shown that autophagy is highly regulated in NCL. This contributes to the accumulation of protein aggregates in the cytoplasm of the cell. He identified, inter alia, the adapter protein p62 and a mitochondrial protein as components of these deposits. Matthew completed his doctoral thesis "The Role of Altered Autophagy and Ubiquitin-Proteasome Function in Disease Pathogenesis NCL" with Prof. Steven Walkley   at the Albert Einstein College of Medicine, New York City U.S. A. He published his results in 2013 in the Journal Journal of Neuroscience. 

 

 

 

Educational Computers (national, 2007-2013)


At the beginning of 2007 the NCL Foundation was able to purchase a total of 20 educational computers for national schools for the blind in Germany thanks to funding from the McDonald's Children's Aid of almost 40,000 Euros. At the pilot school for the blind and visually impaired school in Borgweg Street in Hamburg, training for teachers (and parents) were offered so they learn how to use the tutorial program "Structure". The Griebel Foundation strongly supported the software that then followed, called "Sarepta" in 2011. Since 2013, the software is sold by Handy Tech. Project funding is therefore finished by the NCL Foundation.

 

 

 

 

Development for genetic therapy for JNCL (New York, 2008-2011)


From 2008 to 2011 the NCL Foundation financed the development of genetic therapy for JNCL at Prof. Ronald Crystal’s laboratory at the Weill Cornell Medical College in New York. This project could only be started due to massive funding by “Bild (German newspaper) helps – where there’s lots of love for children”

Four different gene vectors were produced. Provided there are successful functional and toxicological tests in mouse models, studies can be carried out on larger animal models.

 

 

 

Cellzome AG researched NCL interaction partners


Within the framework of an EU-supported collaborative project called APOPIS, the company Cellzome AG (in Heidelberg) has used the protein juvenile Neuronal Ceroid Lipofuscinosis using their TAP-Tag-Technologymethods. These tests were initiated by the NCL Foundation so that Cellzome is the first Biotech company in Germany that became involved in NCL research. This company is the leader in the analysis of protein-protein interactions. Employees at Cellzome have identified potential bonding partners of CLN3.

 

 

Studies of the retina in CLN3 knock-in mice (Berlin, 2005-2008)


Together with Ernst and Elfriede, Griebel's promotion and support foundation, the NCL project "Functional and morphological examination of the retina of CLN3 knock-in mouse model" (Prof. Rüther, Charité, Berlin) was supported from 2005-2008. The focus of this project was in the detailed analysis of the retinal and visual function of CLN3 (Deltaex7/8) in the knock-in mouse model. Several methods such as electroretinography, pupillography, adaptometry and retinal angiography were used. Moreover, various parameters of the mice in the German Mouse Clinic were analysed. Results were published together with Susan Cotman 2012 in the Journal PloS One.

 

Establishing the NCL mouse models (Leipzig, 2004-2008)


Due to the initiative of the NCL Foundation, the NCL mouse model was established by Susan Cotman in Leipzig. Prof. Schliebs the Paul Flechsig Institute campaigned for this project. The project is now complete. A publication in February 2008 in the Journal of Neuroscience Research was the result of the cooperation with Cotman.

 

 

Uncovering of the function of CLN3 (Hamburg, 2004-2008)


In July 2007, the first of the NCL Foundation co-funded NCL doctoral fellowship took place at the University Hospital Hamburg-Eppendorf in the research group of Prof. T. Braulke. The doctoral student Sandra Pohl worked on "Analysis of expression changes in genes in the brains of CLN3 defective mice". The goal was to uncover the unknown function of the CLN3 protein. Due to her during the scholarship, four scientific articles were published in the Journal of Biological ChemistryTrafficJournal of Neurochemistry, and in the Journal of Inherited Metabolic Diseases.

 

This German - English translation was done by the translators Tizzy Mann, Andrea Murphy, Kate Humby and Marcia Neff for the PerMondo initiative that involves providing free translations for NGOs. PerMondo is sponsored and run by the translation agency Mondo Agit.