NCL2TREAT - Neuronal Ceroid Lipofuscinoses
NCL2TREAT wants to enhance the understanding of the biogenesis and role of lysosomes in cellular homeostasis, identify and characterise novel lysosomal components, generate cell and mouse models of lysosomal diseases, to develop novel therapies and acquire clinical data for natural history descriptions for NCLs. NCL2TREAT is built on projects investigating disease mechanisms, genetic modifiers and experimental therapies.
The NCL clinic as part of the International Center for Lysosomal Diseases (ICLD) in Hamburg provides a strong basis for the clinical part of NCL2TREAT. The comprehensive documentation of the natural history for CLN2 and CLN3, was the basis of the worldwide first phase 1/2 study for intraventricular enzyme replacement therapy in CLN2 disease in Hamburg.
The new and upcoming NCL therapies require refined clinical scoring systems and novel clinical biomarkers which might also be applicable for experimental therapeutic approaches performed by the NCL2TREAT consortium. The efficiency of therapies for progressive neurodegenerative disorders, however, depends on early-onset treatments and diagnosis. Therefore, the development of novel highly-sensitive mass spectrometric-based multiplex and bioaffinity technologies plays a central role in NCL2TREAT both for diagnosis and monitoring therapeutic responses in NCL patients.Projects
- Development of clinical outcome measures in neuronal ceroid lipofuscinoses – new tools for evaluation of experimental therapies (Dr. med. Angela Schulz, University Medical Center Hamburg-Eppendorf, Children’s Hospital)
- Clinical diagnostics of neuronal lysosomal storage diseases and quantification of lysosomal enzymes by mass spectrometry (Prof. Dr. rer.nat. Michael Przybylski, Steinbeis- Transfer Centre for Biopolymer Analysis & Biomolecular Mass Spectrometry, Rüsselsheim)
- Transcriptional modulation of CLN3 deficiency (Prof. Dr. rer. nat. Thomas Braulke, University Medical Center Hamburg-Eppendorf, Children’s Hospital, Dept. Biochemistry)
- Pathogenetic mechanisms in CLN6 (Dr. rer. nat. Melanie Thelen, Prof. Dr. med. Volkmar Gieselmann, Institue for Biochemistry and Molecular Biology , University of Bonn )
- Towards a therapeutic correction of autophagic flux in an NCL model by preclinical enzyme replacement therapy using recombinant cathepsin-D (Prof. Dr. rer. nat. Paul Saftig, Biochemical Institute, Kiel University)
Thomas Braulke, Prof. Dr. rer. nat.
University Medical Center Hamburg-Eppendorf
Children’s Hospital, Dept. Biochemistry
Martinistr. 52, N27
Telefon: +49 (0) 40 7410 – 54493
Website International Center for lysosomal disorders: http://www.icld-hamburg
16. July 2019 (NCL2TREAT)
Enzyme replacement therapy with recombinant pro-CTSD (cathepsin D) corrects defective proteolysis and autophagy in neuronal ceroid lipofuscinosis
Autophagy. 2019 Jul 16:1-15. doi: 10.1080/15548627.2019.1637200. [Epub ahead of print]
Marques ARA, Di Spiezio A, Thießen N, Schmidt L, Grötzinger J, Lüllmann-Rauch R, Damme M, Storck SE, Pietrzik CU, Fogh J, Bär J, Mikhaylova M, Glatzel M, Bassal M, Bartsch U, Saftig P
30. April 2019 (NCL2TREAT)
Lysosomal proteome analysis reveals that CLN3-defective cells have multiple enzyme deficiencies associated with changes in intracellular trafficking
J Biol Chem. 2019 Apr 30. pii: jbc.RA119.008852. doi: 10.1074/jbc.RA119.008852. [Epub ahead of print]
Schmidtke C, Tiede S, Thelen M, Käkelä R, Jabs S, Makrypidi G, Sylvester M, Schweizer M6, Braren I, Brocke-Ahmadinejad N, Cotman SL, Schulz A, Gieselmann V, Braulke T
2. July 2018 (NCL2TREAT)
Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study.
Lancet Child Adolesc Health. 2(8):582-590
Nickel M, Simonati A, Jacoby D, Lezius S, Kilian D, Van de Graaf B, Pagovich OE, Kosofsky B, Yohay K, Downs M, Slasor P, Ajayi T, Crystal RG, Kohlschütter A, Sondhi D, Schulz A.
17. May 2018 (NCL2TREAT)
Study of Intraventricular Cerliponase Alfa for CLN2 Disease
N Engl J Med 2018 May 17; 378:1898-1907 DOI: 10.1056/NEJMoa1712649N
Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschütter A; CLN2 Study Group.
26. May 2016 (NCL2TREAT)
Volumetric Description of Brain Atrophy in Neuronal Ceroid Lipofuscinosis 2: Supratentorial Gray Matter Shows Uniform Disease Progression.
AJNR Am J Neuroradiol. 2016 May 26.
Löbel U, Sedlacik J, Nickel M, Lezius S, Fiehler J, Nestrasil I, Kohlschütter A, Schulz A.