Finally back as a face-to-face meeting - our 19th National NCL Congress and the 8th JNCL Young Investigator Symposium were held as a combined meeting in Hamburg, Germany, September 19-21, 2022.

First and foremost, we would like to thank all our sponsors for financial support: We thank the Joachim Herz Stiftung for hosting us in their magnificent facilities (Langenhorner Chaussee 384, 22419 Hamburg), and generously offering excellent meals, drinks and great snacks during the coffee breaks. We were also generously supported by the Beat Batten Foundation in the Netherlands, the Belgian Contactpunt NCL association, the ForeBatten Foundation in the US, the Else Kröner Fresenius Foundation and the Foundation Kindness for Kids in Germany, and the company Theranexus (France) who currently runs a clinical trial testing Miglustat in CLN3 patients. A special thank also to Volker Wendel (Stuttgart, GER) for his courageous and moving speech “Living with a CLN3 child”.

This year`s meeting was entitled “Break-throughs in Translational Science” to underline some of the extraordinary new discoveries in CLN3 basic research and their relevance to translational clinical research. Monther Abu-Remaileh (Stanford University, Stanford, USA) and colleagues showed that CLN3 is required for the clearance of glycerophosphodiesters (GPDs) from lysosomes. Their Nature paper with first author Nouf N. Laqtom sets a milestone in CLN3 research (see previous topic of this Newsletter). GPDs also appear in biofluids, including CSF of patients and the CLN3 minipig model, as well as in the blood of patients, and CLN3-deficient animal models including mouse and minipig as discussed by Mitchell Rechtzigel (jumped in for Jill Weimer), Joelle Anderson and Vicky Swier (Sanford Research, Sanford, USA). These results are described in a recent paper.  Altogether, these findings are likely going to have a great impact on translational clinical research. Daniel Sareela (University of Dundee, Dundee, UK) showed us applications for the analysis of lysosomes from human PBMCs using a non-tagged lysoIP method.

Alessandro Ori (Jena), co-author of the recent Nature paper by Laqtom et al. collaborates with the Abu-Remaileh team. He presented the power of lysosome proteomics in health and disease. Together with lysosomal metabolomics including lipidomics, the analysis of the lysosomal proteome completes the omics picture of the inside of the lysosome and the changes associated with CLN3 disease. One key outstanding question is whether and which therapies might be able to normalize at least part of the aberrant CLN3 omics profiles.   

Martin Giera (LUMC, Leiden, NL) showed us the incredible power of looking at the whole cell lipidome to analyze phenotypes of cells in health and disease, and as an approach to identify drugs that can normalize disease-associated lipidomic fingerprints. This type of omics-analysis has gained a lot of momentum recently to study omics changes in animal and cell models, and their response to treatment.

Several speakers also touched on various therapeutic options that are either in later stages of preclinical validation, or in early clinical development. Kathrin Meyer and Emily De Los Reyes (Nationwide Children`s Hospital, Columbus, Ohio, USA) gave a bench to bedside update on AAV gene therapy for CLN3 disease. Michelle Hastings and Matthew Stratton (Rosalind Franklin University of Medicine and Science, Chicago, USA) updated us on ASO-based exon skipping and its potential to restore CLN3 function.

Daniela Wünkhaus (University of Hamburg and Evotec SE, Hamburg, GER) and Christian Grimm (Ludwig-Maximillians University, Muenich, GER) summarized evidence in CLN3 e.a. cell models and an MLIV mouse model, showing that the activation of two different lysosomal ion channels (TRPML1 and TPC2) can in part reverse cell pathological phenotypes associated with these diseases. These results were recently published (Scotto Rosato et al) in the Journal EMBO Molecular Medicine. The team also published another paper recently by Prat Castro et al in which they review and discuss possible advantages of TPC2 over TRPML1 activation to rescue LSD phenotypes. TRPML1 activity is pH dependent, and it is blocked by sphingomyelin accumulation, which is characteristic of some LSDs. In contrast, TPC2 activation is pH-independent and not blocked by sphingomyelin. In this paper they also show that TRPML1 currents are reduced in iPSC-derived neurons carrying CLN3 knockout and the full-Batten mutation D416G, but interestingly not in isogenic neurons carrying the non-syndromic CLN3 R405W mutation.

Emyr Lloyd Evans (University of Cardiff, UK) highlighted the role of glycosphingolipids (GSLs) in CLN3 disease and how the drug Miglustat that is known to reduce GSL accumulation can improve CLN3 cell pathological phenotypes. Miglustat is currently in clinical development for CLN3 disease by the company Theranexus (France), in partnership with the Beyond Batten Disease Foundation (USA). Note, Emyr Lloyd Evans and Marco Sardiello from Washington University School of Medicine in St. Louis, USA both presented at the recent NCL meeting in Chicago (see  topic "Further intersting meetings" of this Newsletter) where Marco Sardiello discussed the in vivo CLN3 mouse data supporting the beneficial effects of Miglustat.

Angela Schulz (University Children`s Hospital, Hamburg, GER) highlighted results obtained so far in natural history studies of CLN3 patients and their increasingly important role for drug development and clinical trials. Along similar lines, An Dang Do (NIH, Bethesda, USA) showed exciting results in CLN3 biomarker discovery, including changes in several proteins such as NFL e.a. and metabolites including GPDs as mentioned earlier. This is part of an ongoing CLN3 natural history study. Given the large patient-to-patient variation in clinical progression of CLN3 patients, the identification of biomarkers that can track disease status, progression and responses to treatment remains of utmost importance to support clinical trials.

The agenda of the meeting highlights numerous other topics of high interest in CLN3 biology such as the development of additional CLN3 cellular assays (Llinos Honeybun, University of Cardiff, UK), the generation of novel epitope-tagged CLN3 mouse models to track the endogenous CLN3 protein (Jessica Centa, Rosalind Franklin University of Medicine and Science, Chicago, USA), attempts to resolve the cryoEM structure of CLN3 protein (Tobias Raisch, MPI of Molecular Physiology, Dortmund, GER), elucidate the role of CLN3 in the brain`s microglial immune cells (Susan Cotman and Seda Yasa (MGH, Boston, USA), further understand CLN3`s role in autophagy, lysosomal biogenesis and lysosomal reformation (Marcel Klein, ZMNH, Hamburg, GER; Alessia Calcagni, Baylor College of Medicine, Houston, USA), its role in lysosomal and global Ca²⁺ signaling (Sukanya Arcot Kannabiran, University Clinic Hamburg-Eppendorf, Hambrug, GER), and in neuronal signaling (Masood Ahmed Wani, Johannes Gutenberg University, Mainz, GER). Finally, Robert Steinfeld (University Children`s Hospital, Zurich, CH) and Sofia Massaro Tieze (Yale School of Medicine, New Haven, USA) discussed new findings related to CLN5 structure and activity as the first cysteine-based S-depalmitoylase (RS), and novel substrates of the depalmitoylase encoded by the CLN1 gene (SMT).

Picture:

Presentation of the 12th NCL Research Award: From left, Dr. Frank Stehr (CEO NCL-Stiftung), Prof. Robert Steinfeld (member of the Scientific Advisory Council NCL-Stiftung), award winner Prof. Diego Medina from TIGEM, Italy and Ulrich Müller (CEO Joachim Herz Stiftung).