This year’s international Young Investigator Meeting on juvenile CLN3 Batten disease (JNCL) brought together early career scientists, principal investigators, clinicians, representatives from other NCL foundations and NCL organizations, and members of NCL families. The meeting was held in the Renaissance Hamburg Hotel. It was generously sponsored by the Adalbert Zajadacz Stiftung, Stiftung Bostelmann, Else Kröner Fresenius Stiftung, Stiftung Kindness for Kids, Lieselotte Paulsen Stiftung, Marriott Hamburg, PSD Bank Nord eG, Rotary Club Stuttgart-Wildpark and Stichting Beat Batten (NL). Participants were from Germany, The Netherlands, Sweden, UK, USA, Italy, Austria and Portugal. During the four days, participants exchanged new research findings, therapeutic developments, and ideas for how to move the field forward together. 

Frank Stehr (NCL-Stiftung, Hamburg, GER) opened the meeting with a clear message that childhood dementias such as NCL are responsible for as many deaths as childhood cancer. Nonetheless, NCL is often overlooked by national and international dementia and funding organizations underscoring the need for more attention and support. Fortunately, this and other recent meetings and reports highlight several examples of NCL genes and pathways connecting to common adult-onset forms of dementia.

Angela Schulz (UKE, Hamburg, GER) gave a short laudatory speech to honor and congratulate Esther Sammler (Dundee, UK) and Peter van Hasselt (Utrecht, NL) receiving the 2nd NCL Neurodegeneration Research Award for their project to study and compare lysosomal omics profiles in PBMCs from patients with CLN3 and other forms of NCL, including also some adult-onset neurodegenerative diseases. To this end they use the newly developed Tagless LysoIP method, and they collaborate with centers in the UK, Finland and Italy.

Peter van Hasselt presented new insights from following CLN3 Batten patients over time. He showed that mental decline may start earlier than generally noticed, sometimes even before diagnosis. Surprisingly, changes in vision do not reliably predict how disease affects cognitive abilities. Interestingly, in non-syndromic forms of CLN3, vision is impaired, but these patients show no Batten-like neurological symptoms. The team also develops new tools to track disease, such as changes in lysosomes of immune cells that can be monitored using LAMP1 as a fluorescent marker and FACS analysis. Angela Schulz (UKE, Hamburg) gave an overview of the status of enzyme replacement therapy (ERT) for CLN2 disease having a real-world benefit in this patient group, especially when started early. Early diagnosis and treatment are key to obtain best results hence the need for neonatal diagnosis and newborn screening. Furthermore, she gave an overview on the status of therapy developments in NCL including gene therapy, ERT, the use of ASO, as well as some pharmacological approaches. Lena Westermann (UKE, Hamburg) addressed the topic of antibody responses against Cerliponase alfa in CLN2 patients receiving ERT. Two other talks addressed investigations of basic auditory processing using high density EEG recordings in CLN3 patients (Erin Bojanek, University of Rochester Medical Center, USA), and Stefania Della Vecchia (Fondazione Stella Maris, Pisa, Italy) highlighted phenotypic variability and atypical phenotypes seen in some CLN3 patients.

Day two started with Andreas Hellqvist (Swedish NCL Association), who`s son is affected by CLN3 disease. He gave an impressive talk and insights in the lengths he has been going through, in absence of any approved treatment, to nonetheless try and give their son best possible options including the use of supplements, exercise therapy, and drugs approved for other diseases. Frank Edenhofer (University of Innsbruck, Austria) is developing iPSC-derived CLN3 mutant brain organoid models with the aim to study promising treatments in a fully human model system. Daniel Saarela (University of Dundee, UK) presented ongoing efforts using lysoIP and MS-based omics analysis of PBMCs collected from CLN3 (see here) as well as a number of other NCL patients and which genes link to maintaining lysosomal BMP lipid homeostasis. Esther Sammler (University of Dundee, UK) spoke about the genetics of Parkinson’s disease (PD), more specifically, the hundreds of variants now known to exist in the LRRK2 gene, many of which are also activating like G2019S, the use of BMP as a lipid biomarker in urine for enhanced LRKK2 activity and to monitor pharmacodynamic effects of LRRK2 inhibitors in LRRK2 G2019S PD patients, the testing of patient variants at large scale and at the cellular level the role of LRRK2 in lysosomal biology and overlaps with NCL. Lysosomal cross-roads between PD and NCL will hopefully raise interest in strategies targeting these diseases and their lysosomal aspects. Christian Posern (UKE, Hamburg) discussed the strengths and limitations of using NFL and GFAP as biomarkers in CLN2 patients treated with Cerliponase alfa with respect to monitoring disease progression. Erika Ruskie (University of Michigan Medical School, USA) briefly highlighted some latest findings with the personalized ASO Zebronkysen (see here) created for Amelia and Makenzie`s unique variant of CLN3, and Vanguard Clinical Rare Disease Foundation (VCRDF) will continue to develop an individualized ASO therapy targeting the common exon7/8 deletion found in the vast majority of CLN3 patients. Erika moved on to show how the lab tries to improve brain delivery of therapeutic ASOs using antibody-conjugated ASOs for CLN3.

By way of introducing the next session and looking forward, Herman van der Putten (NCL-Stiftung, Hamburg, GER) highlighted recent findings showing that a growing number of NCL genes are involved in lysosomal BMP lipid homeostasis. For a long time, we have been puzzled by both clinical as well as histopathological similarities across various NCL forms. The finding that several NCLs are implicated in BMP lipid homeostasis, a pathway that is key for maintaining lysosomal function as many lysosomal enzymes depend on BMP for activity, seems to provide at least in part an explanation why such similarities exist. Janos Groh (TUM-NCB, Muenich, GER) discussed similarities between NCL and age-related neurodegeneration highlighting the role and therapeutic relevance of targeting maladaptive immune reactions, CD8+ T-cells driving myelin degeneration, and lysosomal dysfunction in microglia (for CLN3 see here) contributing to neurodegeneration (nature; neuron.).

Ewa Ziolkowska (Washington University, St. Louis, USA) discussed the many systemic pathologies (heart muscle, other muscles, NMJs, gut e.a.) seen in CLN3 disease and how targeted therapies using gene therapy can alleviate some of these (science, nature, biorxiv.).
Devin Burris (University of Pennsylvania, USA) described results of the team`s recent study showing significantly elevated levels of the glycerophosphodiester GPI but no other GPDs in CLN3 disease hippocampus in early postnatal development at day 11. The hippocampus proved also significantly hypoexcitable as early as postnatal day 7 and showed aberrant development and in vivo circuit function including slowing observed on EEG recordings at postnatal day 30. Such early postnatal abnormalities are reminiscent of early neurodevelopmental disorders. Masood Ahmad Wani (Johannes Gutenberg University, Mainz, GER) presented a series of AAV-mediated CLN3 rescue experiments at the synaptic level to disentangle pre- and post-synaptic dysfunction and what is needed to rescue both. Hans Aerts (Universities of Leiden and Amsterdam (Emeritus), NL) closed the session by focusing on roles and risks of Glucocerebrosidase inactivation by certain clinically used compounds, and their remarkable effects on biomarkers. He also discussed how certain plant food components can trigger accumulation of exogenous glycolipids when GBA1 is defective perhaps posing risk factors for Parkinson`s Disease (sciencedirect).

On day 3, various researchers shared deeper insights into the molecular biology of CLN3 disease. Michael Ebner (Medical University Innsbruck, AUT) explained how cells try to repair damaged lysosomes and what goes wrong in CLN3 disease, building on earlier observations that CLN3 lysosomes recruit PI4K2A (nature). Julia Heiby (Leibniz Institute on Aging, Jena, GER) and Katharina Hirn (University Duisburg-Essen, GER) highlighted their efforts to use proteomics technologies to discover more about CLN3-deficiency associated lysosomal proteome changes, and using complexome- and interactome-based proteomics to unravel CLN3 protein-protein interactions and complexes. Claudia La Vecchia and Miriam Aurilia ( both TIGEM, Pozzuoli, Napels, IT) discussed new cell biology findings that could shed light on why and how tamoxifen exerts its normalization effects seen in CLN3 and CLN7 cell and animal models (Claudia), and how another in a RNAi screen newly discovered transcription factor and drug target for which tool compounds exist exerts its beneficial effects in similar models (Miriam).

Kasparas Petkevicius (University of Cambridge, UK) summarized work from his own lab and work by the group of Monther Abu-Remaileh in Stanford (science, nature, Annual Review, ) showing how different NCL genes, in particular CLN8 and CLN5, are involved in driving the biosynthesis of bis(monoacylglycero)phosphate (BMP). Watch out, there is more to come! This is a super exciting area of research that may also provide new inroads for therapy for some NCLs and beyond. Neuza Dominguez and Sofia Freire (both University of Coimbra, POR) talked about how CLN3 promotes contacts and modulates nuclear envelope lipids, also showing that functional loss of CLN3 triggers perturbations in the lipid content of the nuclear envelope increasing DNA lesions, c-Abl activation, YAP P-ation and pro-apoptotic signaling (Neuza; see here). Sofia presented a pathway on how CLN3 interacts with motor proteins thereby affecting lysosomal distribution. Valentina Marchica (RVC, London, UK) presented findings in two genetic CLN3 zebrafish models, one based on the use of morpholino-mediated knockdown, the other using CRISPR-technology (see also here). She described several interesting biochemical and phenotypic changes that seem amenable to screening for compounds that can reverse these. The closing lecture was by Lina Schmidt (University Medical Center, Göttingen, GER) on a platform they have established allowing broad omics-based phenotyping, target and pathway analysis comparing a set of lysosomal storage diseases all generated in the same cellular background. One goal is to define organelle and pathway dysfunctions that may be driving pathologies across different storage diseases.

The meeting ended on the fourth day with a workshop where we discussed what's missing in current research and how to build a platform for stronger collaborations in the future. With the 200th anniversary of the first described Batten case coming in 2026, participants were inspired to come up with ideas for highlighting and improve awareness of the disease in their home countries and institutes.

This meeting forged new collaborations and highlighted the progress in both our understanding of NCL disease biology as well as the expanding number of therapeutic possibilities, some of which will hopefully soon find their way into the clinic.