9^th JNCL Young Investigator Symposium
In 2023, Hamburg in Germany was center stage for NCL research, clinical progress, and global patient groups. Thanks to great support the NCL Foundation received from sponsors including the Stiftung Bostelmann (DE), Stichting Beat Batten! (NL), Marriott Hamburg, Theranexus (FR), ForeBatten Foundation (US), Friends of Britain e.V. (DE), Lions Club Deidesheim (DE), Reinhard Frank-Stiftung (DE), and Contactpunt NCL (BE), we were able to host the 9^th JNCL Young Investigator Meeting that took place at the Hamburg Marriott Hotel from September 24-25.

More than twenty young investigators presented their work and covered a wide range of CLN3 research topics including protein structure, protein-protein interactions, protein isoforms and transcripts, CLN3 function, CLN3 deficiency-associated defects in lysosomal phospholipid catabolism, synaptic biology, microglial function, CLN3 function in organs outside the nervous system, zebrafish and minipig models, biomarker discovery, high content imaging, phenotypic approaches to discover new therapeutic targets, and antisense oligonucleotides to treat CLN3 Batten disease. Plenary speakers were Dominic Winter (University of Bonn, DE) and Rebecca Ahrens-Nicklas (University of Pennsylvania, US). Dominic presented an overview of technologies to characterize the lysosomal proteome by mass-spectrometry, while Rebecca gave an overview and discussed challenges and opportunities of therapy development for CLN3 disease. Recently we have seen great progress in understanding the fundamentals of CLN3 disease. With the help of lysosomal omics and translational approaches, we should be able to find therapeutic options that are more predictive and stand a better chance to be disease modifying.

NCL Global Patient Group Meeting
On September 26, the NCL Foundation, BDSRA, and UKE organized a NCL Global Patient Group Meeting with participants from the BDFA (UK), BDSRA (US & AU), Beat Batten! (NL), BBDF (US), ForeBatten (US), Bobby and Robine Foundation (NL), NCL Gruppe Deutschland (DE), NCL Group Finland (FI), and NCL Denmark (DK). The goal was to get to know each other and discuss collaborative opportunities. In the afternoon patient group leaders met with industry representatives (BioMarin, JCR Pharmaceuticals, Neurogene, Regenxbio, Theranexus, and UT Southwestern) who briefly presented their NCL activities, followed by Q & A sessions. 

Picture, from left: Ronald Jansen, chairman of Stichting Beat Batten!, NL, Frank Stehr and Herman van der Putten (both NCL Foundation) and Addy Rouwenhorst, member of the Beat Batten! management team.

18^th International NCL Congress
The 18^th International Congress On Neuronal Ceroid Lipofuscinosis took place in Hamburg from September 26-30 (see program here). This conference covered all forms of NCL and focused on genetics and biology, disease models and mechanisms, biomarker discovery and omics, and translational preclinical and clinical research (recent list of NCL clinical trials).

Many JNCL young investigator meeting participants presented their work also at this conference. Remarkable was the high number of presentations on CLN3.
Two of the keynote lectures were given by investigators that receive funding by the NCL Foundation: Alessia Calcagni showed how the loss of CLN3 leads to mis-trafficking of CI-M6PR and defective autophagic-lysosomal reformation (see here). Monther Abu-Remaileh presented another breakthrough in NCL research, this time regarding the function of CLN5 (see next main topic of this Newsletter).

Altogether, the NCL field is making fantastic progress, both preclinically as well as clinically, and the latter is exemplified by recent announcements of a phase III trial for Miglustat in CLN3 disease, and a CLN5 gene therapy trial.
Unfortunately, Regenxbio recently announced to halt the development of their gene therapy programs for CLN2 (see update NCL literature).

2nd Symposium on Lipids in Brain Diseases

 September 13-15, the 2nd symposium on lipids in brain diseases took place in Leiden, The Netherlands. Focus was on understanding the role of cholesterol and other lipids in neurodegenerative diseases and demyelinating diseases, how Apo E genotypes impact lipids in microglia, astrocytes, and their interaction with neurons, and the manipulation of lipid pathways to promote resolution of inflammation. Alzforum has published a series of 4 commentaries covering several topics at this meeting. For details see here. Not presented at this meeting but a remarkable piece of biology illustrating how lipids control lysosomal function was recently published by Ebner et al. (2023). The lipid PI3P marks mTORC1-complex signaling-active lysosomes in the cell periphery. PI3P is rapidly erased upon starvation and starvation triggers a re-localization of PI4P-metabolizing enzymes to the lysosomal surface and clustering of mTORC1-inactive degradative lysosomes in the nuclear periphery. In brief, a PI3P/PI4P lipid-switch controls nutrient-regulated lysosomal function.