NCL literature and interesting reads

NCL article series: Arzt + Kind (2024). A series of articles (note, all in German) co-authored by some of our Scientific Advisory Board (Angela Schulz, Robert Steindeld) and NCL team members (Frank Stehr, Herman van der Putten) on NCL clinical and research aspects have been published in the Austrian pediatric Journal “Arzt + Kind”. You can download the pdf version here.

 For regular updates on NCL clinical trials please consult the BDSRA site and the ClinicalTrials.gov websites.

Last update: October 2025

Banach-Petrosky et al., 2025 Molecular Therapy - Methods &Clinical Development: CLN3 JNCL is caused by CLN3 mutations and is accompanied by accumulation of both lipids and proteins in the lysosome. In particular, subunit C of mitochondrial ATP synthase (SCMAS) accumulates in CLN3-mutant lysosomes. SCMAS is degraded by tripeptidyl-peptidase 1(TPP1/CLN2) and this group previously showed that haploid insufficiency of TPP1 exacerbates CLN3 disease in the mouse. They now show that transgene-mediated overexpression of the Cln2 protein results in less SCMAS accumulation, and reduced microglial inflammation and less neuronal damage as suggested by lower levels of the biomarker NFL. Whether CLN2 gene or enzyme-replacement therapy given postnatally can also achieve similar benefits remains to be seen.  

Han et al., 2025 bioRxiv developed a 3D human iPSC-derived CLN3^Dex7/8 retina model showing that the mutation leads to reduced levels of acid ceramidase (AC), altered sphingolipid metabolism and signalling, and POS loss mimicking findings in the CLN3 miniswine eye. The authors provide proof-of-concept that recombinant human AC can rescue disease phenotypes.

Sheokand et al., 2025 Science Advances: Several NCL-forms show dysregulation of the levels of the critical lysosomal phospholipid bis(monoacylglycero)phosphate (BMP), but the details of BMP synthesis remain elusive. This study establishes that TLCD-family proteins, of which human TLCD6/CLN8 is a member, act as phospholipid-remodeling enzymes and more specifically, that CLN8, which is an ER-resident protein, is essential for the biosynthesis of BMP precursors, that eventually allow CLN5 which is located inside the lysosome to make BMP. These findings provide a novel role for CLN8 and insights into the BMP synthesis pathway, and open up ways for tuning levels of BMP synthesis. 

Davidson et al., 2025 Molecular Cell: Decreased BMP levels in the lysosome are a hallmark of many forms of NCL. The study demonstrates that cold exposure significantly increases liver BMP lipids, which in turn regulate lysosomal function. It identifies phospholipase A2 group XV (PLA2G15) as a key enzyme in regulating BMP lipid catabolism during cold. Loss of PLA2G15 leads to increased BMP lipids, enhanced lysosomal lipid processing, and elevated energy expenditure. The study also suggests that transcription factor EB (TFEB) is activated during cold and directly represses PLA2G15 transcription. Overall, this study offers insights into mechanisms governing liver adaptation to cold and potential therapeutic targets for lysosomal storage disorders and metabolic diseases. 

Corti et al., 2025 Cell Reports Medicine: Loss of vision is an early clinical symptom in NCL and contributes to decreased quality of life for NCL patients. Researchers at the University of Tübingen established an in vitro human retina model of CLN2 disease using human induced pluripotent stem cell (hiPSC)-derived retinal organoids and a retina-on-chip system. The model recapitulates key pathological hallmarks of CLN2 including accumulation of SCMAS and lipids in the outer retina, as well as cone dysfunction. The study further demonstrates that adeno-associated virus (AAV)-mediated TPP1 gene therapy can restore TPP1 enzyme expression and reduce SCMAS accumulation, further supporting the progression of this therapeutic strategy into clinic. 

Groh et al., 2025 Nature Neuroscience: Yasa et al., 2024 have shown that CLN3-deficient microglia are unable to efficiently turnover myelin and metabolize the associated lipids, showing defects in lipid droplet formation and cholesterol accumulation. Hence these cells fail to support axonal health and integrity. A recent study by Janos Groh et al. explores the contribution of microglia activation to aging-related white matter degeneration.The study revealed that pro-inflammatory microglia activation promotes the accumulation of pathogenic CD8+ T-cells, leading to the degeneration of myelinated axons. They could also find accumulation of these CD*+ T-cells in the brains of aged humans. These findings highlight the role of these T-cells in neuronal deterioration and as possible therapeutic targets for mitigating the effects of neuroinflammation, which could also be applied to NCL disease as shown earlier by the same author (Groh et al., 2021). The next challenge will be how to target these CD8+ T-cells without compromising their benefical role in our immune system. 

Wald et al., 2025 Neurobiology of Disease: This study identifies glucosylsphingosine (GlcSph) as a promising fluid-based biomarker for lysosomal dysfunction in CLN3 disease. Using a Cln3Δex7/8 mouse model and human iPSC-derived neurons, the researchers demonstrate a strong correlation between GlcSph accumulation and hallmark cellular pathologies, including the accumulation of SCMAS and impaired lysosomal function. Elevated GlcSph levels were consistently observed in the brain, retina, and plasma of Cln3Δex7/8 mice, suggesting its utility as a peripheral biomarker for monitoring lysosomal storage and dysfunction in CLN3 disease, as well as drug-mediated normalizations. It remains to be seen if GlcSph levels correlate with disease severity and/or progression in human patients. 

Ziółkowska et al., 2025 Science Translational Medicine: This paper explored peripheral disease manifestations of CLN1 and CLN2. NCL-patients often have debilitating GI-symptoms including constipation and abdominal pain and these have a large impact on quality-of-life. This work from the Cooper team, also presented at the 10th NCL Young Investigator Meeting, used CLN1 and CLN2 mouse models to investigate GI-defects. Both mutants had slow bowel transit that worsened with disease progression. CLN1/2 loss caused a significant reduction in myenteric plexus neurons that play a key role in coordinating peristalsis. Importantly, AAV–mediated gene therapy for CLN1 and CLN2 lowered constipation rates and extended survival in these mice. 

Puszynska et al., 2025 BioRXiv: NCL diseases are characterized by a loss of lysosomal function, accompanied by changes in the lipid and metabolite profile of this organelle. Aging is also accompanied by lysosomal dysfunction, and Weissman and colleagues now describe that lysosomal aging shows a molecular clock of juvenile storage-disorder associated metabolites, in particular glycerophosphodiesters (GPDs as seen in CLN3 disease) and cystine (as seen in cystinosis). They profiled lysosomes in young and old mice across tissues including the brain. Lysosomal levels of GPDs and cystine increased linearly with age in aged mice. Caloric restriction mitigated these changes in heart but not brain. GPDs and cystine were mainly increased in aged lysosomes of microglia and neurons.