Here you will find a regular update of the latest scientific publications on the different forms of NCL.
Last update: June 2022
Kovács et al reported that acidified drinking water attenuates motor
deficits and brain pathology in Cln1R151X nonsense mutant mice. Acidified drinking water sig-nificantly altered the gut microbiota composition of the mutant mice, suggesting a contribution of gut
bacteria to the observed therapeutic effects.
Zhang et al reported seizures occurring in 7-month and older CLN1 (PPT1) knock-in mutant mice. These are associated with inflammatory activation of microglia. Astro-cyte activation preceded microglia activation and an antagonist of the ATP-sensi-tive purinergic P2X7 receptor (P2X7R significantly reduced seizures in PPT1 KI mice.
Taysha Gene Therapies announced the news that Queen’s University in Ontario, Canada, received Clinical Trial Application (CTA) approval from Health Canada for the Phase 1/2 clinical trial of TSHA-118, Taysha’s investigational gene therapy for infants and children living with CLN1 disease.
Mondal et al described defects in lysosomal Ca++ homeostasis in Ppt1-/- mice. The mice have reduced levels of two palmitoyl acyltransferases which activate the tran-scription factor NFATC4. The latter regulates expression of the IP3R in the ER, which mediates lysosomal Ca++ refilling.
Intravitreal ERT efforts to try and prevent retinal disease progression in children with CLN2 have started in two sites, one in the US (Nationwide Children's Hospital;
https://clinicaltrials.gov/ct2/show/NCT05152914), and one in Great Ormond Street hospital in the UK, thanks to a great fund-raising effort
by the BDFA. (The Guardian).
Kovacs et al used a commercially available automated segmentation software in optical coherence tomography scans to characterize the inner and outer retinal de-generation in CLN2 patients, and the authors propose this as a biomarker readout.
Iwan et al reported that CLN2 patients on intracerebral ERT continue to show a de-crease in CSF NFL levels after 2-year treatment. NFL levels appear to correspond and predict improved clinical status of patients on ERT.
Leal-Pardinas et al present evidence indicating that access to early epilepsy gene panel testing helps to increase yield and shorten time to diagnosis.
Nickel and Schulz discuss the relevance of NCL natural history studies for clinical trials, using experience with CLN2 as an example.
Rechtzigel et al
demonstrate a substantial overlap in the protein interactomes of CLN3, CLN6, and CLN8, and that the absence of each of these proteins leads to syn-aptic depletion of SNAREs, tethers, and altered
synaptic SNARE complexing in vivo.
Savvidou et al describe four CLN3 patients with several episodes of drug-induced hyperthermia. Possibly provoking drugs included risperidone, clozapine, olanzap-ine, haloperidol, quetiapine, and sertraline.
Hochstein et al present a natural history study of MRI brain volume changes. The data show that supratentorial grey matter volume changes 4.6% +/- 0.2% per year, and is a sensitive parameter for assessment of disease progression that also shows a strong correlation with disease specific clinical scores.
Handrup et al present a long-term follow-up study of patients that received a pace-maker. Treatment is safe and may have great impact on quality of life, but the med-ical indication is relative. The authors suggest thorough discussion before deciding for this treatment.
Honingh et al present a qualitative and quantitative analysis of patient files and parent interviews on behaviours and emotions. It may provide a lead to adaptable support-modules for children with CLN3 disease.
Ware et al performed exome sequencing in a large cohort of children with cardio-myopathy. They identified a candidate gene set suggesting multigenic mechanisms for cause and presentation. Findings might bear on genetic modifiers in CLN3 cardi-omyopathy.
Do et al provide first support of validity of the Vineland-3 adaptive behaviour scale for monitoring changes in CLN3 disease.
Abdennader et al did seizure phenotyping in a CLN3 cohort and report that seizures and epileptic discharges were frequent, often starting by age 10 years. Vineland-3 scores and CSF NFL levels correlated with UBDRS seizure score.
Dev et al report on an unusual case of a 13-year-old CLN3 patient without typical JNCL disease phenotypes but manifesting seizure episodes.
Honasoge and Smith report an unusual a case of bilateral chorio-retinal scarring due to a CLN3 heterozygous deletion in an asymptomatic patient.
Klein et al describe findings that strongly suggest converging roles of PSENEN and CLN3 in the autophagy-lysosome system, and in a γ-secretase-independent manner.
Ahrens-Nicklas et al describe that neuronal genetic rescue of CLN3 alone in CLN3-deficient mice normalizes brain network dynamics despite persistent storage accu-mulation.
Wibbeler et al report that the UBDRS provides a valid and reliable rating scale that can be used by trained clinicians in different sites to assess the severity and rate of progression of CLN3 disease.
Chear et al describe lysosomal alterations and decreased electrophysiological activ-ity in iPSC-derived cortical neurons, composite heterozygous for the mutant CLN3 alleles delta exon7/9 (966 bp deletion) and the E295K missense mutation.
Relton et al used a HeLa cell CLN3 KO model to show that CLN3-deficiency is asso-ciated with an altered metabolic profile, reduced global protein translation, and perturbations in stress granule dynamics.
Huang et al identified a novel CLN4 mutation in the DNAJC5/CSPα
protein, a mem-brane associated HSC70 co-chaperone. The mutation leads to autosomal dominant adult-onset NCL. This novel C128Y mutation in a young 20-year-old female with memory loss as first
symptom caused abnormal palmitoylation and triggered lipofuscin deposits.
Lee et al reviewed how the deregulation of CLN4/DNAJC5/CSPα perturbs uncon-ventional protein secretion and endosomal micro-autophagy, and contributes to lipofuscin accumulation and neurodegeneration.
Nykanen et al provided further experimental evidence for a role of DNAJC5/CSPα in the processing of APP in cells and an APP mouse model. 5xFAD mice haplo-insuf-ficient for the DNAJC5 gene show increased A plaque burden and a decrease in A plaque latency.
Meiman et al describe a novel canine model of CLN5 disease that manifests
global brain atrophy and neurological signs, progressing to a level of severity that re-quires euthanasia by 21-23 months.
Neurogene announced in February the start of recruiting a small number of CLN5 patients in an AAV9-based CLN5 gene therapy trial.
Doccini et al used lysosomal proteomics showing that CLN5-deficiency is linked to disturbances in lipid homeostasis and sphingolipid metabolism.
Basak et al used CLN5-deficient iPSC-derived neurons and showed reduced acidic organelles, reduced lysosomal enzyme activity, and impairments in lysosomal movement.
Luebben et al solved the crystal structure of CLN5 and showed that the CLN5 pro-tein has catalytic properties as a novel cysteine-based S-depalmitoylation enzyme. They show that CLN5-deficient neuronal progenitor cells have reduced thioester-ase activity.
Amicus Therapeutics announced it will discontinue its investigational
gene therapy program of AT-GTX-501 for CLN6 Batten disease. The decision was based on data from a long-term follow-up study (NCT04273243) that showed AT-GTX-501 failed to stabilize disease
Rus et al present one of the largest cohorts (97 subjects) to date of genetically di-agnosed CLN6 patients screened at a single centre and originating from 20 coun-tries. This study expands the number of published clinical cases and the mutational spectrum of disease associated CLN6 variants.
Koh et al provide experimental results showing that a CLN6-CRMP2-KLC4 complex regulates anterograde ER-derived vesicle trafficking in cortical neurites.
Nicolau et al describe 3 male CLN6 patients from two unrelated Greek-Cypriot fam-ilies which presented with slightly different symptoms that appeared at the age of 6 years. Unusual, both probands were without initial signs of vision and/or hearing loss.
Murray and Mitchell highlight the differential vulnerability of retinal layers, and the time course of retinal atrophy in ovine models of CLN5 and CLN6 disease. These findings have potential impact on targets and timing for ocular therapies.
Barry et al generated aggregation chimeras that provide evidence of in vivo inter-cellular/cross-correction in ovine CLN6.
Lopez-Fabuel et al describe aberrant upregulation of the glycolytic
enzyme PFKFB3 in CLN7, and show that administration of the highly selective PFKFB3 inhibitor AZ67 rectifies key disease hallmarks in the Cln7Δex2 mouse brain in vivo and in CLN7 patients-derived
Garcia-Macia and Bolaños report that CLN7 deficiency in the hypothalamus dam-ages liver lipophagy and results in fat accumulation.
Chen et al report that AAV9/MFSD8 gene therapy is effective in preclinical models of CLN7 disease. A Phase I intrathecal gene transfer trial for AAV9/MFSD8 has been approved by the FDA, and runs at Children’s Health in Dallas, TX, in collaboration with UTSW Medical Center, and Taysha Gene Therapies (see: clinicaltrials.gov NCT04737460).
Reith et al report a novel exonic variant of the CLN7 gene that was found in two closely related subjects that are both homozygous for this variant. Both subjects have clinical features of NCL but displayed a great difference in onset of first neu-rologic as well as ophthalmologic symptoms. This CLN7 variant is silent at the trans-lational level but affects splicing.
Liu et al report that intravitreal gene therapy in cathepsin-D deficient mice restores autophagy-lysosomal pathway function and attenuates retinal degeneration.
Frydas et al report that functional uORFs in the alternative 5′ UTR of
CLN11 (Progranulin) mRNA act as potential regulators of PGRN expression. They also show that genetic variation within the uORFs can increase PGRN protein expression.
Du et al report that sortilin and prosaposin independently regulate lysosomal traf-ficking of PGRN in vivo. Deletion of both prosaposin and sortilin totally abolishes lysosomal localization of PGRN in neurons but not in microglia. Their data suggest the existence of a novel PGRN lysosomal trafficking pathway in microglia.
Reifschneider et al used genetic and pharmacological (antagonistic Abs) ap-proaches to suppress TREM2-dependent transition of microglia from a homeostatic to a disease-associated state. Trem2 deficiency in PGRN KO mice reduced microglia hyperactivation, but lysosomal dysfunction was not rescued, and synaptic loss and CSF neurofilament light-chain levels were further elevated. Altogether, the find-ings suggest that TREM2-dependent microglia hyperactivation in models of PGRN deficiency does not promote neurotoxicity, but rather provides neuroprotection.
Tanaka et al report that two drugs (Abemaciclib and vacuolin-1) which both induce autolysosome vacuole formation promote autophagosome-lysosome fusion. Inter-estingly, vacuole formation was inhibited by knockdown of PGRN, and promoted by its overexpression.
Dang et al review the pathological mechanisms of CLN12/ATP13A2 mutations lead-ing to Parkinson's disease, and its role in protecting dopaminergic neurons.
al debate on processes in neurodegenerative LSDs, and possible drivers including toxic substrate accumulation inside lysosomes as well as nutrient depriva-tion downstream.
Lee et al show that autolysosome acidification declines in Alzheimer`s Disease neu-rons before extracellular amyloid deposition. They report markedly lowered vATPase activity and build-up of Aβ/APP-βCTF selectively within enlarged de-acidi-fied autolysosomes. They describe Aβ-positive autophagic vacuoles (AV) forming flower-like perikaryal rosettes (PANTHOS), and AVs coalescing into peri-nuclear networks of tubules with intraluminal fibrillar Aβ accumulation. Lysosomal mem-brane permeabilization, cathepsin release and lysosomal cell death ensue accompa-nied by microglial invasion. Neurons exhibiting PANTHOS are the principal source of senile plaques in AD models.
Jennings et al present data supporting the hypothesis that LRRK2 inhibition with DNL201 has the potential to correct lysosomal dysfunction in patients with PD at doses that are generally safe and well tolerated. This could be of broader interest as LRRK2 inhibition may ameliorate lysosomal dysfunction more broadly.
Lie et al provide results in Alzheimer-mutant PSEN1 knock-in mice that link dysfunc-tion and mis-trafficking in lysosomal pathways to neuronal dystrophy, which can be rescued by blocking the lysosomal ion channel TRPML1.
Reddy and Brahmbhatt review the application and effectiveness of anti-epileptic drugs, anti-convulsant drugs, and vitamin C, in multiple scenarios to treat Batten disease.
Brudwig and Weimer review breakthroughs in Batten disease research focusing on multiple therapies that show promise in preclinical and clinical studies.
Bantje and Tikkanen discuss splicing therapy options for Lysosomal Storage Disor-ders including also CLN2.
Simonati and Williams focus on recent advances in NCL research and summarize multi-faceted approaches to deal with clinical issues.
Trivisano et al review neurophysiological findings in NCL, and how these findings may facilitate earlier diagnosis and help follow disease progression.
Kaminiów et al provide an overview of the current knowledge regarding NCL dis-ease pathophysiology, genetics, and clinical manifestation, and also discuss ap-proaches to diagnosis.
Guo et al analysed the contribution of Mendelian disorders in a large population-based pediatric neurodegeneration cohort of approximately 100,000 patients. Out of 69 patients with a neurodegenerative phenotype, 42 patients had a genetic diag-nosis, and 32 patients had unique disorders. Common diagnoses included also NCL.
Bartsch and Storch review experimental therapeutic approaches for the treatment of retinal pathology in NCL with special emphasis on ERT and gene therapy.
Gardner and Mole summarize current knowledge and understanding of the genetic basis of NCL and their phenotypic heterogeneity.
Takahashi et al summarize the most up-to-date understanding of glial pathologies and their contribution to the pathogenesis of NCL
Santos et al discuss splicing modulation as a promising therapeutic strategy for ly-sosomal storage disorders using Mucopolysaccharidoses as an example.
Cao et al discuss current opportunities and challenges of targeting lysosomes in hu-man disease.
Zoncu and Perera review emerging molecular mechanisms of lysosome remodelling and repair in health and disease.
Shibuya et al present a proof-of-concept study suggesting that efficient CNS-wide microglia replacement may have therapeutic efficacy for a variety of neurological diseases.
Drobny et al discuss the role of lysosomal cathepsins in neurodegeneration and summarize the potential role of lysosomal cathepsins as clinical biomarkers and therapeutic approaches.
Tang et al discuss the critical roles of sphingolipid metabolism in regulating lysoso-mal functions, and how such regulation may contribute to aging and aging-related diseases.
Kim et al review and discuss our understanding of molecular mechanisms underly-ing the formation and regulation of organelle contact sites, and their role in health, disease, and therapy.
Cisneros et al highlight advances in the field of mitochondria-lysosome contact sites and their mis-regulation across multiple neurodegenerative disorders.
Kuk et al provide arguments for why studying the mitochondrial–lysosomal axis contributes to a better understanding of essential physiological processes underly-ing LSDs, and propose new LSD treatment strategies.
Meraş et al review the mechanisms that regulate the sorting of soluble proteins to lysosomes, highlighting the effects of mutations in this pathway that cause human disease.
Savini et al used the worm Caenorhabditis elegans as a model, presenting results that reveal lysosomes as a signalling hub coordinating metabolism by mediating in-ter-tissue communication and promoting longevity.
Hörner et al used a SPG11 mouse model of Hereditary Spastic Paraplegia to show that targeting the adaptive immune system T-lymphocyte component can attenu-ate the neurodegenerative phenotype. SPG11 dysfunction causes autophagic de-fects, and the protein is involved in autophagic lysosomal reformation (for review see Pozner et al).