Here you will find a regular update of the latest scientific publications on the different forms of NCL.
Last update: November 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.
Nelvagal et al tested the efficacy of enzyme replacement therapy (ERT) by delivering monthly infusions of recombinant human PPT1 (rhPPT1) in PPT1-deficient mice (Cln1−/−), and CLN1R151X sheep. In Cln1−/− mice, intracerebroventricular delivery was the most effective route of administration. It resulted in therapeutically relevant CNS levels of PPT1 activity, improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In sheep, icv infusions resulted in widespread rhPPT1 distribution and positive treatment effects supporting clinical testing of ERT in children with CLN1 disease.
Hahn et al report on a case of a a 68-month-old
boy with CLN1 treated on a compassionate use basis weekly for 26 months with a PPT1 enzyme fused to an anti-insulin receptor antibody enabling brain penetration. During treatment, no side effects
were observed, seizure frequency decreased, life quality improved, and the boy’s general condition remained stable.
Dearborn et al report that chronic Cannabidiol (100 mg/kg/day for six months) in a mouse model of CLN1 disease (Cln1−/−) was well-tolerated and reduced markers of astrocytosis and microgliosis but had no apparent effect on seizure frequency or neuron survival.
Peviani et al provide first evidence that transplantation of wild type Hematopoietic stem and progenitor cells (HSPCs) can lead to the establishment of a long- lasting microglia-like progeny in the brain of myeloablated CLN1 mice and a partial but long-lasting mitigation of symptoms. Transplantation of HSPCs overexpressing hPPT1 enhances therapeutic benefit.
Gorenberg et al identified >100 novel PPT1 substrates with increased in vivo palmitoylation in PPT1 knockout (KO) mouse brains and validated putative substrates through direct depalmitoylation with recombinant PPT1. They identified diverse PPT1 substrates at the synapse, including transmembrane channels and transporters where cysteine depalmitoylation sites frequently participate in disulfide bonds in the mature protein.
Vergoten & Bailly modeled the interaction of three potent selective PPT1 inhibitors with the enzyme based in its crystallographic structure. The molecules fit into the palmitate site of the protein. N-glycans do not impede drug binding suggesting that all glycoforms of PPT1 can be targeted with these compounds. PPT1 is often over-expressed in cancer, and possibly a target to control tumor growth.
Swier et al generated and characterized a new CLN2R208X/R208X porcine
disease model. It manifests behavioral (gait, cognition, seizures), pathological (storage, glial activation), and visual (ERG) phenotypes, and has a short life-span (18 months).
Dulz et al report progression of retinal degeneration in patients with CLN2 disease despite intraventricular enzyme replacement therapy underlining that retina-directed therapies should be initiated as early as possible before or during the phase of rapid retinal degeneration.
Atiskova et al present a longitudinal study showing variable ocular involvement in non-classical CLN2 disease which contributes to the natural history description and that emphasizes the need for regular ophthalmic examination.
Takahashi et al characterized neuropathological and neurological changes in Cln2R207X mice and describe early localized microglial activation months before neuron loss occurs in various brain regions. It is accompanied by astrogliosis and progressive changes in the expression of specific chemokines and cytokines. Gait was impaired only at disease end-stage. EEG recordings revealed progressive epileptiform activity from disease mid-stage, and was accompanied by a loss of cortical GABAergic interneurons.
Theranexus and the Beyond Batten
Disease Foundation (BBDF) have completed enrollment for a Phase 1/2 clinical trial testing Batten-1 (miglustat) in adolescents and adults with CLN3 disease.
Laqtom et al report that CLN3 is required for the clearance of glycerophosphodiesters from lysosomes (see meeting summary).
Scotto Rosato et al show that small molecule activation of the Ca2+-permeable endolysosomal two-pore channel 2 (TPC2) ameliorates cellular phenotypes associated with LSDs. Rescue effects by TPC2 activation, which promotes lysosomal exocytosis and autophagy, were assessed in mucolipidosis type IV (MLIV), Niemann–Pick type C1, and CLN3 Batten disease patient fibroblasts, and in neurons derived from newly generated isogenic human iPSC models for MLIV and CLN3 disease. Results in the MLIV mouse model together with the data in the cell models suggest that TPC2 is a promising target for the treatment of different types of LSDs.
Prat Castro et al discuss possible advantages of TPC2 over TRPML1 activation to rescue LSD phenotypes. Unlike TRPML1, TPC2 activation is pH-independent and not blocked by sphingomyelin. Lysosomal patch clamp studies show that TRPML1 currents are reduced in iPSC-derived neurons carrying a CLN3 knockout and the Batten disease mutation D416G, but not in neurons carrying the non-syndromic CLN3 R405W mutation.
Swier et al present a longitudinal
characterization of a miniswine model of CLN3 disease that recapitulates the genetic defect of the most common human pathogenic variant (CLN3Δex7/8). Progressive pathology and neuron loss is
observed in various regions of the brain and retina, and is accompanied by vision impairment and motor abnormalities demonstrating its value in studying CLN3 and novel disease modifying
Hochstein et al report on the natural history of MRI brain volumes in CLN3 patients and conclude that supratentorial cortical GM volume is a sensitive parameter for assessment of disease progression in early and late disease stages and representing a potential reliable outcome measure for evaluation of experimental therapies.
Todiere et al describe cardiac MRI findings in a CLN3 patient showing
basal inferior interventricular septal hypertrophy, maintained indexed LV mass, and low T1-native values. The authors recommend more routine use of cardiac MRI for early diagnosis of cardiac
involvement and to monitor effects of therapies on the myocardium.
Savvidou et al report on the occurrence of drug-induced hyperthermia in pediatric patients with CLN3 and possibly provoking drugs (risperidone, clozapine, olanzapine, haloperidol, quetiapine, sertraline). The course was atypical. Three of the patients died which points to a vulnerability to drug-induced hyperthermia. This may involve dysregulation of the sympathetic nervous system.
Brudvig et al report that CLN3 pig serum samples exhibit large elevations in four glycerophosphodiesters (GPI, GPE, GPC, GPS). GPI and GPE showing the largest increases. Similar elevations were found in CLN3 pig CSF, CLN3 mouse serum, and plasma samples from CLN3 patients suggesting the potential utility of GPDs as diagnostic biomarkers and/or as efficacy measures for disease-modifying therapies.
Soldati et al followed up on their earlier paper (https://www.embopress.org/doi/full/10.15252/emmm.202013742)) where they discovered (i) accumulation of Globotriaosylceramide (Gb3) in cellular and murine models of CLN3 and CLN7 Batten`s Disease (BD), and (ii) tamoxifen (TAM) as an FDA-approved hit that ameliorates BD phenotypes. TAM might offer an opportunity for BD-affected children. Here they discuss TAM's safety and compile data on TAM in young non-BD patients.
Malysheva et al profiled
promoter-anchored chromosomal contacts in human primary innate type 3 lymphoid cells (ILC3s), a rare tissue-resident “helper” lymphocyte type that does not express diversified antigen receptors.
ILC3s are enriched in the respiratory and intestinal mucosa. Promoter-interacting regions in ILC3s are enriched for genetic variants associated with Crohn’s disease (CD), in which ILC3s are
established mediators. They identify genes including CLN3 conferring genetic risk of CD. In Cln3 mutant mice they show that CLN3 is a putative negative regulator of IL-17 production in
Krantz et al interviewed CLN3 parents to collect parental experiences and how these experiences relate to family resilience.
Barker et al describe a Caenorhabditis elegans animal model of autosomal dominant adult-onset CLN4 (DNAJC5/CSPα) disease. The disease-causing mutations were introduced into the endogenous C. elegans dnj-14 gene. Homozygous and heterozygous mutant worms exhibited reduced lifespans and severely impaired chemotaxis like isogenic dnj-14 null mutants. The anti-epileptic drug ethosuximide could restore chemotaxis in dnj-14 mutants to wild-type levels.
Murray & Mitchell describe the surgical protocol for intravitreal
(IVT) delivery of a therapeutic viral vector to the ovine eye. The team previously demonstrated the efficacy of intravitreal delivery of AAV-mediated gene therapy in CLN5 sheep. CLN5 gene therapy
was granted IND by the FDA in September 2021.
Doccini et al used a lysosome-focused, label-free quantitative proteomics approach and revealed a key role of CLN5 protein in lipid homeostasis and sphingolipid metabolism. Their cln5 morpholino-based knockdown zebrafish model recapitulated pathological features seen in NCL disease. Two FDA-approved drugs (trehalose and miglustat) improved pathological features in cell models and the zebrafish model.
Lange et al report on a patient with adult-onset CLN5 disease with atypical parkinsonism and pathological Dopamine Transporter Imaging signals. The patient showed a partial response to dopaminergic treatment.
Sharaireh et al document that post-natal intracerebral administration of AAV9-hCLN7 to Cln7Δex2 knockout mice results in extended lifespan. However, dose escalation resulted in reduced acuity in neurophysiology tests, cerebral atrophy and elevated neuroinflammation. Using proteomics, the authors identified a profound nuclear defect in mutant iPSC-derived neuronal precursor cells (iNPC) and a 37kDa isoform that accumulates only in mutant iNPC nuclei suggesting that treatment of CLN7 might have to address both loss and aberrant gain of protein function.
Rowe et al performed visual examinations on five patients with CLN7 Batten disease and found that patients were far progressed in degeneration within their first five years of life. Because the natural progression of retinal degeneration in CLN7 Batten disease patients is not well-known, the authors characterized the retina of a preclinical CLN7 mouse model. Using histology and live retinal imaging, they show that the mice show signs of photoreceptor to bipolar synaptic defects early and displays rod-cone dystrophy with late loss of bipolar cells.
Priluck & Breazzano describe a previously unreported combination of compound heterozygous variants in the CLN7/MFSD8 gene (Gly52Arg : Gluc336Gln) that causes a non-syndromic, bilateral central macular dystrophy presenting in adulthood.
Holmes et al describe
several sex differences in the Cln8mnd mouse model such as greater GFAP+ astrocytosis and CD68+ microgliosis in brain areas of female mice, also showing poorer motor performance and earlier death
than males. Treatment response after AAV9 CLN8 gene therapy revealed no appreciable sex differences.
Sharkia et al report on two CLN8 patients who presented with atypical phenotypic manifestation and protracted clinical course. They carry a novel compound heterozygous variant of the CLN8 gene and presented with mild epilepsy, cognitive decline, mild learning disability, attention-deficit/hyperactivity disorder, and a markedly protracted course of motor decline. Bioinformatic analyses suggest the variants might compromise structural integrity of the protein and likely its stability.
Suzuki et al generated a CNS‐specific CtsD‐knockout mouse (CtsD‐CKO). This mouse is viable, without intestinal symptoms unlike full KO mice, develops seizures, growth is stunted at around postnatal day 23, and autofluorescent material accumulates in brain. Analyses suggest an impaired autophagy‐lysosome system. In thalamus, microglia and astrocytes were activated. Protein deposits of α‐synuclein and Tau were found.
Boland et al report that PGRN-deficient human
cells, murine brains, and frontal lobes from GRN-mutation FTD patients have increased levels of glycosphingolipids that contain sialic acid (gangliosides). Levels of lysosomal enzymes that
catabolize gangliosides were normal. However, levels of bis(monoacylglycero)phosphates (BMP) lipids required for ganglioside catabolism were reduced. Granulins might be required to maintain BMP
levels needed to support ganglioside catabolism and gangliosidosis may contribute to neurodegeneration in GRN-FTD and other neurodegenerative diseases.
Reho et al found significant enrichment of GRN loss-of-function mutations in patients with Lewy Body Dementia. They report several cases with both Lewy body pathology and TDP-43-positive neuronal inclusions.
Bossolasco et al investigated pathological phenotypes associated with FTLD and NCL in iPSC-derived cortical neurons from a GRN−/− patient affected by NCL. These neurons displayed TDP-43 and phospho-TDP-43 mislocalization, enlarged autofluorescent lysosomes, and electron-dense vesicles containing NCL-like storage material, hence showing both FTLD- and NCL-linked pathological features.
Simon et al review lysosomal functions of PGRN and implications for treatment. They highlight critical roles of PGRN in regulating lysosomal proteolysis and lipid degradation via chaperone activities and interactions with prosaposin and the anionic phospholipid bis(monoacylglycero)phosphate (BMP).
Takahashi et al performed RNAi-mediated knock-down of progranulin in primary human RPE cells. It did not affect the biogenesis of lysosomes in RPE cells but was necessary for the activation of lysosomal proteases.
Peng et al conducted a phenotypic screen for PGRN enhancers in murine BV-2 cells. Using an annotated small molecule library they identified the M3 muscarinic antagonist solifenacin. Further chemical optimization yielded compounds with increased potency in BV-2 cells and greatly reduced activity at the M3 receptor and hERG channels.
Gerrits et al used single-nucleus RNA sequencing of microglia, astrocytes, and the neurovasculature from cortical tissue of control and FTD-GRN brains to identify disease-associated subtypes of astrocytes and endothelial cells. The results indicate a perturbed BBB and suggest that the neurovascular unit is severely affected in FTD-GRN.
Wang et al demonstrate that KCTD7/CLN14 and CLN5 are biochemically linked. KCTD7 encodes an adaptor of the CUL3-RING E3 ubiquitin ligase complex that degrades CLN5. KCTD7 mutations disrupt the interaction between KCTD7-CUL3 or KCTD7-CLN5 which leads to an excessive accumulation of CLN5. This disrupts the interaction between CLN6/8 and lysosomal enzymes at the endoplasmic reticulum (ER), and impairs ER-to-Golgi trafficking of lysosomal enzymes.
Murley et al review recent studies that explore the roles of the ER,
lysosomes, and their contact sites in quiescent cells.
Stepien et al discuss putative mechanisms that may be responsible for mitochondrial dysfunction in LSDs and new potential therapeutic developments.
Guelbert et al present an analysis of NCL cases in South America and the Caribbean reviewing 71 publications from seven countries and data from 261 individuals.
Kulsirichawaroj et al present two cases (CLN1 and CLN6) with Rett-like clinical features.ant drugs, and vitamin C, in multiple scenarios to treat Batten disease.
McShane & Mole review sex differences in severity and progression of
NCL and the confound that preclinical research using model organisms shows a profound (male) sex bias and female omission which may affect understanding sex-specific differences also for
Scerra et al review advances in the knowledge of cellular and molecular mechanisms linking lysosomal positioning and trafficking to lysosomal storage diseases.
Gaudioso et al provide a summary of the techniques and models used in LSD research including animal models.
Mistry et al discuss lessons learned and future directions of Rare Lysosomal Disease Registries which help to inform scientific understanding and the development of comprehensive monitoring and treatment guidelines.
Tan & Finkel used proteomics to show that lysosomal membrane
permeabilization stimulates a phosphoinositide-initiated membrane tethering and lipid transport pathway for rapid lysosomal repair. This pathway involves rapid recruitment of
phosphatidylinositol-4 kinase type 2α (PI4K2A) on damaged lysosomes, the generation of high levels of PI4P, recruitment of oxysterol-binding protein-related proteins and ATG2, and membrane repair
through direct lysosomal lipid transfer.
Yu et al isolated lysosomes from transgenic C. elegans expressing a lysosomal 3×HA Lyso-Tag and did proteomic profiling comparing wild-type and long-lived worms. They show that lysosomal protein composition changes with longevity and show lysosomal proteome heterogeneity across different tissues. By comparing proteomes using different lysosomal Tags they show that the Ragulator complex and other mTORC1 regulators are enriched on lysosomes that contain the cysteine transporter Cystinosin.
Savini et al report a fat-to-neuron lipid signalling pathway induced by lysosomal metabolism and its longevity-promoting role in Caenorhabditis elegans. Lysosomal lipolysis in peripheral fat storage tissue upregulates the neuropeptide signalling pathway in the nervous system to promote longevity. This cell-non-autonomous regulation is mediated by a specific polyunsaturated fatty acid.
Pantazis et al, a stem cell
consortium, identified KOLF2.1J as an all-around well-performing iPSC line and have made KOLF2.1J and hundreds of its gene- edited derivative clones accessible to promote the standardization
required for large-scale collaborative science in the stem cell field.
Papandreou et al (https://pubmed.ncbi.nlm.nih.gov/35833379/) used Niemann-Pick type C as a paradigm and a selective panel of known biomarkers to improve biomarker discovery using a dried blood spot assay and multiplexed liquid chromatography tandem mass spectrometry. The panel had far superior performance as compared with individual biomarkers.
Yuan et al show that TPC2 can differentially regulate its cation permeability when co-activated by its endogenous ligands, NAADP and PI(3,5)P2. NAADP renders the channel Ca2+-permeable and PI(3,5)P2 renders the channel Na+-selective. A combination of the two increased Ca2+ but not Na+ flux. The data show that flux of different ions through the same pore can be independently controlled. TPC2 likely functions as a coincidence detector forlysosomal Ca2+ signaling.
Riederer et al provide an overview of lysosomal ion channels, their roles, and drugability.
He et al identified a phospholipid salvage pathway from lysosomes to the cytosol. The team deorphanized Spinster 1 (SPNS1) as a proton-dependent lysosomal lysolipid transporter for lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE). SPNS1 mediates the rate-limiting lysosomal efflux of these lysophospholipids for their recycling into cellular phospholipid pools.