Here you will find a regular update of the latest scientific publications on the different forms of NCL.
Last update: August 2023
Single Patient Compassionate Use ERT Trial: Hahn et al. (2022) report a 68-month-old boy with CLN1 who was treated on a compassionate use basis weekly for 26 months with a PPT1enzyme fused to an anti-insulin receptor
antibody (AGT-194), thereby enabling penetration of the blood-brain barrier (BBB). During treatment, no side effects were observed, while seizure frequency decreased, life quality improved, and
the boy's general condition remained stable. This case documents for the first time that enzyme replacement therapy of CLN1 is principally feasible by using
an intravenous BBB crossing PPT1 enzyme fused to an anti-human insulin receptor antibody. The treatment raised no unacceptable or unexpected safety concerns whereas improvement of life quality
(ameliorated epilepsy control) raises hope that clinical trials including patients in earlier stages of disease may show positive outcomes.
Peviani et al. (2023) show that transplantation of hematopoietic stem and progenitor cells (HSPCs) into PPT1-/- mice using a novel intracerebroventricular approach can establish a long-lasting microglia-like progeny in the CNS of properly myelo-ablated hosts. The authors also report that the therapeutic benefits can be further enhanced by transplanting HSPCs over-expressing hPPT1 by lentiviral gene transfer.
Ostergaard et al. (2022) compare propagation of disease in CLN1 and CLN3 and propose that CLN1 disease represents a “Body-first” or bottom-up disease propagation, whereas CLN3 disease seems to have a “Brain-first” and top-down propagation.
Bhardwaj et al. (2023) show that a dimeric form of chloroquine that inhibits PPT1, promotes lysosomal lipid peroxidation, resulting in lysosomal membrane permeabilization and tumor cell death. This lysosomal cell death pathway promoted T lymphocyte–mediated tumor cell clearance.
Retinal Gene Therapy Trial. Regenxbio is going forward with the
first-in-human, open-label, single ascending dose study of a CLN2 retinal gene therapy trial using subretinal delivery of RGX-381 (AAV9.CB7.hCLN2) to evaluate safety and tolerability in patients
age 1-12 years (see also here).
Kick et al. (2023) show that a single intravitreal injection of AAV2.CAG.hTPP1 inhibits ocular disease progression and preserves retinal function in a canine model of CLN2.
Takahashi et al. (2023) report that neonatal gene therapy using AAV9.hCLN2 ameliorates seizure and gait phenotypes and prolongs life span of CLN2R207X mice, attenuating most pathological changes.
Munescue et al. (2023) report the discovery of a cynomolgus macaque model of CLN2 carrying a homozygous single-base deletion (c.42delC) that results in a frameshifted premature stop codon.
Nickel et al. (2023) together with disease experts, report how language development is affected by CLN2 disease, and conclude that CLN2 disease should be considered in children presenting with language delay and/or seizures, to facilitate earlier diagnosis and treatment.
Knoernschild et al. (2023) track disease progression in a genetically modified CLN2R208X/R208X miniswine model and show that MRI brain volumetry in this mini swine model is sensitive to early disease detection and longitudinal change monitoring.
El-Hage et al. (2023) report the development of a novel extracellular vesicle-based drug delivery system for the transport of the lysosomal enzyme tripeptidyl peptidase-1 (TPP1) to treat Batten disease.
Albers et al. (2023) report that engineered tRNAs can suppress nonsense mutations in cells with the most common CLN2 R208X PTC mutation while their work mainly focused on clinically important PTC mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR).
Sivananthan et al. (2023) studied the proportion of cells with abnormal storage inclusions of peripheral blood buffy coats and propose the use of this parameter as a biomarker of response to ERT in CLN2.
Miglustat trial. Theranexus report encouraging preliminary 6-month results in their Phase I/II trial of Batten-1
(Miglustat) such as an average 17% decline in neurofilament light chain levels in the blood of dosed patients, and motor symptoms (assessed by the modified physical subscale of the UBDRS) that
did not progress over the same period (). The Phase III trial design has been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Theranexus has launched a global offering of around $4.5 million to help fund its
pivotal Phase 3 trial, and the Beyond Batten Disease Foundation (BBDF) acquired about $1.3 million in shares before the offering, making BBDF a new shareholder. The pivotal trial is expected to
begin enrollment by 2023 year’s end at international sites, including the U.S. and Europe, and should be completed by the end of 2026. Estimated costs amount to about $5.6 million a year.
Gene Therapy Trial. Official report and outcome of the Amicus Therapeutics trial (AT-GTX-502 AAV9 gene therapy) are still awaited. This trial was a phase 1/2, open-label, single dose, dose-escalation clinical trial to evaluate the safety and efficacy of AT-GTX-502 delivered intrathecally into the lumbar spinal cord region of subjects with CLN3 Batten disease.
Calcagni et al. (2023) show that CLN3 is a vesicular trafficking hub connecting Golgi and lysosome compartments. CLN3 interacts with several endo-lysosomal trafficking proteins, including CI-M6PR, and CLN3 depletion results in mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation.
Relton et al. (2023) use a CLN3-deficient HeLa cell model and show that absence of CLN3 is associated with an altered metabolic profile, reduced global translation, and altered stress signaling including perturbations in Stress Granule dynamics. The latter result in SG assembly and disassembly defects, and altered expression of the key SG nucleating factor G3BP1.
Sleat et al. (2023) created CLN2:CLN3 double mutant mice and report that the phenotype is indistinguishable from single CLN2 KO mutant mice in terms of survival and brain pathology. CLN3-/-:CLN2+/- mice with only a single CLN2 KO allele, however show a significantly decreased lifespan as compared CLN3KO mutants making CLN3-/-:CLN2+/- mice potentially useful in assessing therapies given that CLN3 KO mice only display very mild phenotypes.
Centa et al. (2023) generated a mouse model that constitutively expresses the CLN3 spliced isoform that is induced by an antisense oligonucleotide (ASO) that skips exon 5. Behavioral and pathological analyses of these mice demonstrate a less severe phenotype compared with the CLN3Δ7/8 mice. Therefore, ASO-induced exon-5 skipping may have therapeutic benefit in CLN3 patients that carry at least one CLN3Δ7/8 allele.
Jana et al. (2023) show that oral administration of the FDA approved lipid-lowering PPARα activator gemfibrozil in CLN3Δ7/8 mice reduces micro- and astroglial activation, attenuats neuroinflammation, restors TFEB levels, decreases SubC accumulation in a cortical region, and improves locomotor activity. In contrast, disease pathologies are aggravated in CLN3Δ7/8 mice lacking PPARα.
Johnson et al. (2023) report that early postnatal intracerebroventricular administration of the gene therapy vector scAAV.Mecp2.CLN3 into CLN3Δ7/8 mice results in robust expression of human CLN3 throughout the CNS over the 24-month duration of the study. The therapy consistently and persistently rescued hallmarks of disease while being safe and well-tolerated.
Wünkhaus et al. (2023) report that TRPML1 activation using the agonist ML-SA5 ameliorates lysosomal storage phenotypes (Gb3 and SubC) in CLN3 deficient retinal pigment epithelial (RPE) cells. CLN3 KO RPE cells have significantly decreased lysosomal bis(monoacylglycero)phosphate (BMP/LBPA) lipid levels. BMP is a key co-factor needed by many lysosomal enzymes to exert their activity. Activation of TRPML1 reduced lysosomal storage of Gb3 and SubC but failed to restore BMP levels. TRPML1-mediated decrease of storage was TFEB-independent, and the authors provide evidence for enhanced lysosomal exocytosis as a likely mechanism for clearing storage products including GPDs.
Swier et al. (2023) present a longitudinal characterization of a novel CLN3Δ7/8 mini swine model of CLN3 disease with progressive pathology and neuronal loss in brain regions and retina supporting its value in studying the disease and safety & efficacy of novel therapeutics.
Do et al. (2023) describe proteomics analysis of CSF samples comparing CLN3-affected and age-similar non-CLN3 individuals. The authors used proximal extension assays (PEA) and untargeted mass-spectrometry (MS). Known and unknown candidate biomarkers identified included NFL, CHIT1, NELL1, and ISLR2 as well as others.
Do et al. (2023) report brain magnetic resonance spectroscopy (MRS) data on 27 patients with typical CLN3 presentation ages 6-20.7 years and propose that NAA and glutamine/glutamate/GABA measured in the midline parietal grey matter may be useful indicators of CLN3 disease state.
Chen et al. (2023) present evidence that CLN3 is also a lysosomal cholesterol storage disorder based on findings of cholesterol accumulation in LE/Lys isolated from human brain tissue homogenates. Cholesterol accumulation in CLN3 samples was comparable to the extent seen in NPC samples. Lipid profiles of LE/lys were similar in CLN3 and NPC patients, except for the levels of bis(monoacylglycero)phosphate (BMP), that are up in NPC and down in CLN3, as compared to controls.
Kasapkara et al. (2023) report a pronounced elevation of the NPC biomarker lyso-sphingomyelin-509 in a 16-year-old CLN3 patient with a homozygous variant (p.Thr80fs) in exon 4.
Heins-Marroquin et al. (2023) report that CLN3 deficiency in zebrafish leads to neurological and metabolic perturbations durng early development. The authors show significant accumulation of several glycerophosphodiesters (GPDs) and a global decrease of bis(monoacylglycero)phosphate (BMP) species, two classes of molecules first reported in human CLN3 cell models and a CLN3-deficient mouse model by Laqtom et al..
Ostergaard (2023) discusses the etiology of anxious and fearful behavior that typically increases during the terminal phase of CLN3 disease and proposes ways for managing this clinical phenotype.
Pezzini et al. (2023) report enhanced expression of the autophagosomal marker LC3-II in detergent-resistant protein lysates from a CLN3 patient’s post-mortem brain and present fractionation data suggesting a different lipid composition of the membranes where LC3-II is stacked.
Chear et al. (2022) corrected the 966 bp Δ7/8 deletion mutation in human induced pluripotent stem cells (iPSCs) derived from a compound heterozygous patient (CLN3Δ7/8 : E295K), differentiated these isogenic iPSCs into neurons, and identified disease-related changes relating to protein synthesis, trafficking and degradation. CLN3 neurons also had lower electrophysical activity.
Kolesnikova et al. (2023) describe the phenotype of retinal dystrophy in a subset of patients carrying CLN3, CLN7, CLN8 and CLN11 mutations, respectively. 4 CLN3 patients without neurological symptoms had different age-at-onset retinal disease. Two patients (CLN3Δ7/8 : R405W) were diagnosed at 17 and 19 years with autosomal-recessive pigmentosa (aRP), a homozygous Glu295Gly carrier (novel unique mutation) was diagnosed with aRP at age 16, and a homozygous Ala59Thr carrier (previously reported mutation) at age 32 with autosomal recessive one rod dystrophy. Interestingly, earlier patients carrying a Glu295Lys mutation were reported to show protracted JNCL.
Cameron et al. (2023) describe a cohort of Australian patients with protracted CLN3 disease that includes patients homozygous for the common CLN3Δ7/8 allele, thereby supporting the notion that no definitive genotype-phenotype correlations can be drawn to explain variable clinical manifestations.
Guo et al. (2023) describe a patient carrying a L116 deletion and
diagnosed with adult-onset neuronal ceroid lipofuscinoses, progressive parkinsonism, epilepsy, and cognitive impairment. The authors present evidence that the L116 deletion in CSPα promotes
α-synuclein pathology and neurotoxicity.
Huang and Zhang (2022) review the functional properties of CSPα and pathogenic mechanisms related to neurodegeneration.
Neurogene gene therapy trial. Neurogene announced that it is recruiting for a phase 1/2 trial for intracerebroventricular and intravitreal administration of NGN-101.
Murray et al. (2023) describe progressive MRI brain volume changes in
ovine models of CLN5 and CLN6 that correlate with clinical scores and indicate selective vulnerability and a timeline of degeneration of specific brain regions.
Mitchell et al. (2023) describe a comprehensive natural history of the progressive neuropathological changes in ovine CLN5 and CLN6 disease
providing insight into the optimal age/disease stage for therapeutic intervention and terminal efficacy endpoints to assess outcome of future therapy studies.
Kim and Huber (2022) describe the impact of CLN5-deficiency on gene expression in Dictyostelium discoideum during growth and starvation and highlight the multifaceted role of CLN5 in cell and lysosome homeostasis.
Kulsirichawaroj et al. (2023) present two girls in Thailand (age 2 and 7.5 years) diagnosed with CLN6 and Rett-like clinical features, including global developmental regression and hand-wringing action.
Neurogene CLN7 gene therapy. As announced late January Neurogene has discontinued its
efforts to run a CLN7 gene therapy trial.
Heinl et al. (2022) provide evidence that CLN7 is involved in SARS-CoV-2 infection. CLN7-deficient HEK293T cells exhibited a 90% reduced viral load compared to wild-type cells. It may be linked to significantly reduced GM1 content in the cell membrane and lipid rafts, which are thought to play an important role in SARS-CoV-2 infection.
Pasquetti et al. (2023) describe a new pathogenic CLN7 variant that skips exon 8.
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.
Mitsui et al. (2023) document that Cathepsin D deficiency in the mouse model leads to intracellular lysosome and autophagic vacuole abnormalities in activated microglia and astrocytes in addition to abnormalities seen in neurons and neuronal degeneration.
Feng et al. (2023) show that
intracerebro ventricular injection of PGRN-expressing AAV1/9 viruses partially rescues motor deficits, neuronal loss, glial activation, and lysosomal abnormalities in TMEM106B : GRN double
Reich et al. (2023) report rescue of FTLD-associated TDP-43 pathology and neurodegeneration by peripheral (liver) AAV-mediated expression of brain-penetrant progranulin in GRN single and GRN TMEM106B double knockout mice.
Du et al. (2023) show that progranulin interacts with and inhibits phospholipase sPLA2-IIA to control neuroinflammation. The authors also document that FTLD patients with GRN mutations show increased levels of sPLA-IIa in astrocytes.
Anderson and Tansey (2023) demonstrate that there is increased cathepsin B activity in GRN-/- MEFs in comparison to GRN+/+ MEFs and this cathepsin B activity is reduced when GRN-/- MEFs are rescued with recombinant PGRN protein.
Fujimori et al. (2023) show increased PGRN protein expression in striatum of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model mice. Intracerebroventricular administration of PGRN ameliorated the decrease in expression of tyrosine hydroxylase and ameliorated 6-hydroxydopamine-induced motor deficits in these mice. In MMP+ treated SH-SY5Y cells PGRN ameliorated the increase of LC3 puncta and reduced α-synuclein accumulation.
Root et al. (2023) show that rAAV delivery of either human granulin-2 or granulin-4 to GRN-/- mouse brain ameliorates lysosome dysfunction, lipid dysregulation, microgliosis, and lipofuscinosis similar to full-length PGRN. Therefore, individual granulins are the functional units of PGRN and likely mediate neuroprotection within the lysosome.
Takahashi et al. (2023) propose that a lysosomal PGRN–GCase pathway may be a common therapeutic target for age-related comorbid proteinopathies. The authors show that PGRN regulates tau- and synucleinopathies via GCase and GlcCer.
Smith et al. (2023) show that targeting nonsense-mediated RNA decay (NMD) is likely not a viable approach for increasing PGRN levels in GRN-FTD patients. Progranulin levels in the GRN(R493X) mouse model of FTLD did neither increase when using ASOs targeting an exonic region in GRN(R493X) mRNA and predicted to block its degradation, nor when depleting the NMD factor UPF3b.
Smith et al. (2023) performed an in-depth characterization of heterozygous and homozygous GRNR493X knock-in mice. They found increased expression of lysosomal genes, markers of microgliosis and astrogliosis, pro-inflammatory cytokines, and complement factors in homozygous mice. Heterozygous mice exhibited more limited increases in lysosomal and inflammatory gene expression. While homozygous GRNR493X mice closely phenocopy GRN full knockouts, heterozygous mice don`t. The latter also lack elevated levels of fluid biomarkers (NFL & GFAP) in plasma and CSF.
Thomasen et al. (2023) identify SorCS2 as a novel receptor for progranulin (PGRN) that is required for motor axon outgrowth in zebrafish and mice. The authors also show that when co-expressed in the same cells, SorCS2 controls secretion of PGRN.
Khrouf et al. (2023) analyzed plasma levels of four lysosphingolipids (lysoSPL) in 131 GRN mutation carriers and 142 non-carriers and found that LGL1, LSM18:1 and LSM509 were increased in GRN carriers compared to non-carriers and FTD patients without GRN mutations. LSM18:1 and LGL1 increased over a 3.4-year follow-up suggesting lysoSPLs may be suitable for non-invasive disease tracking.
Zambusi et al. (2023) used wound injury model in zebrafish to identify an injury-induced microglial state with accumulation of lipid droplets and TDP-43+ protein condensates. Granulin-mediated clearance of both lipid droplets and TDP-43+ condensates was necessary and sufficient to promote the return of microglia back to the basal state and achieve scarless regeneration.
Zhao et al. (2023) and ex vivo evidence (fibroblasts) for PGRN deficiency exacerbating GBA1 mutation-related pathologies, and show that a brain penetrant PGRN derivatived peptide can ameliorate neuronal Gaucher Disease manifestations in Gba9v/null and PG9V mice.
Rodríguez-Periñán (2023) show that PGRN deficiency reduces mitochondrial membrane potential, decreases ATP production, and impairs mitochondrial respiration levels in GRN knockdown (KD) SH-SY5Y neuroblastoma cells and lymphoblasts from FTLD-TDP patients. Lysosomal degradation of damaged mitochondria is impaired. The authors also report that inhibition of TDP-43 phosphorylation restores mitochondrial bioenergetics in GRN KD cells.
Hasan et al. (2023) use lysosome proximity labeling and immuno-purification of intact lysosomes to characterize lysosome composition and interactomes in iPSC-derived glutamatergic neurons and mouse brains. The authors measured global protein half-lives in iPSC-neurons and show impact of PGRN-deficiency including increased levels of lysosomal v-ATPase subunits and catabolic enzymes, elevated lysosomal pH, and pronounced alterations in neuron protein turnover.
Marian et al. (2023) present a brain lipidomic analysis of FTD-GRN, FTD-C9orf72 and age-matched neurologically normal controls. GRN mutations seem to cause a more pronounced disruption of myelin lipid homeostasis including loss of myelin-enriched spingolipids, and myelin proteins. FTD-GRN cases also stood out showing increased acylcarnitines, cholesterol esters, and lysososmal galactocerebrosidase activity.
Elia et al. (2023) generated GRN(R493X) iPSC-derived neurons which show reduced PGRN levels, dystrophic neurites, simplified neurite arbors, impaired lysosomal function and elevated pH, defective TDP-43 turnover and accumulation, neurodegeneration, and premature death. Proteomic analysis revealed downregulation of proteins linked to the autophagy-lysosome pathway, and the ubiquitin-proteasome system.
Marsan et al. (2023) uncovered a highly conserved astroglial pathology that promotes profound synaptic degeneration across mouse and human. Toxicity was recapitulated in mouse astrocyte-neuron cocultures and by transplanting induced
iPSC–derived PGRN-deficient astrocytes to cortical organoids, where these promoted synaptic degeneration, neuronal stress, and TDP-43 proteinopathy (see also accompanying editorial: https://www.jci.org/articles/view/168215).
Lee et al. (2023) present MRI-based white matter changes in predementia individuals carrying mutations in GRN and C9orf72, suggesting that these may represent early markers of familial FTD.
Simon et al. (2023) review emerging lysosomal biology of PGRN focusing on PGRN regulating glucocerebrosidase activity as a chaperone and indirectly via prosaposin, and the anionic lipid BMP.
Life et al. (2023) present a novel FTD-GRN mouse model (GRNTg) that expresses a single copy of human GRN (on a BAC in the HPRT locus) in the absence of mouse PGRN. The authors compared GRN-/-, GRNTg, and GRN+/- mice and identified reproducible behavioral, neuropathological, and biochemical phenotypes as well as differential cortical transcriptomics across the lines.
Houser et al. (2023) use deep immunophenotyping by flow cytometry and describe sex-dependent dysregulation of peripheral and central immune system cell surface markers on microglia, T-cells and monocytes. The lysosomal protein GPNMB seems to be modulated in a sex-specific manner in myeloid cells.
Davis et al. (2023) report that many of the lysosomal abnormalities observed in frontal cortex of patients with FTD-GRN are also present in frontal cortex of patients with other types of sporadic FTLD. Nonetheless, patients with FTD-GRN and sporadic FTLD-TDP type A exhibited unique changes in expression of lysosomal genes.
Cabron et al. (2023) generated a knockin mouse model harboring the TMEM106bT186S protective variant and analyzed its effect on FTLD pathology in GRN-/-: Tmem106bT186S double mutant mice. The authors observe no amelioration of any of the investigated GRN-/-knockout phenotypes and conclude that the Tmem106bT186S variant is not protective in the GRN-/- knockout mouse model. Hence, the modifying effects of the associated SNPs are not directly linked to the amino acid exchange in TMEM106B.
Edwards et al. (2023) present evidence that TMEM106B deletion or coding variation are disease modifying in a mouse model of tauopathy (MAPT P301S). In this model, TMEM106B deletion worsens cognitive impairment, enhances neurodegeneration, and accelerates paralysis caused by pathogenic tau, whereas expression of T186S coding variant protects against cognitive decline and delays paralysis in tau mice although without changing tau pathology.
Fujii et al. (2023) report that ATP13A2 functions as a
lysosomal H+, K+-ATPase that is inhibited by thapsigargin and competitive inhibitors of gastric H+, K+-ATPase. These inhibitors cause lysosomal alkalinization and α-synuclein accumulation, a
pathological hallmark of PD. PD-associated mutants of ATP13A2 (A746T and R449Q) significantly reduce ATP13A2 activity and K+ transport. ATP13A2 therefore regulates lysosomal homeostasis and was
earlier shown to be functionally associated with polyamine transport.
Mu et al. (2023) present the high-resolution structures of human ATP13A2 in six intermediate states, including structures comprising a nearly complete conformational cycle spanning the polyamine transport process. The structures capture multiple substrate binding sites along the transmembrane regions and suggest a potential polyamine transport pathway.