RARE DISEASE
CLN3 disease
CLN3 disease
CLN3 disease
Synonyms: Batten-Spielmeyer-Vogt-Sjögren disease, Classic juvenile NCL, Classic juvenile neuronal ceroid lipofuscinosis, Neuronal ceroid lipofuscinosis type 3
Synonyms: Batten-Spielmeyer-Vogt-Sjögren disease, Classic juvenile NCL, Classic juvenile neuronal ceroid lipofuscinosis, Neuronal ceroid lipofuscinosis type 3
Synonyms: Batten-Spielmeyer-Vogt-Sjögren disease, Classic juvenile NCL, Classic juvenile neuronal ceroid lipofuscinosis, Neuronal ceroid lipofuscinosis type 3
Drug discovery
2
drugs
With orphan designations
Overview
CLN3 disease is an autosomal recessive neurodegenerative disorder and the most common neuronal ceroid lipofuscinosis (Batten disease). Caused by CLN3 gene mutations, it manifests with progressive vision loss (4-8 years), cognitive regression, motor decline, seizures, and psychiatric symptoms [1][2][12]. Lysosomal dysfunction leads to neuronal death, with blindness typically occurring by adolescence and survival into early adulthood [1][5][12]. No disease-modifying therapies exist, though experimental gene therapies show preclinical promise [7][15].
Burden
Functional: 100% develop blindness, wheelchair dependence by adolescence, early death (15-35 years) [1][5][12]
Care: Requires multidisciplinary teams, adaptive education, and 24/7 support in late stages [6][12]
Economic: Lifetime costs exceed $5M/patient; 78% of families report income loss due to care demands [6][12]
Therapies
Supportive care: Antiepileptics, physical/occupational therapy, palliative interventions [12][15]
Emerging therapies: AAV9-mediated CLN3 gene therapy (reduces lysosomal storage, neuroinflammation) [7][13], phosphodiesterase-4 inhibitors (rolipram/roflumilast) [3], immunomodulators (fingolimod) [3]
Trials: 1st CNS-targeted gene therapy trial pending based on murine efficacy [7][13]
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
319 drug discovery papers about CLN3 disease, with 6 first-in-class and 14 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
319 drug discovery papers about CLN3 disease, with 6 first-in-class and 14 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-18 | Thapsigargin-induced autophagic flux impairment and inflammation are potentiated by CLN3 deficiency and alleviated by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) in human ARPE-19 cells.
Juvenile neuronal lipofuscinosis (JNCL) is a rare disease caused by mutations in the CLN3 gene. It leads to early vision loss mediated by retinal degeneration. Impaired autophagosomal-lysosomal degradation is a major hallmark of JNCL pathology, and neuroinflammation has also been postulated to play a role in its pathogenesis. Thapsigargin, a selective inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase, inhibits autophagy, leading to an accumulation of autophagosomes/autophagophores in cells. Cells with defective CLN3 protein function have been found to be particularly sensitive to the anti-autophagic effects of thapsigargin. Here, we characterized the effects of thapsigargin on inflammatory cytokines and autophagic markers in ARPE-19 cells using ELISA and western blotting. We further examined these effects in cells deficient in CLN3 function by exposing the cells to CLN3 siRNA and testing whether the effects of thapsigargin could be modulated by the well-known autophagy activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). Thapsigargin induced the accumulation of LC3 and p62/SQSTM1, consistent with impaired autophagic flux in ARPE-19 cells. Additionally, we observed that thapsigargin possessed pro-inflammatory potential, as it induced the release of IL-6 in ARPE-19 cells, no inflammasome activation was detected. Both effects were enhanced by CLN3 siRNA and alleviated by AICAR. In conclusion, thapsigargin-induced impaired autophagic flux and the accompanying inflammatory response are more pronounced in CLN3-deficient ARPE-19 cells, indicating that loss of CLN3 function affects both autophagy and inflammatory signaling.
2026-05-18 | PPARα and RXRα in the regulation of neuronal ceroid lipofuscinosis genes: implications for Batten disease therapy.
Neuronal ceroid lipofuscinosis or Batten disease comprises a category of autosomal recessive neurodegenerative disorders that primarily affect children. Mutations in different genes lead to different forms of neuronal ceroid lipofuscinoses (CLN1-14). At present, there is no established therapy to cure most of the neuronal ceroid lipofuscinoses and the treatments are symptomatic. Enzyme replacement therapy, gene therapy, stem cell transplantation, and pharmacological chaperone therapy are being tested in different animal models and human patients. Peroxisome proliferator-activated receptor alpha (PPARα) is a member of the nuclear hormone receptor superfamily, which along with its transcription partner retinoid X receptor alpha (RXRα) regulates the expression of their target genes. This review highlights the potential role of PPARα and RXRα in the regulation of CLN genes. Here, using the MatInspector program of the Genomatix software, we performed promoter analyses of all CLN genes and observed that most of the CLN genes harbor one or more potential binding sites for PPAR and RXR in their promoter region. We further grouped them according to a binding prediction of the transcription factors to indicate high affinity binding of PPAR to CLN2, CLN3, CLN4, CLN5, CLN7, CLN10, CLN11, CLN12, and CLN14. On the other hand, we observed high affinity binding of RXR to CLN1, CLN3, CLN6, CLN7, CLN8, CLN10, and CLN13. Since PPARα and RXRα have been demonstrated to control the transcription of CLN2 gene, our current promoter analysis findings highlight a possible treatment strategy for neuronal ceroid lipofuscinoses using agonists of PPARα and RXRα.
2026-05-15 | Computational drug repurposing identifies N -acetylglucosamine as a potential therapeutic compound for CLN3 Batten disease
Abstract Batten disease, also known as neuronal ceroid lipofuscinoses, is one of the most common causes of childhood dementia. It is characterized by the accumulation of lipofuscin in lysosomes, leading to loss of brain cell function, onset of dementia-like symptoms, vision loss and seizures and has extremely limited treatment options. Here, we performed computational drug repurposing analysis to identify existing compounds that may target Batten disease risk genes. A total of 81 candidate compounds were identified, 6 of which were selected based on clinical tractability for downstream testing in Batten disease (CLN3) iPSC-derived models. After confirming disease phenotype and drug candidate safety, CLN3 brain cell cultures treated with and without drug candidates underwent bulk RNA-seq to identify drug responses. One of the candidate drugs N -acetylglucosamine (GlcNAc) significantly upregulated Batten disease risk gene CLN5 expression and several other lysosomal markers within CLN3 brain cells, and modulated several pathways implicated in lysosomal storage disorders. Importantly, GlcNAc significantly reduced lipofuscin burden in both CLN3 iPSC-derived neurons and astrocytes, supporting its investigation as an additional therapy for Batten disease.
2026-05-13 | Modeling CLN3 Batten disease in astrocytes reveals alterations in mitochondria homeostasis, fatty acid metabolism and oxidative stress response
Abstract Background CLN3 Batten disease is a severe pediatric neurodegenerative disorder caused by mutations in the CLN3 gene, most commonly a 1 kb deletion encompassing exons 7 and 8. CLN3 deficiency is associated with lysosomal dysfunction, impaired cellular clearance and disrupted metabolism. While neurons are particularly vulnerable in CLN3 Batten disease and have been the primary focus of research, glial cells are increasingly recognized as active contributors to disease pathology. Among them, astrocytes—the most abundant glial cell type in the brain—play critical roles in maintaining neuronal health and homeostasis. However, astrocytes remain understudied in CLN3 patient-derived models. Methods We present the first iPSC-derived astrocyte model from a skin biopsy of a CLN3 patient carrying the common 1 kb deletion. Cellular and molecular features of iPSC and astrocytes derived from both healthy controls and the CLN3 patient were characterized via qPCR, immunocytochemistry and targeted mass spectrometry. In addition, comprehensive omics-based profiling, through transcriptomic and label-free quantitative proteomics, was performed to uncover novel molecular mechanisms and generate hypotheses that can guide future mechanistic and functional studies. Results Transcriptomic and proteomic analyses during astrocyte differentiation revealed an upregulation of mitochondrial respiratory chain complexes I and IV—contrasting with the downregulation typically observed in CLN3-deficient neurons. We also identified a metabolic shift favoring the elongation of very-long-chain saturated fatty acids, accompanied by reduced lipid synthesis and enhanced fatty acid oxidation. These metabolic alterations were paralleled by an upregulation of proteins involved in oxidative stress responses, likely reflecting a compensatory adaptation to mitochondrial and lipid metabolic dysregulation. Furthermore, we observed significant changes in chromatin organization during astrocyte differentiation in CLN3 cells, suggesting epigenetic remodeling as a contributing factor to disease pathology. Conclusion Our findings prompt the hypothesis that mitochondrial dysfunction may precede lysosomal defects in CLN3-deficient astrocytes. Restoring mitochondrial health could improve brain metabolism, inflammation control, neurotransmitter regulation, and neuronal survival, highlighting mitochondria as promising therapeutic targets in CLN3 Batten disease.
2026-04-27 | Influence of Fingolimod Treatment on Disease Outcome and MRI Brain Volumes in Children with CLN 3
Background/Purpose: CLN3 is a neurodegenerative disorder leading to progressive loss of vision, motor function, and language skills, as well as dementia and epilepsy. Loss of brain volume has been shown to be a sensitive marker of disease progression corresponding with clinical scores. Fingolimod, a sphingosine-1-phosphate receptor modulator used in the treatment of MS, ameliorates the disease’s course in a CLN mouse model. Methods: Fifteen children with CLN3 were included (nine females, six males, age 5–16 years). Twelve were treated with Fingolimod over a period of at least 1 year, and nine of these additionally with Miglustat in the course of the study. Three patients were treated only with Miglustat from the beginning. MRI studies, including MPrage sequences, were performed at the onset of treatment and after 1 year. Volumetry data were compared with those of a natural history cohort including 47 MRI sequences. Standardized cognitive testing, the Hamburg JNCL score, and a 6-minute walking test were applied at baseline and at yearly intervals. Serum NFL measurements were performed at the same intervals. Results: Treatment with Fingolimod was well tolerated. None of the patients had side effects such as an increased rate of infections and raised liver enzymes. Lymphocyte count was generally within the target range of 300 to 500 lymphocytes/µL. NFl serum levels were mildly elevated before treatment (median range: 5–79 pg/mL). Follow-up values as well as clinical scores were stable. There was a significant difference in whole brain volume and gray matter volume between NCL3 patients and matched healthy controls at baseline and after 1 year of treatment. After 1 year, a further reduction of brain and cortical gray matter volume could be found in 10/15 patients. The results of 5/15 patients and evaluations of treated patients compared with MRI natural history data are pending. Conclusion: Our results indicate that Fingolimod is well tolerated and may alleviate the disease progression in CLN3 patients by influencing the secondary immunological reactions. Publication History Article published online: 27 April 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
cell therapies
2025-02-10 | Neuronal Ceroid Lipofuscinosis-Concepts, Classification, and Avenues for Therapy.
Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders characterized by excessive accumulation of lysosomal lipofuscin. Thirteen subtypes of NCL have been identified, each associated with distinct genes encoding various transmembrane proteins, secretory proteins, or lysosomal enzymes. Clinically, NCL manifests in infants through vision impairment, motor and cognitive dysfunctions, epilepsy, and premature death. The pathological complexity of NCL has hindered the development of effective clinical protocols. Current treatment modalities, including enzyme replacement therapy, pharmacological approaches, gene therapy, and stem cell therapy, have demonstrated limited efficacy. However, emerging evidence suggests a significant relationship between NCL and microglial cells, highlighting the potential of novel microglial cell replacement therapies. This review comprehensively examines the pathogenic genes associated with various NCL subtypes, elucidating their roles, clinical presentations, and corresponding mouse models. Especially, we thoroughly discuss the advances in the clinical study of potential therapeutics, which crucially calls for early diagnosis and treatment more than ever.
2024-10-30 | Safety and feasibility of umbilical cord blood transplantation in children with neuronal ceroid lipofuscinosis: a retrospective study.
Ceroid lipofuscinosis neuronal (CLN) encompasses rare inherited neurodegenerative disorders that present in childhood with clinical features including epilepsy, psychomotor delay, progressive vision loss, and premature death. Published experience utilizing umbilical cord blood transplant (UCBT) for these disorders is limited. This retrospective analysis includes patients with CLN (2, 3, and 5) who underwent UCBT from 2012 to 2020. All subjects (n = 8) received standard-of-care myeloablative conditioning. Four also enrolled in clinical trial NCT02254863 and received intrathecal DUOC-01 cells posttransplant. Median age at UCBT was 5.9 years. All subjects achieved neutrophil engraftment with >95% donor chimerism at a median of 28.5 days. Sinusoidal obstructive syndrome was not observed. Severe acute graft-versus-host disease occurred in 12.5%. Other complications included autoimmune hemolytic anemia (25%) and viral reactivation/infection (62.5%). No transplant-related mortality was observed. Two CLN2 patients died, 1 from progressive disease and 1 from unknown cause at days +362 and +937, respectively. With median follow-up of 8 years, overall survival at 100 days and 24 months was 100% and 88%, respectively. Three of 4 CLN3 subjects stabilized Hamburg motor and language scores. While UCBT appears safe and feasible in these patients, given the variable expression and natural history, extended follow-up and further studies are needed to elucidate the potential impact of UCBT on clinical outcomes.
2024-02-28 | Haploidentical haematopoietic stem cell transplantation combined with post-transplant cyclophosphamide in neuronal ceroid lipofuscinosis: Experience in eight patients.
Neuronal ceroid lipofuscinoses (NCLs) are rare lysosomal storage disorders characterized by progressive mental retardation and motor developmental regression and myoclonic seizures. Hematopoietic stem cell transplantation (HSCT) has been suggested to be used in the treatment of lysosomal disorders and brain damage caused by a deficiency of soluble lysosomal enzymes. There are no previous reports on treating NCLs with HSCT in China. NCL pediatric patients who underwent allo-HSCT at Affiliated Children's Hospital of Capital Institute of Pediatrics were involved. A combination of medical histories, clinical features, and genetic analyses was used for the diagnosis of all patients. The written consent form for allo-HSCT was attained from the patient's guardian, which was then reviewed and approved by the ethics committee before the procedure. From January 2018 to May 2019, the haplo-HSCT followed by PT/Cy on eight NCL pediatric patients was performed. The median age was 4.5 years (ranging from 2.8 to 7 years). The donors were their haploidentical HLA-matched parents, as no identically matched donors were found. The median nucleated cell count was 25.37 (10-34.41)×108/kg, and the median CD34+ count was 13.7 (8.95-22)×106/kg. Neutrophil reconstitution occurred 12 days (11-14 days) after transplantation, and the median platelet reconstitution time was 12 days (9-14 days) after transplantation. All patients achieved full donor chimerism and did not develop Grade II-IV acute GvHD or chronic GvHD after transplantation. The median follow-up period was 2.2 (1.5-2.6) years. All patients are still alive at present and develop no severe transplantation-related complications. The mental motor disorders, myoclonic seizures, and vision loss of all patients continued to progress. However, the progression slowed at 12 months after transplantation. This study demonstrated that it is safe and efficacious to treat NCLs with haplo-HSCT. Transplantation should be performed at an early stage for the survival quality of pediatric patients.
2021-09-29 | Neuronal Ceroid Lipofuscinosis Treated with Haploidentical Hematopoietic Stem Cell Transplantation Combined with Post-Transplant Cyclophosphamide
Abstract Background: Neuronal ceroid lipofuscinoses (NCLs) are rare lysosomal storage disorders, characterized by progressive mental retardation and motor developmental regression, and myoclonic seizures. Hematopoietic stem cell transplantation (HSCT) has been suggested to be used in the treatment of lysosomal disorders and brain damage caused by a deficiency of soluble lysosomal enzymes. However, there are no reports on treating NCLs with HSCT in China. Results: From January 2018 to May 2019, we performed haplo-HSCT followed by PT/Cy on 8 NCL pediatric patients. The median age was 4.5 years (range from 2.8 to 7 years). And the donors were their haploidentical HLA-matched parents, as no identically matched donor was found. The median nucleated cell count was 25.37 (10–34.41) ×10 8 /kg and the median CD34+ count was 13.7(8.95–22)×10 6 /kg. Neutrophil reconstitution occurred at 12 days (11–14 days) after transplantation, and median platelet reconstitution time was 12 days (9–14 days) after transplantation. All patients achieved full donor chimerism and did not develop Grade II–IV acute GvHD or chronic GvHD after transplantation. The median follow-up period was 2.2 (1.5–2.6) years. All patients are still alive at present, and develop no severe transplantation-related complications. The mental and motor disorders, myoclonic seizures, and vision loss of all patients continue to progress, but the progression slows down at 12 months after the transplantation. Conclusion: Observations reported in this study suggest it is safe and efficacy to treat NCLs with haplo-HSCT. Transplantation should be performed as early as possible for the survival quality of pediatric patients.
2021-03-18 | Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease
Juvenile CLN3 disease is a recessively inherited paediatric neurodegenerative disorder, with most patients homozygous for a 1-kb intragenic deletion in CLN3. The btn1 gene is the Schizosaccharomyces pombe orthologue of CLN3. Here, we have extended the use of synthetic genetic array (SGA) analyses to delineate functional signatures for two different disease-causing mutations in addition to complete deletion of btn1. We show that genetic-interaction signatures can differ for mutations in the same gene, which helps to dissect their distinct functional effects. The mutation equivalent to the minor transcript arising from the 1-kb deletion (btn1102-208del) shows a distinct interaction pattern. Taken together, our results imply that the minor 1-kb deletion transcript has three consequences for CLN3: to both lose and retain some inherent functions and to acquire abnormal characteristics. This has particular implications for the therapeutic development of juvenile CLN3 disease. In addition, this proof of concept could be applied to conserved genes for other mendelian disorders or any gene of interest, aiding in the dissection of their functional domains, unpacking the global consequences of disease pathogenesis, and clarifying genotype-phenotype correlations. In doing so, this detail will enhance the goals of personalised medicine to improve treatment outcomes and reduce adverse events.
gene therapies
2026-08-09 | Phenotypic and Genetic Characterization of 64 Egyptian Children With Neuronal Ceroid Lipofuscinosis.
Neuronal ceroid lipofuscinoses (NCLs) are the most common neurodegenerative diseases in childhood. This study aimed to investigate the phenotypic and genetic spectrum of NCLs in Egypt. This descriptive study involved children with NCLs diagnosed and managed at five Egyptian centers between 2019 and 2024. Demographic, clinical, brain imaging, and genetic data were systematically evaluated. Identified variants in NCL-related genes were classified following the American College of Medical Genetics and Genomics guidelines. The cohort included 64 Egyptian children (from 57 families) with eight NCL types. The most commonly identified genotype was CLN2 (17/64, 27%), followed by CLN1 and CLN7 (12/64, 19% each). Patients generally exhibited the classic manifestations of NCLs, particularly motor regression (64/64, 100%), cognitive decline (64/64, 100%), language impairment (64/64, 100%), epilepsy (57/64, 89%), and vision loss (47/64, 73%). Notably, developmental regression (12/17, 71%) was the predominant presenting symptom for CLN2. Brain imaging generally showed typical cerebral and cerebellar atrophy in 95% (61/64) and 84% (54/64) of cases, respectively. Nevertheless, thalamic abnormalities were observed in only 16% (10/64) of cases. A total of 46 distinct variants were identified across eight NCL-related genes, including 23 novel ones, with the majority (33/46, 72%) being private. There was a median diagnostic delay of 2 years, and none of the patients received specific therapy. This study reports the largest cohort of children with NCLs from Egypt, including 12 patients with the less-commonly reported CLN7 subtype, which expands the demographic, clinical, and molecular spectrum of these diseases.
2026-01-08 | A timeline of symptom onset and disease progression in CLN3 disease.
CLN3 disease, or Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), is a rare, genetic neurodegenerative condition, typically manifesting in the first decade of life and progressing in severity, with death typically occurring in early adulthood. Despite two decades of natural history research, a clear timeline of CLN3 disease symptom onset and progression remains poorly defined, limiting optimal patient management and therapeutic development. We conducted a literature review and analysed the natural history data to better understand the age of core symptom onset and chronological disease progression. A literature review was undertaken using a pre-defined search strategy focused on CLN3 disease natural history studies, where age at onset for one or more core symptoms was reported in cohorts of ≥ 15 subjects. For each symptom, weighted mean age at onset and weighted standard deviation were calculated, with 95% confidence intervals derived from the weighted standard error. Symptom onset ages were compared using ANOVA. We identified nine natural history studies that met our pre-defined criteria. In total, 423 discrete patients aged between 4 and 39 years were reported. Thirteen core symptoms and a weighted average age at onset and weighted standard deviation were (in years): vision loss (6.1 ± 1.6, N = 254), behavioural changes (8.5 ± 3.9, N = 194), cognitive decline (9.3 ± 3.1, N = 219), seizures (10.2 ± 3.0, N = 243), sleep disturbance (11.0 ± 6.1, N = 111), motor decline (11.0 ± 3.8, N = 108), complete blindness (11.4 ± 3.6, N = 171), speech and language impairment (12.7 ± 4.8, N = 136), Parkinsonian gait (14.1 ± 2.5, N = 111), cardiac manifestations (17.8 ± 4.4, N = 45), loss of independent walking (19.5 ± 3.2, N = 70), feeding difficulties requiring enteral feeding tube (22.0 ± 1.6, N = 35), and death (22.4 ± 4.4, N = 95). This comprehensive summary of available natural history data illustrates mean age at onset of 13 core symptoms of CLN3 disease, and characterises a chronological timeline of disease progression. These results provide much-needed practical, anticipatory guidance to those involved in caring for individuals with CLN3 disease, and serve to highlight the critical importance of collecting globally standardised, quantifiable, longitudinal data for optimising patient management and advancing therapeutic approaches for CLN3 disease. The online version contains supplementary material available at 10.1186/s13023-025-04174-5.
2025-11-27 | Canine Neuronal Ceroid Lipofuscinosis-like Disorder Associated with Sequence Variants in AP3B1 and TRAPPC9.
A Petit Bleu de Gascogne (PBDG) dog presented with a progressive neurological disorder characterized by hind-limb weakness, anxiety and hallucinatory episodes, lip smacking, progressive vision loss, muscle atrophy, and ataxia. Magnetic resonance imaging revealed diffuse brain atrophy. The dog was euthanized at approximately 23 months of age due to the progression of neurological signs. A study was undertaken to identify the molecular genetic basis of the disorder in this dog. Microscopic analyses were performed to characterize the disease pathology and whole-genome sequencing was performed to identify the molecular genetic basis of the disorder. The proband exhibited pronounced accumulations of autofluorescent intracellular inclusions in the brain, retina, and heart with ultrastructural appearances similar to those of lysosomal storage bodies that accumulate in the neuronal ceroid lipofuscinosis (NCLs), a group of progressive neurodegenerative disorders. Whole-genome sequence analysis of DNA from the proband identified homozygous missense variants in AP3B1 and TRAPPC9 that encode proteins involved in sorting and transport of proteins through the Golgi apparatus to lysosomes. Screening of unaffected PBDGs for these variants identified dogs that were homozygous for either variant, but no other dogs that were homozygous for both. These findings raise the possibility that the disease involves the combined influence of the two variants, and that the proteins encoded by these genes interact within the Golgi apparatus to mediate protein sorting and transport to lysosomes. An alteration in this interaction could underlie the NCL-like lysosomal storage disorder observed in the proband.
2025-11-23 | Progressive rod bipolar cell loss, ubiquitin accumulation, and subretinal drusenoid deposits in Cln3Δex7/8 mice: New insights into juvenile neuronal ceroid lipofuscinosis pathogenesis.
Juvenile neuronal ceroid lipofuscinosis (JNCL) is a rare neurodegenerative disorder caused by mutations in the CLN3 gene and characterized by early vision loss and a progressive neurological decline. To characterize the progression of retinal pathology, we conducted a 15-month study using the Cln3Δex7/8 mouse model which carries the most common causative mutation of JNCL. Retinal function was assessed every three months from the age of 3-15 months using electroretinography (ERG), optical coherence tomography (OCT), fundus imaging, and immunohistochemistry. OCT and fundus imaging in the Cln3Δex7/8 mice revealed a progressive thinning of the inner nuclear layer (INL) and an accumulation of subretinal drusenoid deposits. We detected a progressive loss of rod bipolar cells (RBCs) with immunofluorescence staining which was accompanied by ubiquitin-positive punctae, indicative of a potential role of the ubiquitin-proteasome system (UPS) in the selective loss of RBCs and the associated inner retinal dysfunction. Furthermore, late-stage immune cell activity was observed in the subretinal space of the Cln3Δex7/8 mice. ERG measurements confirmed previous findings of a predominant inner retinal dysfunction and revealed also a more pronounced photoreceptor impairment, as well as an earlier onset of retinal dysfunction than previously reported. These findings provide new insights into the pathological features of retinal degeneration in Cln3Δex7/8 mice, including subretinal drusenoid deposits, tubular subretinal fluid, and ubiquitin accumulation as well as a better overview of the rate of the degeneration process, thus expanding our understanding of JNCL pathogenesis.
2025-11-08 | Persistent lymphopenia in a Japanese boy with neuronal ceroid lipofuscinosis type 3.
Neuronal ceroid lipofuscinosis (NCL) is a heterogeneous group of lysosomal disorders characterized by progressive psychomotor regression, visual impairment, and intractable seizures. Genetically, NCL type 3 (CLN3) is associated with variants in the gene encoding a lysosomal transmembrane protein. To date, few Japanese patients with CLN3 have been reported. Thus, their neurodevelopmental and clinical features remain unclear. Here, we report the clinical course of a genetically confirmed Japanese patient with CLN3. A 17-year-old Japanese boy was diagnosed with retinitis pigmentosa at age 7. Visual impairment progressed over a 10-year follow-up period. Generalized tonic-clonic seizures also began at age 7. Developmental regression was recognized at age 13, with an accelerated decline in motor and communication skills following a COVID-19 infection at age 17. Tube feeding and gastrostomy were initiated for dysphagia and recurrent respiratory infections. Serial MRI revealed progressive cerebral and cerebellar atrophy. Lymphopenia (351-1467/μL) was present from age 9; peripheral blood smear revealed vacuolated lymphocytes. Exome sequencing identified a heterozygous CLN3 variant, NM_001042432.2:c.295-2A > C. SpliceAI suggested exon 6 skipping and/or an 80-bp deletion, leading to nonsense-mediated mRNA decay. Manual inspection using Integrated Genomic Viewer revealed a second variant (c.178_180delinsACATCCTTAGCCACAAGAG) missed initially. Trio Sanger sequencing confirmed compound heterozygosity: NM_001042432.2:c.[295-2A > C]; [178_180delinsACATCCTTAGCCACAAGAG] p.[?]; [His60Thrfs∗10]. A review of 430 genetically confirmed CLN3 patients (1989-2025) identified no hematologic abnormalities. This Japanese CLN3 patient developed visual impairment 7-8 years before systemic deterioration. Retinal degeneration, together with vacuolated peripheral lymphocytes, may provide early diagnostic clues for CLN3 in Japanese patients.
proteins
2026-08-26 | A 3D human retina model reveals a non-cell-autonomous and non-neuronal mechanism of photoreceptor loss in a lysosomal storage disorder.
Disruption of the photoreceptor-retinal pigment epithelium (RPE) interface, with loss of photoreceptor outer segments (POSs) in the retina, is a pathological hallmark of several neurodegenerative and retinal diseases, including lysosomal storage disorders like juvenile neuronal ceroid lipofuscinosis (CLN3) disease. However, in vitro stem cell models that enable investigation of the photoreceptor-RPE interface are lacking. Here, we developed a 3D human pluripotent stem cell-derived retina organoid-RPE (hPSC-RO-RPE) model to investigate the photoreceptor-RPE interface in healthy and diseased tissues. Using this 3D hPSC-RO-RPE retina model, we showed that the most common disease-causing CLN3 mutation (CLN3Δex7-8) leads to reduced levels of acid ceramidase (AC), sphingosine 1 phosphate, and POS loss. Furthermore, by analyzing control versus CLN3 mutant (CLN3Δex7-8) hPSC-derived RPE monoculture and hPSC-RO-RPE model, (i) we identified a pathogenic role of AC-mediated lysosomal sphingolipid metabolism in promoting CLN3 disease pathobiology, and (ii) we showed a cell autonomous role of the RPE dysfunction in promoting POS loss/retina degeneration in CLN3 disease. We validated the molecular and structural changes observed in the CLN3Δex7-8 hPSC-RO-RPE model in the CLN3 miniswine model (CLN3Δex7-8) and donor eyes from two patients with CLN3 disease. High-resolution retinal imaging of the living eye in two patients with CLN3 disease suggested decreased RPE autofluorescence in early-stage CLN3 disease. Treatment with recombinant human acid ceramidase (rhAC) ameliorated photoreceptor degeneration in both the CLN3 disease RO-RPE model and CLN3 miniswine eyes. These findings suggest that rhAC could be a therapeutic approach for retinal degeneration in CLN3 disease.
2025-09-05 | Neuronal ceroid lipofuscinosis: underlying mechanisms and emerging therapeutic targets.
The neuronal ceroid lipofuscinoses (NCLs), more commonly known as Batten disease, are a group of fatal inherited neurodegenerative lysosomal storage disorders. Each form is caused by mutations in a different gene, resulting in lysosomal dysfunction, which, by largely unknown mechanisms, has a devastating impact on the central nervous system. The NCLs are grouped together owing to their broadly shared clinical presentations and the presence of autofluorescent storage material. Nevertheless, being caused by deficiencies in dissimilar proteins, marked differences are apparent between NCLs in their clinical presentation and pathology. The effects of disease are not confined to neurons and appear unrelated to autofluorescent storage material, with glial cells also affected. The rest of the body is also affected, with life-limiting disease in the bowel and effects on other body systems, which will also require treatment for maximal therapeutic benefit. Since the development of enzyme replacement therapy for CLN2 disease, much has been learnt about the practicalities of its delivery. Considerable progress has also been made in the understanding of NCL cell biology, disease pathogenesis and potential links to other disorders. Here, we highlight these advances and how they inform the ongoing development of therapeutic strategies and their future prospects.
2025-08-06 | A 3D iPSC retina model reveals non-cell-autonomous and non-neuronal mechanism of photoreceptor degeneration in a lysosomal storage disorder.
Disruption of photoreceptor-retinal pigment epithelium (RPE) interface with loss of photoreceptor outer segments (POSs) in the retina is a pathological hallmark of several neurodegenerative and retinal diseases including lysosomal storage disorder's like CLN3 disease. However, the retina is a functional composite in vivo; and in vitro stem cell models of retina that enable investigation of the photoreceptor-RPE interface in healthy and diseased retina are lacking. Here, we developed a 3D human pluripotent stem cell (hPSC)-derived retina model to investigate the photoreceptor-RPE interface in healthy and disease tissue. Using this 3D hPSC retina model, we demonstrated that the most common disease causing CLN3 mutation ( CLN3 Δ ex7-8 ) leads to reduced levels of acid ceramidase (AC) and consequently altered sphingolipid metabolism and signaling and POS loss in CLN3 disease. Consistent with the 3D hPSC retina model, altered sphingolipid metabolism and signaling coincided with POS loss in a large animal model of CLN3 disease, CLN3 miniswine. Therapeutically, recombinant human acid ceramidase (rhAC) targeted both altered sphingolipid metabolism and retina degeneration in the CLN3 hPSC retina model and the CLN3 miniswine eye. These findings demonstrate a proof-of-concept that rhAC can rescue disease phenotype in a large animal model of CLN3 disease and suggest that rhAC could be a therapeutic approach for CLN3 disease. Acid ceramidase deficiency and consequently altered sphingolipid signaling promotes disease phenotype(s) in a lysosomal storage disorder, CLN3 disease.
2025-04-10 | Genetic Reasons for Phenotypic Diversity in Neuronal Ceroid Lipofuscinoses and High-Resolution Imaging as a Marker of Retinal Disease.
To describe the clinical characteristics, natural history, genetic landscape, and phenotypic spectrum of neuronal ceroid lipofuscinosis (NCL)-associated retinal disease. Multicenter retrospective cohort study complemented by a cross-sectional examination. Twelve pediatric subjects with biallelic variants in 5 NCL-causing genes (CLN3 lysosomal/endosomal transmembrane protein [CLN3], CLN6 transmembrane ER protein [CLN6], Major facilitator superfamily domain containing 8 [MFSD8], Palmitoyl-protein thioesterase 1 ([PPT1], and tripeptidyl peptidase 1 [TPP1]). Review of clinical notes, retinal imaging, electroretinography (ERG), and molecular genetic testing. Two subjects underwent a cross-sectional examination comprising adaptive optics scanning laser ophthalmoscopy imaging of the retina and optoretinography (ORG). Clinical/demographic data, multimodal retinal imaging data, electrophysiology parameters, and molecular genetic testing. Our cohort included a diverse set of subjects with CLN3-juvenile NCL (n = 3), TPP1-late infantile NCL (n = 5), PPT1-late infantile or juvenile NCL (n = 2), CLN6-infantile NCL (n = 1), and CLN7/MFSD8-late infantile NCL (n = 1). Five novel pathogenic or likely pathogenic variants were identified. Age at presentation ranged from 2 to 16 years old (mean 7.9 years). Subjects presented with varying phenotypes ranging from severe neurocognitive features (n = 8; 67%), including seizures and developmental delays and regressions, to nonsyndromic retinal dystrophies (n = 2; 17%). Visual acuities at presentation ranged from light perception to 20/20. In those with recordable ERGs, the traces were electronegative and suggestive of early cone dysfunction. Fundus imaging and OCTs demonstrated outer retinal loss that varied with underlying genotype. High-resolution adaptive optics imaging and functional measures with ORG in 2 subjects with atypical TPP1-associated disease revealed significantly different phenotypes of cellular structure and function that could be followed longitudinally. Our cohort data demonstrates that the underlying genetic variants drive the phenotypic diversity in different forms of NCL. Genetic testing can provide molecular diagnosis and ensure appropriate disease management and support for children and their families. With intravitreal enzyme replacement therapy on the horizon as a potential treatment option for NCL-associated retinal degeneration, precise structural and functional measures will be required to more accurately monitor disease progression. We show that adaptive optics imaging and ORG can be used as highly sensitive methods to track early retinal changes, which can be used to establish eligibility for future therapies and provide metrics for determining the efficacy of interventions on a cellular scale. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
2024-01-12 | Mechanistic Insights into S-Depalmitolyse Activity of Cln5 Protein Linked to Neurodegeneration and Batten Disease: A QM/MM Study.
Ceroid lipofuscinosis neuronal protein 5 (Cln5) is encoded by the CLN5 gene. The genetic variants of this gene are associated with the CLN5 form of Batten disease. Recently, the first crystal structure of Cln5 was reported. Cln5 shows cysteine palmitoyl thioesterase S-depalmitoylation activity, which was explored via fluorescent emission spectroscopy utilizing the fluorescent probe DDP-5. In this work, the mechanism of the reaction between Cln5 and DDP-5 was studied computationally by applying a QM/MM methodology at the ωB97X-D/6-31G(d,p):AMBER level. The results of our study clearly demonstrate the critical role of the catalytic triad Cys280-His166-Glu183 in S-depalmitoylation activity. This is evidenced through a comparison of the pathways catalyzed by the Cys280-His166-Glu183 triad and those with only Cys280 involved. The computed reaction barriers are in agreement with the catalytic efficiency. The calculated Gibb's free-energy profile suggests that S-depalmitoylation is a rate-limiting step compared to the preceding S-palmitoylation, with barriers of 26.1 and 25.3 kcal/mol, respectively. The energetics were complemented by monitoring the fluctuations in the electron density distribution through NBO charges and bond strength alterations via local mode stretching force constants during the catalytic pathways. This comprehensive protocol led to a more holistic picture of the reaction mechanism at the atomic level. It forms the foundation for future studies on the effects of gene mutations on both the S-palmitoylation and S-depalmitoylation steps, providing valuable data for the further development of enzyme replacement therapy, which is currently the only FDA-approved therapy for childhood neurodegenerative diseases, including Batten disease.
other
2025-06-12 | Therapeutic antisense oligonucleotide mitigates retinal dysfunction in a pig model of CLN3 Batten disease.
CLN3 Batten disease is a lethal pediatric autosomal recessive neurodegenerative disease caused by mutations in the CLN3 gene. Typically, the disease manifests as vision loss early in life and progresses to neurological dysfunction and death in young adulthood. Therapeutic development has focused on treating the central nervous system. However, such therapies may not protect against vision loss, which has a significant impact on quality of life. We have shown that a splice-switching antisense oligonucleotide (ASO) delivered to the central nervous system can reduce neurological disease burden in mouse models of CLN3 disease. Here, we report on a similar ASO approach for treating CLN3 Batten disease retinal dysfunction in a pig model of the disease, which is more representative of human vision. A single intravitreal injection of ASO induces robust exon skipping in the retina for up to 12 months. The ASO treatment resulted in higher amplitudes on electroretinograms, suggesting mitigation of retinal dysfunction at early timepoints of disease. One ASO that efficiently induces exon skipping in vivo was well-tolerated and targets a region of CLN3 that is conserved in humans, making it a promising candidate for treating the disease in humans. Our findings demonstrate the potential utility of an ASO-based approach to treat retinal dysfunction in CLN3 Batten disease and generally supports the use of ASOs for treating eye diseases.
2025-02-17 | Purifying and profiling lysosomes to expand understanding of lysosomal dysfunction-associated diseases.
Lysosome storage dysfunction plays a central role in numerous human diseases, but a lack of appropriate tools has hindered lysosomal content profiling in clinical settings. In this issue of the JCI, Saarela et al. introduce a method called tagless LysoIP that enabled rapid isolation of intact lysosomes from blood and brain cells via immunoprecipitation of the endogenous protein TMEM192. Applied to the neurodegenerative lysosomal storage disorder known as Batten disease (caused by mutations in the CLN3 gene), tagless LysoIP revealed substantial accumulation of glycerophosphodiesters (GPDs) in patient lysosomes. These findings highlight the role of CLN3 in GPD clearance and present an innovative method that will enable biomarker discovery and therapeutic advancement in lysosomal diseases.
2023-06-26 | Protracted CLN3 Batten disease in mice that genetically model an exon-skipping therapeutic approach.
Genetic mutations that disrupt open reading frames and cause translation termination are frequent causes of human disease and are difficult to treat due to protein truncation and mRNA degradation by nonsense-mediated decay, leaving few options for traditional drug targeting. Splice-switching antisense oligonucleotides offer a potential therapeutic solution for diseases caused by disrupted open reading frames by inducing exon skipping to correct the open reading frame. We have recently reported on an exon-skipping antisense oligonucleotide that has a therapeutic effect in a mouse model of CLN3 Batten disease, a fatal pediatric lysosomal storage disease. To validate this therapeutic approach, we generated a mouse model that constitutively expresses the Cln3 spliced isoform induced by the antisense molecule. Behavioral and pathological analyses of these mice demonstrate a less severe phenotype compared with the CLN3 disease mouse model, providing evidence that antisense oligonucleotide-induced exon skipping can have therapeutic efficacy in treating CLN3 Batten disease. This model highlights how protein engineering through RNA splicing modulation can be an effective therapeutic approach.
2020-12-21 | Experimental gene therapies for the NCLs.
The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of rare monogenic neurodegenerative diseases predominantly affecting children. All NCLs are lethal and incurable and only one has an approved treatment available. To date, 13 NCL subtypes (CLN1-8, CLN10-14) have been identified, based on the particular disease-causing defective gene. The exact functions of NCL proteins and the pathological mechanisms underlying the diseases are still unclear. However, gene therapy has emerged as an attractive therapeutic strategy for this group of conditions. Here we provide a short review discussing updates on the current gene therapy studies for the NCLs.
2020-11-04 | Therapeutic efficacy of antisense oligonucleotides in mouse models of CLN3 Batten disease.
CLN3 Batten disease is an autosomal recessive, neurodegenerative, lysosomal storage disease caused by mutations in CLN3, which encodes a lysosomal membrane protein1-3. There are no disease-modifying treatments for this disease that affects up to 1 in 25,000 births, has an onset of symptoms in early childhood and typically is fatal by 20-30 years of life4-7. Most patients with CLN3 Batten have a deletion encompassing exons 7 and 8 (CLN3∆ex7/8), creating a reading frameshift7,8. Here we demonstrate that mice with this deletion can be effectively treated using an antisense oligonucleotide (ASO) that induces exon skipping to restore the open reading frame. A single treatment of neonatal mice with an exon 5-targeted ASO-induced robust exon skipping for more than a year, improved motor coordination, reduced histopathology in Cln3∆ex7/8 mice and increased survival in a new mouse model of the disease. ASOs also induced exon skipping in cell lines derived from patients with CLN3 Batten disease. Our findings demonstrate the utility of ASO-based reading-frame correction as an approach to treat CLN3 Batten disease and broaden the therapeutic landscape for ASOs in the treatment of other diseases using a similar strategy.
small molecules
2026-06-18 | Thapsigargin-induced autophagic flux impairment and inflammation are potentiated by CLN3 deficiency and alleviated by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) in human ARPE-19 cells.
Juvenile neuronal lipofuscinosis (JNCL) is a rare disease caused by mutations in the CLN3 gene. It leads to early vision loss mediated by retinal degeneration. Impaired autophagosomal-lysosomal degradation is a major hallmark of JNCL pathology, and neuroinflammation has also been postulated to play a role in its pathogenesis. Thapsigargin, a selective inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase, inhibits autophagy, leading to an accumulation of autophagosomes/autophagophores in cells. Cells with defective CLN3 protein function have been found to be particularly sensitive to the anti-autophagic effects of thapsigargin. Here, we characterized the effects of thapsigargin on inflammatory cytokines and autophagic markers in ARPE-19 cells using ELISA and western blotting. We further examined these effects in cells deficient in CLN3 function by exposing the cells to CLN3 siRNA and testing whether the effects of thapsigargin could be modulated by the well-known autophagy activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). Thapsigargin induced the accumulation of LC3 and p62/SQSTM1, consistent with impaired autophagic flux in ARPE-19 cells. Additionally, we observed that thapsigargin possessed pro-inflammatory potential, as it induced the release of IL-6 in ARPE-19 cells, no inflammasome activation was detected. Both effects were enhanced by CLN3 siRNA and alleviated by AICAR. In conclusion, thapsigargin-induced impaired autophagic flux and the accompanying inflammatory response are more pronounced in CLN3-deficient ARPE-19 cells, indicating that loss of CLN3 function affects both autophagy and inflammatory signaling.
2026-05-18 | PPARα and RXRα in the regulation of neuronal ceroid lipofuscinosis genes: implications for Batten disease therapy.
Neuronal ceroid lipofuscinosis or Batten disease comprises a category of autosomal recessive neurodegenerative disorders that primarily affect children. Mutations in different genes lead to different forms of neuronal ceroid lipofuscinoses (CLN1-14). At present, there is no established therapy to cure most of the neuronal ceroid lipofuscinoses and the treatments are symptomatic. Enzyme replacement therapy, gene therapy, stem cell transplantation, and pharmacological chaperone therapy are being tested in different animal models and human patients. Peroxisome proliferator-activated receptor alpha (PPARα) is a member of the nuclear hormone receptor superfamily, which along with its transcription partner retinoid X receptor alpha (RXRα) regulates the expression of their target genes. This review highlights the potential role of PPARα and RXRα in the regulation of CLN genes. Here, using the MatInspector program of the Genomatix software, we performed promoter analyses of all CLN genes and observed that most of the CLN genes harbor one or more potential binding sites for PPAR and RXR in their promoter region. We further grouped them according to a binding prediction of the transcription factors to indicate high affinity binding of PPAR to CLN2, CLN3, CLN4, CLN5, CLN7, CLN10, CLN11, CLN12, and CLN14. On the other hand, we observed high affinity binding of RXR to CLN1, CLN3, CLN6, CLN7, CLN8, CLN10, and CLN13. Since PPARα and RXRα have been demonstrated to control the transcription of CLN2 gene, our current promoter analysis findings highlight a possible treatment strategy for neuronal ceroid lipofuscinoses using agonists of PPARα and RXRα.
2026-05-15 | Computational drug repurposing identifies N -acetylglucosamine as a potential therapeutic compound for CLN3 Batten disease
Abstract Batten disease, also known as neuronal ceroid lipofuscinoses, is one of the most common causes of childhood dementia. It is characterized by the accumulation of lipofuscin in lysosomes, leading to loss of brain cell function, onset of dementia-like symptoms, vision loss and seizures and has extremely limited treatment options. Here, we performed computational drug repurposing analysis to identify existing compounds that may target Batten disease risk genes. A total of 81 candidate compounds were identified, 6 of which were selected based on clinical tractability for downstream testing in Batten disease (CLN3) iPSC-derived models. After confirming disease phenotype and drug candidate safety, CLN3 brain cell cultures treated with and without drug candidates underwent bulk RNA-seq to identify drug responses. One of the candidate drugs N -acetylglucosamine (GlcNAc) significantly upregulated Batten disease risk gene CLN5 expression and several other lysosomal markers within CLN3 brain cells, and modulated several pathways implicated in lysosomal storage disorders. Importantly, GlcNAc significantly reduced lipofuscin burden in both CLN3 iPSC-derived neurons and astrocytes, supporting its investigation as an additional therapy for Batten disease.
2026-05-13 | Modeling CLN3 Batten disease in astrocytes reveals alterations in mitochondria homeostasis, fatty acid metabolism and oxidative stress response
Abstract Background CLN3 Batten disease is a severe pediatric neurodegenerative disorder caused by mutations in the CLN3 gene, most commonly a 1 kb deletion encompassing exons 7 and 8. CLN3 deficiency is associated with lysosomal dysfunction, impaired cellular clearance and disrupted metabolism. While neurons are particularly vulnerable in CLN3 Batten disease and have been the primary focus of research, glial cells are increasingly recognized as active contributors to disease pathology. Among them, astrocytes—the most abundant glial cell type in the brain—play critical roles in maintaining neuronal health and homeostasis. However, astrocytes remain understudied in CLN3 patient-derived models. Methods We present the first iPSC-derived astrocyte model from a skin biopsy of a CLN3 patient carrying the common 1 kb deletion. Cellular and molecular features of iPSC and astrocytes derived from both healthy controls and the CLN3 patient were characterized via qPCR, immunocytochemistry and targeted mass spectrometry. In addition, comprehensive omics-based profiling, through transcriptomic and label-free quantitative proteomics, was performed to uncover novel molecular mechanisms and generate hypotheses that can guide future mechanistic and functional studies. Results Transcriptomic and proteomic analyses during astrocyte differentiation revealed an upregulation of mitochondrial respiratory chain complexes I and IV—contrasting with the downregulation typically observed in CLN3-deficient neurons. We also identified a metabolic shift favoring the elongation of very-long-chain saturated fatty acids, accompanied by reduced lipid synthesis and enhanced fatty acid oxidation. These metabolic alterations were paralleled by an upregulation of proteins involved in oxidative stress responses, likely reflecting a compensatory adaptation to mitochondrial and lipid metabolic dysregulation. Furthermore, we observed significant changes in chromatin organization during astrocyte differentiation in CLN3 cells, suggesting epigenetic remodeling as a contributing factor to disease pathology. Conclusion Our findings prompt the hypothesis that mitochondrial dysfunction may precede lysosomal defects in CLN3-deficient astrocytes. Restoring mitochondrial health could improve brain metabolism, inflammation control, neurotransmitter regulation, and neuronal survival, highlighting mitochondria as promising therapeutic targets in CLN3 Batten disease.
2026-04-27 | Influence of Fingolimod Treatment on Disease Outcome and MRI Brain Volumes in Children with CLN 3
Background/Purpose: CLN3 is a neurodegenerative disorder leading to progressive loss of vision, motor function, and language skills, as well as dementia and epilepsy. Loss of brain volume has been shown to be a sensitive marker of disease progression corresponding with clinical scores. Fingolimod, a sphingosine-1-phosphate receptor modulator used in the treatment of MS, ameliorates the disease’s course in a CLN mouse model. Methods: Fifteen children with CLN3 were included (nine females, six males, age 5–16 years). Twelve were treated with Fingolimod over a period of at least 1 year, and nine of these additionally with Miglustat in the course of the study. Three patients were treated only with Miglustat from the beginning. MRI studies, including MPrage sequences, were performed at the onset of treatment and after 1 year. Volumetry data were compared with those of a natural history cohort including 47 MRI sequences. Standardized cognitive testing, the Hamburg JNCL score, and a 6-minute walking test were applied at baseline and at yearly intervals. Serum NFL measurements were performed at the same intervals. Results: Treatment with Fingolimod was well tolerated. None of the patients had side effects such as an increased rate of infections and raised liver enzymes. Lymphocyte count was generally within the target range of 300 to 500 lymphocytes/µL. NFl serum levels were mildly elevated before treatment (median range: 5–79 pg/mL). Follow-up values as well as clinical scores were stable. There was a significant difference in whole brain volume and gray matter volume between NCL3 patients and matched healthy controls at baseline and after 1 year of treatment. After 1 year, a further reduction of brain and cortical gray matter volume could be found in 10/15 patients. The results of 5/15 patients and evaluations of treated patients compared with MRI natural history data are pending. Conclusion: Our results indicate that Fingolimod is well tolerated and may alleviate the disease progression in CLN3 patients by influencing the secondary immunological reactions. Publication History Article published online: 27 April 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
cell therapies
2025-02-10 | Neuronal Ceroid Lipofuscinosis-Concepts, Classification, and Avenues for Therapy.
Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders characterized by excessive accumulation of lysosomal lipofuscin. Thirteen subtypes of NCL have been identified, each associated with distinct genes encoding various transmembrane proteins, secretory proteins, or lysosomal enzymes. Clinically, NCL manifests in infants through vision impairment, motor and cognitive dysfunctions, epilepsy, and premature death. The pathological complexity of NCL has hindered the development of effective clinical protocols. Current treatment modalities, including enzyme replacement therapy, pharmacological approaches, gene therapy, and stem cell therapy, have demonstrated limited efficacy. However, emerging evidence suggests a significant relationship between NCL and microglial cells, highlighting the potential of novel microglial cell replacement therapies. This review comprehensively examines the pathogenic genes associated with various NCL subtypes, elucidating their roles, clinical presentations, and corresponding mouse models. Especially, we thoroughly discuss the advances in the clinical study of potential therapeutics, which crucially calls for early diagnosis and treatment more than ever.
2024-10-30 | Safety and feasibility of umbilical cord blood transplantation in children with neuronal ceroid lipofuscinosis: a retrospective study.
Ceroid lipofuscinosis neuronal (CLN) encompasses rare inherited neurodegenerative disorders that present in childhood with clinical features including epilepsy, psychomotor delay, progressive vision loss, and premature death. Published experience utilizing umbilical cord blood transplant (UCBT) for these disorders is limited. This retrospective analysis includes patients with CLN (2, 3, and 5) who underwent UCBT from 2012 to 2020. All subjects (n = 8) received standard-of-care myeloablative conditioning. Four also enrolled in clinical trial NCT02254863 and received intrathecal DUOC-01 cells posttransplant. Median age at UCBT was 5.9 years. All subjects achieved neutrophil engraftment with >95% donor chimerism at a median of 28.5 days. Sinusoidal obstructive syndrome was not observed. Severe acute graft-versus-host disease occurred in 12.5%. Other complications included autoimmune hemolytic anemia (25%) and viral reactivation/infection (62.5%). No transplant-related mortality was observed. Two CLN2 patients died, 1 from progressive disease and 1 from unknown cause at days +362 and +937, respectively. With median follow-up of 8 years, overall survival at 100 days and 24 months was 100% and 88%, respectively. Three of 4 CLN3 subjects stabilized Hamburg motor and language scores. While UCBT appears safe and feasible in these patients, given the variable expression and natural history, extended follow-up and further studies are needed to elucidate the potential impact of UCBT on clinical outcomes.
2024-02-28 | Haploidentical haematopoietic stem cell transplantation combined with post-transplant cyclophosphamide in neuronal ceroid lipofuscinosis: Experience in eight patients.
Neuronal ceroid lipofuscinoses (NCLs) are rare lysosomal storage disorders characterized by progressive mental retardation and motor developmental regression and myoclonic seizures. Hematopoietic stem cell transplantation (HSCT) has been suggested to be used in the treatment of lysosomal disorders and brain damage caused by a deficiency of soluble lysosomal enzymes. There are no previous reports on treating NCLs with HSCT in China. NCL pediatric patients who underwent allo-HSCT at Affiliated Children's Hospital of Capital Institute of Pediatrics were involved. A combination of medical histories, clinical features, and genetic analyses was used for the diagnosis of all patients. The written consent form for allo-HSCT was attained from the patient's guardian, which was then reviewed and approved by the ethics committee before the procedure. From January 2018 to May 2019, the haplo-HSCT followed by PT/Cy on eight NCL pediatric patients was performed. The median age was 4.5 years (ranging from 2.8 to 7 years). The donors were their haploidentical HLA-matched parents, as no identically matched donors were found. The median nucleated cell count was 25.37 (10-34.41)×108/kg, and the median CD34+ count was 13.7 (8.95-22)×106/kg. Neutrophil reconstitution occurred 12 days (11-14 days) after transplantation, and the median platelet reconstitution time was 12 days (9-14 days) after transplantation. All patients achieved full donor chimerism and did not develop Grade II-IV acute GvHD or chronic GvHD after transplantation. The median follow-up period was 2.2 (1.5-2.6) years. All patients are still alive at present and develop no severe transplantation-related complications. The mental motor disorders, myoclonic seizures, and vision loss of all patients continued to progress. However, the progression slowed at 12 months after transplantation. This study demonstrated that it is safe and efficacious to treat NCLs with haplo-HSCT. Transplantation should be performed at an early stage for the survival quality of pediatric patients.
2021-09-29 | Neuronal Ceroid Lipofuscinosis Treated with Haploidentical Hematopoietic Stem Cell Transplantation Combined with Post-Transplant Cyclophosphamide
Abstract Background: Neuronal ceroid lipofuscinoses (NCLs) are rare lysosomal storage disorders, characterized by progressive mental retardation and motor developmental regression, and myoclonic seizures. Hematopoietic stem cell transplantation (HSCT) has been suggested to be used in the treatment of lysosomal disorders and brain damage caused by a deficiency of soluble lysosomal enzymes. However, there are no reports on treating NCLs with HSCT in China. Results: From January 2018 to May 2019, we performed haplo-HSCT followed by PT/Cy on 8 NCL pediatric patients. The median age was 4.5 years (range from 2.8 to 7 years). And the donors were their haploidentical HLA-matched parents, as no identically matched donor was found. The median nucleated cell count was 25.37 (10–34.41) ×10 8 /kg and the median CD34+ count was 13.7(8.95–22)×10 6 /kg. Neutrophil reconstitution occurred at 12 days (11–14 days) after transplantation, and median platelet reconstitution time was 12 days (9–14 days) after transplantation. All patients achieved full donor chimerism and did not develop Grade II–IV acute GvHD or chronic GvHD after transplantation. The median follow-up period was 2.2 (1.5–2.6) years. All patients are still alive at present, and develop no severe transplantation-related complications. The mental and motor disorders, myoclonic seizures, and vision loss of all patients continue to progress, but the progression slows down at 12 months after the transplantation. Conclusion: Observations reported in this study suggest it is safe and efficacy to treat NCLs with haplo-HSCT. Transplantation should be performed as early as possible for the survival quality of pediatric patients.
2021-03-18 | Global network analysis in Schizosaccharomyces pombe reveals three distinct consequences of the common 1-kb deletion causing juvenile CLN3 disease
Juvenile CLN3 disease is a recessively inherited paediatric neurodegenerative disorder, with most patients homozygous for a 1-kb intragenic deletion in CLN3. The btn1 gene is the Schizosaccharomyces pombe orthologue of CLN3. Here, we have extended the use of synthetic genetic array (SGA) analyses to delineate functional signatures for two different disease-causing mutations in addition to complete deletion of btn1. We show that genetic-interaction signatures can differ for mutations in the same gene, which helps to dissect their distinct functional effects. The mutation equivalent to the minor transcript arising from the 1-kb deletion (btn1102-208del) shows a distinct interaction pattern. Taken together, our results imply that the minor 1-kb deletion transcript has three consequences for CLN3: to both lose and retain some inherent functions and to acquire abnormal characteristics. This has particular implications for the therapeutic development of juvenile CLN3 disease. In addition, this proof of concept could be applied to conserved genes for other mendelian disorders or any gene of interest, aiding in the dissection of their functional domains, unpacking the global consequences of disease pathogenesis, and clarifying genotype-phenotype correlations. In doing so, this detail will enhance the goals of personalised medicine to improve treatment outcomes and reduce adverse events.
gene therapies
2026-08-09 | Phenotypic and Genetic Characterization of 64 Egyptian Children With Neuronal Ceroid Lipofuscinosis.
Neuronal ceroid lipofuscinoses (NCLs) are the most common neurodegenerative diseases in childhood. This study aimed to investigate the phenotypic and genetic spectrum of NCLs in Egypt. This descriptive study involved children with NCLs diagnosed and managed at five Egyptian centers between 2019 and 2024. Demographic, clinical, brain imaging, and genetic data were systematically evaluated. Identified variants in NCL-related genes were classified following the American College of Medical Genetics and Genomics guidelines. The cohort included 64 Egyptian children (from 57 families) with eight NCL types. The most commonly identified genotype was CLN2 (17/64, 27%), followed by CLN1 and CLN7 (12/64, 19% each). Patients generally exhibited the classic manifestations of NCLs, particularly motor regression (64/64, 100%), cognitive decline (64/64, 100%), language impairment (64/64, 100%), epilepsy (57/64, 89%), and vision loss (47/64, 73%). Notably, developmental regression (12/17, 71%) was the predominant presenting symptom for CLN2. Brain imaging generally showed typical cerebral and cerebellar atrophy in 95% (61/64) and 84% (54/64) of cases, respectively. Nevertheless, thalamic abnormalities were observed in only 16% (10/64) of cases. A total of 46 distinct variants were identified across eight NCL-related genes, including 23 novel ones, with the majority (33/46, 72%) being private. There was a median diagnostic delay of 2 years, and none of the patients received specific therapy. This study reports the largest cohort of children with NCLs from Egypt, including 12 patients with the less-commonly reported CLN7 subtype, which expands the demographic, clinical, and molecular spectrum of these diseases.
2026-01-08 | A timeline of symptom onset and disease progression in CLN3 disease.
CLN3 disease, or Juvenile Neuronal Ceroid Lipofuscinosis (JNCL), is a rare, genetic neurodegenerative condition, typically manifesting in the first decade of life and progressing in severity, with death typically occurring in early adulthood. Despite two decades of natural history research, a clear timeline of CLN3 disease symptom onset and progression remains poorly defined, limiting optimal patient management and therapeutic development. We conducted a literature review and analysed the natural history data to better understand the age of core symptom onset and chronological disease progression. A literature review was undertaken using a pre-defined search strategy focused on CLN3 disease natural history studies, where age at onset for one or more core symptoms was reported in cohorts of ≥ 15 subjects. For each symptom, weighted mean age at onset and weighted standard deviation were calculated, with 95% confidence intervals derived from the weighted standard error. Symptom onset ages were compared using ANOVA. We identified nine natural history studies that met our pre-defined criteria. In total, 423 discrete patients aged between 4 and 39 years were reported. Thirteen core symptoms and a weighted average age at onset and weighted standard deviation were (in years): vision loss (6.1 ± 1.6, N = 254), behavioural changes (8.5 ± 3.9, N = 194), cognitive decline (9.3 ± 3.1, N = 219), seizures (10.2 ± 3.0, N = 243), sleep disturbance (11.0 ± 6.1, N = 111), motor decline (11.0 ± 3.8, N = 108), complete blindness (11.4 ± 3.6, N = 171), speech and language impairment (12.7 ± 4.8, N = 136), Parkinsonian gait (14.1 ± 2.5, N = 111), cardiac manifestations (17.8 ± 4.4, N = 45), loss of independent walking (19.5 ± 3.2, N = 70), feeding difficulties requiring enteral feeding tube (22.0 ± 1.6, N = 35), and death (22.4 ± 4.4, N = 95). This comprehensive summary of available natural history data illustrates mean age at onset of 13 core symptoms of CLN3 disease, and characterises a chronological timeline of disease progression. These results provide much-needed practical, anticipatory guidance to those involved in caring for individuals with CLN3 disease, and serve to highlight the critical importance of collecting globally standardised, quantifiable, longitudinal data for optimising patient management and advancing therapeutic approaches for CLN3 disease. The online version contains supplementary material available at 10.1186/s13023-025-04174-5.
2025-11-27 | Canine Neuronal Ceroid Lipofuscinosis-like Disorder Associated with Sequence Variants in AP3B1 and TRAPPC9.
A Petit Bleu de Gascogne (PBDG) dog presented with a progressive neurological disorder characterized by hind-limb weakness, anxiety and hallucinatory episodes, lip smacking, progressive vision loss, muscle atrophy, and ataxia. Magnetic resonance imaging revealed diffuse brain atrophy. The dog was euthanized at approximately 23 months of age due to the progression of neurological signs. A study was undertaken to identify the molecular genetic basis of the disorder in this dog. Microscopic analyses were performed to characterize the disease pathology and whole-genome sequencing was performed to identify the molecular genetic basis of the disorder. The proband exhibited pronounced accumulations of autofluorescent intracellular inclusions in the brain, retina, and heart with ultrastructural appearances similar to those of lysosomal storage bodies that accumulate in the neuronal ceroid lipofuscinosis (NCLs), a group of progressive neurodegenerative disorders. Whole-genome sequence analysis of DNA from the proband identified homozygous missense variants in AP3B1 and TRAPPC9 that encode proteins involved in sorting and transport of proteins through the Golgi apparatus to lysosomes. Screening of unaffected PBDGs for these variants identified dogs that were homozygous for either variant, but no other dogs that were homozygous for both. These findings raise the possibility that the disease involves the combined influence of the two variants, and that the proteins encoded by these genes interact within the Golgi apparatus to mediate protein sorting and transport to lysosomes. An alteration in this interaction could underlie the NCL-like lysosomal storage disorder observed in the proband.
2025-11-23 | Progressive rod bipolar cell loss, ubiquitin accumulation, and subretinal drusenoid deposits in Cln3Δex7/8 mice: New insights into juvenile neuronal ceroid lipofuscinosis pathogenesis.
Juvenile neuronal ceroid lipofuscinosis (JNCL) is a rare neurodegenerative disorder caused by mutations in the CLN3 gene and characterized by early vision loss and a progressive neurological decline. To characterize the progression of retinal pathology, we conducted a 15-month study using the Cln3Δex7/8 mouse model which carries the most common causative mutation of JNCL. Retinal function was assessed every three months from the age of 3-15 months using electroretinography (ERG), optical coherence tomography (OCT), fundus imaging, and immunohistochemistry. OCT and fundus imaging in the Cln3Δex7/8 mice revealed a progressive thinning of the inner nuclear layer (INL) and an accumulation of subretinal drusenoid deposits. We detected a progressive loss of rod bipolar cells (RBCs) with immunofluorescence staining which was accompanied by ubiquitin-positive punctae, indicative of a potential role of the ubiquitin-proteasome system (UPS) in the selective loss of RBCs and the associated inner retinal dysfunction. Furthermore, late-stage immune cell activity was observed in the subretinal space of the Cln3Δex7/8 mice. ERG measurements confirmed previous findings of a predominant inner retinal dysfunction and revealed also a more pronounced photoreceptor impairment, as well as an earlier onset of retinal dysfunction than previously reported. These findings provide new insights into the pathological features of retinal degeneration in Cln3Δex7/8 mice, including subretinal drusenoid deposits, tubular subretinal fluid, and ubiquitin accumulation as well as a better overview of the rate of the degeneration process, thus expanding our understanding of JNCL pathogenesis.
2025-11-08 | Persistent lymphopenia in a Japanese boy with neuronal ceroid lipofuscinosis type 3.
Neuronal ceroid lipofuscinosis (NCL) is a heterogeneous group of lysosomal disorders characterized by progressive psychomotor regression, visual impairment, and intractable seizures. Genetically, NCL type 3 (CLN3) is associated with variants in the gene encoding a lysosomal transmembrane protein. To date, few Japanese patients with CLN3 have been reported. Thus, their neurodevelopmental and clinical features remain unclear. Here, we report the clinical course of a genetically confirmed Japanese patient with CLN3. A 17-year-old Japanese boy was diagnosed with retinitis pigmentosa at age 7. Visual impairment progressed over a 10-year follow-up period. Generalized tonic-clonic seizures also began at age 7. Developmental regression was recognized at age 13, with an accelerated decline in motor and communication skills following a COVID-19 infection at age 17. Tube feeding and gastrostomy were initiated for dysphagia and recurrent respiratory infections. Serial MRI revealed progressive cerebral and cerebellar atrophy. Lymphopenia (351-1467/μL) was present from age 9; peripheral blood smear revealed vacuolated lymphocytes. Exome sequencing identified a heterozygous CLN3 variant, NM_001042432.2:c.295-2A > C. SpliceAI suggested exon 6 skipping and/or an 80-bp deletion, leading to nonsense-mediated mRNA decay. Manual inspection using Integrated Genomic Viewer revealed a second variant (c.178_180delinsACATCCTTAGCCACAAGAG) missed initially. Trio Sanger sequencing confirmed compound heterozygosity: NM_001042432.2:c.[295-2A > C]; [178_180delinsACATCCTTAGCCACAAGAG] p.[?]; [His60Thrfs∗10]. A review of 430 genetically confirmed CLN3 patients (1989-2025) identified no hematologic abnormalities. This Japanese CLN3 patient developed visual impairment 7-8 years before systemic deterioration. Retinal degeneration, together with vacuolated peripheral lymphocytes, may provide early diagnostic clues for CLN3 in Japanese patients.
proteins
2026-08-26 | A 3D human retina model reveals a non-cell-autonomous and non-neuronal mechanism of photoreceptor loss in a lysosomal storage disorder.
Disruption of the photoreceptor-retinal pigment epithelium (RPE) interface, with loss of photoreceptor outer segments (POSs) in the retina, is a pathological hallmark of several neurodegenerative and retinal diseases, including lysosomal storage disorders like juvenile neuronal ceroid lipofuscinosis (CLN3) disease. However, in vitro stem cell models that enable investigation of the photoreceptor-RPE interface are lacking. Here, we developed a 3D human pluripotent stem cell-derived retina organoid-RPE (hPSC-RO-RPE) model to investigate the photoreceptor-RPE interface in healthy and diseased tissues. Using this 3D hPSC-RO-RPE retina model, we showed that the most common disease-causing CLN3 mutation (CLN3Δex7-8) leads to reduced levels of acid ceramidase (AC), sphingosine 1 phosphate, and POS loss. Furthermore, by analyzing control versus CLN3 mutant (CLN3Δex7-8) hPSC-derived RPE monoculture and hPSC-RO-RPE model, (i) we identified a pathogenic role of AC-mediated lysosomal sphingolipid metabolism in promoting CLN3 disease pathobiology, and (ii) we showed a cell autonomous role of the RPE dysfunction in promoting POS loss/retina degeneration in CLN3 disease. We validated the molecular and structural changes observed in the CLN3Δex7-8 hPSC-RO-RPE model in the CLN3 miniswine model (CLN3Δex7-8) and donor eyes from two patients with CLN3 disease. High-resolution retinal imaging of the living eye in two patients with CLN3 disease suggested decreased RPE autofluorescence in early-stage CLN3 disease. Treatment with recombinant human acid ceramidase (rhAC) ameliorated photoreceptor degeneration in both the CLN3 disease RO-RPE model and CLN3 miniswine eyes. These findings suggest that rhAC could be a therapeutic approach for retinal degeneration in CLN3 disease.
2025-09-05 | Neuronal ceroid lipofuscinosis: underlying mechanisms and emerging therapeutic targets.
The neuronal ceroid lipofuscinoses (NCLs), more commonly known as Batten disease, are a group of fatal inherited neurodegenerative lysosomal storage disorders. Each form is caused by mutations in a different gene, resulting in lysosomal dysfunction, which, by largely unknown mechanisms, has a devastating impact on the central nervous system. The NCLs are grouped together owing to their broadly shared clinical presentations and the presence of autofluorescent storage material. Nevertheless, being caused by deficiencies in dissimilar proteins, marked differences are apparent between NCLs in their clinical presentation and pathology. The effects of disease are not confined to neurons and appear unrelated to autofluorescent storage material, with glial cells also affected. The rest of the body is also affected, with life-limiting disease in the bowel and effects on other body systems, which will also require treatment for maximal therapeutic benefit. Since the development of enzyme replacement therapy for CLN2 disease, much has been learnt about the practicalities of its delivery. Considerable progress has also been made in the understanding of NCL cell biology, disease pathogenesis and potential links to other disorders. Here, we highlight these advances and how they inform the ongoing development of therapeutic strategies and their future prospects.
2025-08-06 | A 3D iPSC retina model reveals non-cell-autonomous and non-neuronal mechanism of photoreceptor degeneration in a lysosomal storage disorder.
Disruption of photoreceptor-retinal pigment epithelium (RPE) interface with loss of photoreceptor outer segments (POSs) in the retina is a pathological hallmark of several neurodegenerative and retinal diseases including lysosomal storage disorder's like CLN3 disease. However, the retina is a functional composite in vivo; and in vitro stem cell models of retina that enable investigation of the photoreceptor-RPE interface in healthy and diseased retina are lacking. Here, we developed a 3D human pluripotent stem cell (hPSC)-derived retina model to investigate the photoreceptor-RPE interface in healthy and disease tissue. Using this 3D hPSC retina model, we demonstrated that the most common disease causing CLN3 mutation ( CLN3 Δ ex7-8 ) leads to reduced levels of acid ceramidase (AC) and consequently altered sphingolipid metabolism and signaling and POS loss in CLN3 disease. Consistent with the 3D hPSC retina model, altered sphingolipid metabolism and signaling coincided with POS loss in a large animal model of CLN3 disease, CLN3 miniswine. Therapeutically, recombinant human acid ceramidase (rhAC) targeted both altered sphingolipid metabolism and retina degeneration in the CLN3 hPSC retina model and the CLN3 miniswine eye. These findings demonstrate a proof-of-concept that rhAC can rescue disease phenotype in a large animal model of CLN3 disease and suggest that rhAC could be a therapeutic approach for CLN3 disease. Acid ceramidase deficiency and consequently altered sphingolipid signaling promotes disease phenotype(s) in a lysosomal storage disorder, CLN3 disease.
2025-04-10 | Genetic Reasons for Phenotypic Diversity in Neuronal Ceroid Lipofuscinoses and High-Resolution Imaging as a Marker of Retinal Disease.
To describe the clinical characteristics, natural history, genetic landscape, and phenotypic spectrum of neuronal ceroid lipofuscinosis (NCL)-associated retinal disease. Multicenter retrospective cohort study complemented by a cross-sectional examination. Twelve pediatric subjects with biallelic variants in 5 NCL-causing genes (CLN3 lysosomal/endosomal transmembrane protein [CLN3], CLN6 transmembrane ER protein [CLN6], Major facilitator superfamily domain containing 8 [MFSD8], Palmitoyl-protein thioesterase 1 ([PPT1], and tripeptidyl peptidase 1 [TPP1]). Review of clinical notes, retinal imaging, electroretinography (ERG), and molecular genetic testing. Two subjects underwent a cross-sectional examination comprising adaptive optics scanning laser ophthalmoscopy imaging of the retina and optoretinography (ORG). Clinical/demographic data, multimodal retinal imaging data, electrophysiology parameters, and molecular genetic testing. Our cohort included a diverse set of subjects with CLN3-juvenile NCL (n = 3), TPP1-late infantile NCL (n = 5), PPT1-late infantile or juvenile NCL (n = 2), CLN6-infantile NCL (n = 1), and CLN7/MFSD8-late infantile NCL (n = 1). Five novel pathogenic or likely pathogenic variants were identified. Age at presentation ranged from 2 to 16 years old (mean 7.9 years). Subjects presented with varying phenotypes ranging from severe neurocognitive features (n = 8; 67%), including seizures and developmental delays and regressions, to nonsyndromic retinal dystrophies (n = 2; 17%). Visual acuities at presentation ranged from light perception to 20/20. In those with recordable ERGs, the traces were electronegative and suggestive of early cone dysfunction. Fundus imaging and OCTs demonstrated outer retinal loss that varied with underlying genotype. High-resolution adaptive optics imaging and functional measures with ORG in 2 subjects with atypical TPP1-associated disease revealed significantly different phenotypes of cellular structure and function that could be followed longitudinally. Our cohort data demonstrates that the underlying genetic variants drive the phenotypic diversity in different forms of NCL. Genetic testing can provide molecular diagnosis and ensure appropriate disease management and support for children and their families. With intravitreal enzyme replacement therapy on the horizon as a potential treatment option for NCL-associated retinal degeneration, precise structural and functional measures will be required to more accurately monitor disease progression. We show that adaptive optics imaging and ORG can be used as highly sensitive methods to track early retinal changes, which can be used to establish eligibility for future therapies and provide metrics for determining the efficacy of interventions on a cellular scale. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
2024-01-12 | Mechanistic Insights into S-Depalmitolyse Activity of Cln5 Protein Linked to Neurodegeneration and Batten Disease: A QM/MM Study.
Ceroid lipofuscinosis neuronal protein 5 (Cln5) is encoded by the CLN5 gene. The genetic variants of this gene are associated with the CLN5 form of Batten disease. Recently, the first crystal structure of Cln5 was reported. Cln5 shows cysteine palmitoyl thioesterase S-depalmitoylation activity, which was explored via fluorescent emission spectroscopy utilizing the fluorescent probe DDP-5. In this work, the mechanism of the reaction between Cln5 and DDP-5 was studied computationally by applying a QM/MM methodology at the ωB97X-D/6-31G(d,p):AMBER level. The results of our study clearly demonstrate the critical role of the catalytic triad Cys280-His166-Glu183 in S-depalmitoylation activity. This is evidenced through a comparison of the pathways catalyzed by the Cys280-His166-Glu183 triad and those with only Cys280 involved. The computed reaction barriers are in agreement with the catalytic efficiency. The calculated Gibb's free-energy profile suggests that S-depalmitoylation is a rate-limiting step compared to the preceding S-palmitoylation, with barriers of 26.1 and 25.3 kcal/mol, respectively. The energetics were complemented by monitoring the fluctuations in the electron density distribution through NBO charges and bond strength alterations via local mode stretching force constants during the catalytic pathways. This comprehensive protocol led to a more holistic picture of the reaction mechanism at the atomic level. It forms the foundation for future studies on the effects of gene mutations on both the S-palmitoylation and S-depalmitoylation steps, providing valuable data for the further development of enzyme replacement therapy, which is currently the only FDA-approved therapy for childhood neurodegenerative diseases, including Batten disease.
other
2025-06-12 | Therapeutic antisense oligonucleotide mitigates retinal dysfunction in a pig model of CLN3 Batten disease.
CLN3 Batten disease is a lethal pediatric autosomal recessive neurodegenerative disease caused by mutations in the CLN3 gene. Typically, the disease manifests as vision loss early in life and progresses to neurological dysfunction and death in young adulthood. Therapeutic development has focused on treating the central nervous system. However, such therapies may not protect against vision loss, which has a significant impact on quality of life. We have shown that a splice-switching antisense oligonucleotide (ASO) delivered to the central nervous system can reduce neurological disease burden in mouse models of CLN3 disease. Here, we report on a similar ASO approach for treating CLN3 Batten disease retinal dysfunction in a pig model of the disease, which is more representative of human vision. A single intravitreal injection of ASO induces robust exon skipping in the retina for up to 12 months. The ASO treatment resulted in higher amplitudes on electroretinograms, suggesting mitigation of retinal dysfunction at early timepoints of disease. One ASO that efficiently induces exon skipping in vivo was well-tolerated and targets a region of CLN3 that is conserved in humans, making it a promising candidate for treating the disease in humans. Our findings demonstrate the potential utility of an ASO-based approach to treat retinal dysfunction in CLN3 Batten disease and generally supports the use of ASOs for treating eye diseases.
2025-02-17 | Purifying and profiling lysosomes to expand understanding of lysosomal dysfunction-associated diseases.
Lysosome storage dysfunction plays a central role in numerous human diseases, but a lack of appropriate tools has hindered lysosomal content profiling in clinical settings. In this issue of the JCI, Saarela et al. introduce a method called tagless LysoIP that enabled rapid isolation of intact lysosomes from blood and brain cells via immunoprecipitation of the endogenous protein TMEM192. Applied to the neurodegenerative lysosomal storage disorder known as Batten disease (caused by mutations in the CLN3 gene), tagless LysoIP revealed substantial accumulation of glycerophosphodiesters (GPDs) in patient lysosomes. These findings highlight the role of CLN3 in GPD clearance and present an innovative method that will enable biomarker discovery and therapeutic advancement in lysosomal diseases.
2023-06-26 | Protracted CLN3 Batten disease in mice that genetically model an exon-skipping therapeutic approach.
Genetic mutations that disrupt open reading frames and cause translation termination are frequent causes of human disease and are difficult to treat due to protein truncation and mRNA degradation by nonsense-mediated decay, leaving few options for traditional drug targeting. Splice-switching antisense oligonucleotides offer a potential therapeutic solution for diseases caused by disrupted open reading frames by inducing exon skipping to correct the open reading frame. We have recently reported on an exon-skipping antisense oligonucleotide that has a therapeutic effect in a mouse model of CLN3 Batten disease, a fatal pediatric lysosomal storage disease. To validate this therapeutic approach, we generated a mouse model that constitutively expresses the Cln3 spliced isoform induced by the antisense molecule. Behavioral and pathological analyses of these mice demonstrate a less severe phenotype compared with the CLN3 disease mouse model, providing evidence that antisense oligonucleotide-induced exon skipping can have therapeutic efficacy in treating CLN3 Batten disease. This model highlights how protein engineering through RNA splicing modulation can be an effective therapeutic approach.
2020-12-21 | Experimental gene therapies for the NCLs.
The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of rare monogenic neurodegenerative diseases predominantly affecting children. All NCLs are lethal and incurable and only one has an approved treatment available. To date, 13 NCL subtypes (CLN1-8, CLN10-14) have been identified, based on the particular disease-causing defective gene. The exact functions of NCL proteins and the pathological mechanisms underlying the diseases are still unclear. However, gene therapy has emerged as an attractive therapeutic strategy for this group of conditions. Here we provide a short review discussing updates on the current gene therapy studies for the NCLs.
2020-11-04 | Therapeutic efficacy of antisense oligonucleotides in mouse models of CLN3 Batten disease.
CLN3 Batten disease is an autosomal recessive, neurodegenerative, lysosomal storage disease caused by mutations in CLN3, which encodes a lysosomal membrane protein1-3. There are no disease-modifying treatments for this disease that affects up to 1 in 25,000 births, has an onset of symptoms in early childhood and typically is fatal by 20-30 years of life4-7. Most patients with CLN3 Batten have a deletion encompassing exons 7 and 8 (CLN3∆ex7/8), creating a reading frameshift7,8. Here we demonstrate that mice with this deletion can be effectively treated using an antisense oligonucleotide (ASO) that induces exon skipping to restore the open reading frame. A single treatment of neonatal mice with an exon 5-targeted ASO-induced robust exon skipping for more than a year, improved motor coordination, reduced histopathology in Cln3∆ex7/8 mice and increased survival in a new mouse model of the disease. ASOs also induced exon skipping in cell lines derived from patients with CLN3 Batten disease. Our findings demonstrate the utility of ASO-based reading-frame correction as an approach to treat CLN3 Batten disease and broaden the therapeutic landscape for ASOs in the treatment of other diseases using a similar strategy.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for CLN3 disease.
2 orphan drug designations for CLN3 disease.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Non-replicating recombinant, self-complementary adeno-associated virus serotype 9 containing the human CLN3 gene | gene therapies | FDA | Nationwide Children's Hospital | |
scAAV9.MeCP2.hCLN3, a self-complementary AAV serotype 9 expressing human CLN3 (hCLN3) | gene therapies | FDA | — | UNeMed Corporation |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.