RARE DISEASE
CLN6 disease
CLN6 disease
CLN6 disease
Synonyms: Neuronal ceroid cipofuscinosis type 6, vLINCL
Synonyms: Neuronal ceroid cipofuscinosis type 6, vLINCL
Synonyms: Neuronal ceroid cipofuscinosis type 6, vLINCL
Drug discovery
1
drug
With orphan designation
Overview
CLN6 disease is a rare autosomal recessive neuronal ceroid lipofuscinosis (NCL) marked by progressive neurodegeneration due to CLN6 mutations. Childhood-onset forms (18 months–8 years) feature developmental regression, seizures, ataxia, and vision loss, with rapid functional decline and death typically by adolescence. Adult-onset cases (>30 years) manifest with myoclonus, cognitive decline, and epilepsy, often without vision impairment, and survival ≤10 years post-diagnosis. Pathologically, lysosomal storage accumulation drives neuronal death [1][2][9].
Therapies
Symptomatic management: Antiseizure medications (lamotrigine, levetiracetam), spasticity control (baclofen), and multidisciplinary palliative care [5][8].
Emerging options: Intrathecal AAV9-mediated gene therapy (preclinical efficacy in restoring CLN6 expression, reducing neurodegeneration) [7][10].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
66 drug discovery papers about CLN6 disease, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
66 drug discovery papers about CLN6 disease, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-04-28 | PPARα and RXRα in the regulation of neuronal ceroid lipofuscinosis genes: implications for Batten disease therapy
Abstract 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.
2026-03-14 | A Flupirtine Benzyl Carbamate Improves Neurocognitive Deficits and Molecular Pathology in the Cln6nclf Mouse.
Neuronal ceroid lipofuscinosis type 6 (CLN6) is a fatal, autosomal recessive neurodegenerative disorder characterized by cognitive/motor impairment, vision loss, as well as neuronal loss and gliosis in the brain, and premature death. Onset typically occurs in childhood. No approved pharmacological treatments exist that halt or reverse disease progression. A novel flupirtine benzyl carbamate was orally administered to male and female Cln6nclf mice from 4 to 28 weeks of age to evaluate its neuroprotective and antispastic effects. Drug treatment produced significant, sex-dependent phenotypic improvements. Treated mice of both sexes exhibited reduced hindlimb spasticity, but only treated males demonstrated diminution in locomotor hyperactivity and recovery of visuospatial performance. In the brains of male and female Cln6nclf mice, flupirtine benzyl carbamate significantly decreased astrocytosis, microgliosis and mitochondrial ATP synthase subunit C (SCMAS) accumulation, increased neuronal marker expression and reduced the number of TUNEL-positive cells. The treatment failed to rescue photoreceptor loss or clear retinal SCMAS storage. These outcomes result in distinct sex-specific differences in neuronal vulnerability and drug responsiveness. Overall, these findings demonstrate that flupirtine benzyl carbamate diminishes key motor, visual and pathological deficits in CLN6 disease, highlighting its promise as a potential disease-modifying therapy for CLN6 in humans despite sex-specific differences.
2025-10-30 | Phenotype, EEG, neuroimaging and Genetic profile of Progressive Myoclonic Epilepsy in Bangladesh: An observational study
Background: Progressive myoclonic epilepsy (PME) is an epilepsy syndrome characterized by myoclonus, cognitive deficit and ataxia. Common PMEs are Unverricht–Lundborg disease, myoclonic epilepsy with ragged-red fiber (MERRF) syndrome, Lafora body disease, neuronal ceroid lipofuscinoses, and sialidases. This study was conducted to obtain baseline information on PME in terms of phenotype, EEG, MRI of the brain, and overall genetic profile. Methodology: This retrospective observational study was conducted in the Department of Pediatric Neurology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. The duration of the study was from January 2020 to December 2023. Children diagnosed as PME on the basis of phenotype, EEG, imaging and genotype were included in this study. The genetic diagnosis was done by next-generation sequencing. Result: A total of 11 patients were analyzed in this study. The age of onset ranges from 6 months to 5 years. Consanguinity of the parents was present in 8 cases; one patient had a positive family history of a similar type of illness. The key clinical features were seizure, ataxia, neuroregression, visual impairment, dystonia etc. EEG features showed focal epileptic discharges (6), generalized discharges (5), with progressive deterioration of background in most of the cases. In MRI, 8 out of 11 patients had cerebello-cerebral atrophy. In all cases, next-generation sequencing was done; of them, three cases had KCTD7 gene mutation, three had CLN6 gene mutation causing Neuronal ceroid lipofuscinosis, another three had TPP1 gene mutation and the remaining two had MFSD8(-) gene mutation. Conclusion: This study will highlight the pattern of genotype and phenotype of children with PME in Bangladesh. J Bangladesh Coll Phys Surg 2025; 43: 269-276
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.
2024-01-30 | Cellular Modeling of CLN6 with IPSC-derived Neurons and Glia
ABSTRACT Neuronal ceroid lipofuscinosis (NCL), type 6 (CLN6) is a neurodegenerative disorder associated with progressive neurodegeneration leading to dementia, seizures, and retinopathy. CLN6 encodes a resident-ER protein involved in trafficking lysosomal proteins to the Golgi. CLN6p deficiency results in lysosomal dysfunction and deposition of storage material comprised of Nile Red + lipids/proteolipids that include subunit C of the mitochondrial ATP synthase (SUBC). White matter involvement has been recently noted in several CLN6 animal models and several CLN6 subjects had neuroimaging was consistent with leukodystrophy. CLN6 patient-derived induced pluripotent stem cells (IPSCs) were generated from several of these subjects. IPSCs were differentiated into oligodendroglia or neurons using well-established small-molecule protocols. A doxycycline-inducible transgenic system expressing neurogenin-2 (the I3N-system) was also used to generate clonal IPSC-lines (I3N-IPSCs) that could be rapidly differentiated into neurons (I3N-neurons). All CLN6 IPSC-derived neural cell lines developed significant storage material, CLN6-I3N-neuron lines revealed significant Nile Red + and SUBC + storage within three and seven days of neuronal induction, respectively. CLN6-I3N-neurons had decreased tripeptidyl peptidase-1 activity, increased Golgi area, along with increased LAMP1 + in cell bodies and neurites. SUBC + signal co-localized with LAMP1 + signal. Bulk-transcriptomic evaluation of control- and CLN6-I3N-neurons identified >1300 differentially-expressed genes (DEGs) with Gene Ontogeny (GO) Enrichment and Canonical Pathway Analyses having significant changes in lysosomal, axonal, synaptic, and neuronal-apoptotic gene pathways. These findings indicate that CLN6-IPSCs and CLN6-I3N-IPSCs are appropriate cellular models for this disorder. These I3N-neuron models may be particularly valuable for developing therapeutic interventions with high-throughput drug screening assays and/or gene therapy.
2026-04-28 | PPARα and RXRα in the regulation of neuronal ceroid lipofuscinosis genes: implications for Batten disease therapy
Abstract 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.
2026-03-14 | A Flupirtine Benzyl Carbamate Improves Neurocognitive Deficits and Molecular Pathology in the Cln6nclf Mouse.
Neuronal ceroid lipofuscinosis type 6 (CLN6) is a fatal, autosomal recessive neurodegenerative disorder characterized by cognitive/motor impairment, vision loss, as well as neuronal loss and gliosis in the brain, and premature death. Onset typically occurs in childhood. No approved pharmacological treatments exist that halt or reverse disease progression. A novel flupirtine benzyl carbamate was orally administered to male and female Cln6nclf mice from 4 to 28 weeks of age to evaluate its neuroprotective and antispastic effects. Drug treatment produced significant, sex-dependent phenotypic improvements. Treated mice of both sexes exhibited reduced hindlimb spasticity, but only treated males demonstrated diminution in locomotor hyperactivity and recovery of visuospatial performance. In the brains of male and female Cln6nclf mice, flupirtine benzyl carbamate significantly decreased astrocytosis, microgliosis and mitochondrial ATP synthase subunit C (SCMAS) accumulation, increased neuronal marker expression and reduced the number of TUNEL-positive cells. The treatment failed to rescue photoreceptor loss or clear retinal SCMAS storage. These outcomes result in distinct sex-specific differences in neuronal vulnerability and drug responsiveness. Overall, these findings demonstrate that flupirtine benzyl carbamate diminishes key motor, visual and pathological deficits in CLN6 disease, highlighting its promise as a potential disease-modifying therapy for CLN6 in humans despite sex-specific differences.
2025-10-30 | Phenotype, EEG, neuroimaging and Genetic profile of Progressive Myoclonic Epilepsy in Bangladesh: An observational study
Background: Progressive myoclonic epilepsy (PME) is an epilepsy syndrome characterized by myoclonus, cognitive deficit and ataxia. Common PMEs are Unverricht–Lundborg disease, myoclonic epilepsy with ragged-red fiber (MERRF) syndrome, Lafora body disease, neuronal ceroid lipofuscinoses, and sialidases. This study was conducted to obtain baseline information on PME in terms of phenotype, EEG, MRI of the brain, and overall genetic profile. Methodology: This retrospective observational study was conducted in the Department of Pediatric Neurology, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh. The duration of the study was from January 2020 to December 2023. Children diagnosed as PME on the basis of phenotype, EEG, imaging and genotype were included in this study. The genetic diagnosis was done by next-generation sequencing. Result: A total of 11 patients were analyzed in this study. The age of onset ranges from 6 months to 5 years. Consanguinity of the parents was present in 8 cases; one patient had a positive family history of a similar type of illness. The key clinical features were seizure, ataxia, neuroregression, visual impairment, dystonia etc. EEG features showed focal epileptic discharges (6), generalized discharges (5), with progressive deterioration of background in most of the cases. In MRI, 8 out of 11 patients had cerebello-cerebral atrophy. In all cases, next-generation sequencing was done; of them, three cases had KCTD7 gene mutation, three had CLN6 gene mutation causing Neuronal ceroid lipofuscinosis, another three had TPP1 gene mutation and the remaining two had MFSD8(-) gene mutation. Conclusion: This study will highlight the pattern of genotype and phenotype of children with PME in Bangladesh. J Bangladesh Coll Phys Surg 2025; 43: 269-276
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.
2024-01-30 | Cellular Modeling of CLN6 with IPSC-derived Neurons and Glia
ABSTRACT Neuronal ceroid lipofuscinosis (NCL), type 6 (CLN6) is a neurodegenerative disorder associated with progressive neurodegeneration leading to dementia, seizures, and retinopathy. CLN6 encodes a resident-ER protein involved in trafficking lysosomal proteins to the Golgi. CLN6p deficiency results in lysosomal dysfunction and deposition of storage material comprised of Nile Red + lipids/proteolipids that include subunit C of the mitochondrial ATP synthase (SUBC). White matter involvement has been recently noted in several CLN6 animal models and several CLN6 subjects had neuroimaging was consistent with leukodystrophy. CLN6 patient-derived induced pluripotent stem cells (IPSCs) were generated from several of these subjects. IPSCs were differentiated into oligodendroglia or neurons using well-established small-molecule protocols. A doxycycline-inducible transgenic system expressing neurogenin-2 (the I3N-system) was also used to generate clonal IPSC-lines (I3N-IPSCs) that could be rapidly differentiated into neurons (I3N-neurons). All CLN6 IPSC-derived neural cell lines developed significant storage material, CLN6-I3N-neuron lines revealed significant Nile Red + and SUBC + storage within three and seven days of neuronal induction, respectively. CLN6-I3N-neurons had decreased tripeptidyl peptidase-1 activity, increased Golgi area, along with increased LAMP1 + in cell bodies and neurites. SUBC + signal co-localized with LAMP1 + signal. Bulk-transcriptomic evaluation of control- and CLN6-I3N-neurons identified >1300 differentially-expressed genes (DEGs) with Gene Ontogeny (GO) Enrichment and Canonical Pathway Analyses having significant changes in lysosomal, axonal, synaptic, and neuronal-apoptotic gene pathways. These findings indicate that CLN6-IPSCs and CLN6-I3N-IPSCs are appropriate cellular models for this disorder. These I3N-neuron models may be particularly valuable for developing therapeutic interventions with high-throughput drug screening assays and/or gene therapy.
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
1 orphan drug designation for CLN6 disease.
1 orphan drug designation for CLN6 disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
non-replicating recombinant, self-complementary adeno-associated virus serotype 9 containing the human CLN6 gene | gene therapies | FDA | 2019-11-27 | — | The Charlotte & Gwenyth Gray Foundation to Cure Batten Disease |
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