RARE DISEASE
CLN7 disease
CLN7 disease
CLN7 disease
Synonyms: Neuronal ceroid cipofuscinosis type 7, Turkish variant late infantile, vLINCL
Synonyms: Neuronal ceroid cipofuscinosis type 7, Turkish variant late infantile, vLINCL
Synonyms: Neuronal ceroid cipofuscinosis type 7, Turkish variant late infantile, vLINCL
Drug discovery
2
drugs
With orphan designations
Overview
CLN7 disease is a rare autosomal recessive neuronal ceroid lipofuscinosis (Batten disease) caused by mutations in the MFSD8 gene. Characterized by lysosomal dysfunction, it manifests between ages 2–7 with vision loss, myoclonus, ataxia, drug-resistant epilepsy, and speech impairment. Progressive neurodegeneration leads to motor/cognitive decline, blindness, and premature death, typically in adolescence [1][5][10].
Therapies
Supportive care: Antiseizure medications (e.g., valproate, levetiracetam), physical/occupational therapy, and gastrostomy for dysphagia [2][9].
Emerging therapies: Intrathecal AAV9-based gene therapy targeting MFSD8 shows preclinical efficacy in reducing neuropathology and extending survival in murine models [6][7].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
37 drug discovery papers about CLN7 disease, with 4 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
37 drug discovery papers about CLN7 disease, with 4 first-in-class and 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-04 | Clinical Symptoms in Late Infantile and Juvenile Onset Neuronal Ceroid Lipofuscinosis Type 7 (CLN7 Disease).
Neuronal ceroid lipofuscinosis type 7 (CLN7 disease) can present with late-infantile or juvenile onset phenotypes. Current understanding of disease progression is limited as most published data derive from case reports or case series. Our goal was to characterize clinical aspects of CLN7 disease across phenotypes. Participants with CLN7 disease were enrolled in a longitudinal observational study. We obtained medical and developmental histories, assessed adaptive behavior ability, and conducted standardized NCL-specific assessments, including the Unified Batten Disease Rating Scale and/or the Hamburg late infantile NCL rating scale. We enrolled 5 participants with late infantile onset and 2 participants with juvenile onset CLN7 disease. Those with late-infantile CLN7 disease typically demonstrated normal early development followed by a plateau in language development. Initial symptoms were commonly cognitive/learning problems (median onset 3.0 years). Developmental regression started between ages 4 and 6 years, with loss of independent ambulation and expressive language by age 6 years. In contrast, both participants with juvenile onset CLN7 disease had normal early development with vision loss as the initial symptom (ages 10-12.5 years), followed by seizure onset within 4 years. Late-infantile and juvenile onset phenotypes of CLN7 disease have distinct natural histories and progression patterns, including typical presenting symptoms, presence of developmental regression and differences in disease course. Disease progression in the juvenile cohort was more protracted compared to the late infantile cohort. Characterizing the natural history of CLN7 disease phenotypes is essential for improving early diagnosis, improving clinical management, and supporting therapeutic development for this devastating disorder.
2026-07-01 | TTYH3 regulates a lysosomal chloride conductance and controls lysosomal fusion, autophagy and senescence
Chloride is the most abundant anion within lysosomes and plays a pivotal role in regulating lysosomal physiology and function. However, the mechanisms governing lysosomal chloride homeostasis remain largely elusive. Here, we identified TTYH3 as a regulator of lysosomal chloride permeability. TTYH3 mediates chloride efflux from the lysosomal lumen and enhances TRPML1-mediated lysosomal calcium release. Overexpression of TTYH3 results in markedly enlarged lysosomes by promoting lysosomal fusion via the Ca 2+ /CaM and HSP90 pathways. Moreover, TTYH3 enhances autophagy by inhibiting the AKT/mTOR signaling pathway and alleviates cellular senescence via activation of the ERK pathway. Notably, TTYH3 expression mitigates cellular phenotypes associated with lysosomal storage diseases caused by deficiencies in another lysosomal chloride channel CLN7. Collectively, our findings demonstrate that TTYH3 mediates a lysosomal chloride conductance and regulates lysosomal physiology and autophagy, and may serve as a potential therapeutic target for interventions in aging and lysosome-related diseases.
2026-05-28 | Cellular and molecular characterisation of MFSD8 mutations associated with the variant late-infantile NCL CLN7
Batten disease (BD), also known as neuronal ceroid lipofuscinoses (NCLs), is a collective group of inherited neurodegenerative disorders. NCLs are the most prevalent cause of dementia in children, and they are distinguished by a common symptomatology that includes epileptic seizures, visual impairment, and a progressive decline in cognitive and physical function that results in early mortality. There are currently 12 different NCLs genetically identified in humans (CLN1-CLN8, CLN10-CLN13), with four newly identified genes (CLN9, CLN14, CLCN6, and SGSH). This study specifically focused on the variant late-infantile NCL (vLINCL) CLN7, which is caused primarily by homozygous mutations in CLN7/MFSD8, a major facilitator superfamily gene. MFSD8 encodes a multispanning integral lysosomal membrane protein with 12 transmembrane domains and has recently been described as a potential chloride channel on endosomes and lysosomes. However, there is still no cure or treatment available for CLN7 disease. Additionally, there is strong evidence demonstrating that MFSD8 is involved in the pathogenesis and pathobiology of other adult dementias, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), as well as maculopathies and retinopathies, which share common disease-causing mutations in a heterozygosity manner. Considering the emerging relevance of the use of induced pluripotent stem cells (iPSCs) as a model for the investigation of neurodegenerative diseases, in this thesis, I studied CLN7 disease employing CLN7 patient-derived iPSCs. Specifically, two iPS cell lines were utilised, which were derived from a female patient diagnosed at the age of 2.5 years, who exhibited homozygosity for the common missense mutation p.T294K and a male patient diagnosed at the age of 4.5 years, who was also homozygous for a more severe missense mutation corresponding to p.R465W. These iPS cell lines were further differentiated into Neural Progenitor Cells (NPCs), constituting a novel approach to study the variant late-infantile NCL CLN7 and providing an opportunity to examine the disease using cell types that could more closely resemble those affected in vivo. In light of previous proteomic studies conducted in CLN7 patient-derived NPCs by our group, resulting in a downregulation of several nuclear proteins and, consistent with the observation of other studies, we identify the localisation of MFSD8 in the nucleus. These findings provide evidence of the potential existence of several co-existing MFSD8 variants within the cells, suggesting that MFSD8 might exert different functions depending on the different isoform expressed and its localisation. Additionally, this work also reveals an impairment in the autophagy-lysosomal pathway and mitochondria produced by disease-causing mutations in NPCs and the improvement of these phenotypes with the use of existing compounds. Furthermore, through the study of the post-translational modifications of MFSD8 and different protein stability assays, this work also provides more evidence of the intricacy of this protein. Therefore, further studies on the potential protein binding partners of MFSD8 were conducted to gain a deeper understanding of novel signalling pathways or molecular mechanisms in which MFSD8 might be involved. In summary, this thesis provides significant insights into the cellular and molecular biology of MFSD8 through the use of a clinically relevant model, which sheds new light on future directions for the study of CLN7 disease. These findings can contribute to the development of significant therapeutic strategies to ameliorate CLN7 disease and, as a consequence, improve other adult neurodegenerative diseases which share the same disease-causing mutations as CLN7 disease.
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.
2025-11-29 | First-in-human high dose AAV9 intrathecal gene therapy for paediatric CLN7 disease: a phase 1, open-label, single ascending dose, non-randomised clinical trial.
Neuronal Ceroid Lipofuscinoses type 7 (CLN7) is a paediatric lysosomal storage disease caused by mutations of the MFSD8 gene. Affected children have normal early development, but then suffer from progressive cognitive, motor, verbal, and visual decline. Ataxia and myoclonic epilepsy are predominant features of the condition, and there are no effective therapies. Death usually occurs by approximately age 11 years. While adeno-associated virus serotype 9 (AAV9) based gene therapy holds promise for treating monogenetic neurologic disorders, the impact of this intervention is limited by the maximum safe tolerable dose and the host immune response to the capsid and gene product. This study sought to confirm the safety of high dose intrathecal AAV-based gene therapy under a comprehensive immunosuppression regimen. This was a two-year open label, dose escalation, phase 1 first-in-human study of AAV9-based intrathecal gene therapy for CLN7. 4 participants (1 low dose, 3 high dose) were followed at regular intervals with blood work, CSF analysis, EEG, MRI, and measures of neurologic and neuropsychological function. This study provided evidence of safety for high dose intrathecal AAV9 based gene therapy in CLN7 disease under a specific immunosuppression regimen. Additionally, this study provides preliminary evidence of efficacy for this gene therapy. High dose intrathecal AAV based gene therapy can be pursued with adequate immunosuppression and monitoring for immune responses to the gene product. Additional long-term monitoring of the immune system during tapering of immunosuppression is needed to identify potential reactions to the gene product. This study was funded by The Batten's Hope Foundation, Mila's Miracle Foundation, Children's Health Dallas and Philanthropic Gifts to UT Southwestern. In addition, Emily R. Nettesheim received funding from NIH training grant 5T32GM131945-03 and Hamza Dahshi was supported in part by NIH award T32 GM152319.
2026-07-04 | Clinical Symptoms in Late Infantile and Juvenile Onset Neuronal Ceroid Lipofuscinosis Type 7 (CLN7 Disease).
Neuronal ceroid lipofuscinosis type 7 (CLN7 disease) can present with late-infantile or juvenile onset phenotypes. Current understanding of disease progression is limited as most published data derive from case reports or case series. Our goal was to characterize clinical aspects of CLN7 disease across phenotypes. Participants with CLN7 disease were enrolled in a longitudinal observational study. We obtained medical and developmental histories, assessed adaptive behavior ability, and conducted standardized NCL-specific assessments, including the Unified Batten Disease Rating Scale and/or the Hamburg late infantile NCL rating scale. We enrolled 5 participants with late infantile onset and 2 participants with juvenile onset CLN7 disease. Those with late-infantile CLN7 disease typically demonstrated normal early development followed by a plateau in language development. Initial symptoms were commonly cognitive/learning problems (median onset 3.0 years). Developmental regression started between ages 4 and 6 years, with loss of independent ambulation and expressive language by age 6 years. In contrast, both participants with juvenile onset CLN7 disease had normal early development with vision loss as the initial symptom (ages 10-12.5 years), followed by seizure onset within 4 years. Late-infantile and juvenile onset phenotypes of CLN7 disease have distinct natural histories and progression patterns, including typical presenting symptoms, presence of developmental regression and differences in disease course. Disease progression in the juvenile cohort was more protracted compared to the late infantile cohort. Characterizing the natural history of CLN7 disease phenotypes is essential for improving early diagnosis, improving clinical management, and supporting therapeutic development for this devastating disorder.
2026-07-01 | TTYH3 regulates a lysosomal chloride conductance and controls lysosomal fusion, autophagy and senescence
Chloride is the most abundant anion within lysosomes and plays a pivotal role in regulating lysosomal physiology and function. However, the mechanisms governing lysosomal chloride homeostasis remain largely elusive. Here, we identified TTYH3 as a regulator of lysosomal chloride permeability. TTYH3 mediates chloride efflux from the lysosomal lumen and enhances TRPML1-mediated lysosomal calcium release. Overexpression of TTYH3 results in markedly enlarged lysosomes by promoting lysosomal fusion via the Ca 2+ /CaM and HSP90 pathways. Moreover, TTYH3 enhances autophagy by inhibiting the AKT/mTOR signaling pathway and alleviates cellular senescence via activation of the ERK pathway. Notably, TTYH3 expression mitigates cellular phenotypes associated with lysosomal storage diseases caused by deficiencies in another lysosomal chloride channel CLN7. Collectively, our findings demonstrate that TTYH3 mediates a lysosomal chloride conductance and regulates lysosomal physiology and autophagy, and may serve as a potential therapeutic target for interventions in aging and lysosome-related diseases.
2026-05-28 | Cellular and molecular characterisation of MFSD8 mutations associated with the variant late-infantile NCL CLN7
Batten disease (BD), also known as neuronal ceroid lipofuscinoses (NCLs), is a collective group of inherited neurodegenerative disorders. NCLs are the most prevalent cause of dementia in children, and they are distinguished by a common symptomatology that includes epileptic seizures, visual impairment, and a progressive decline in cognitive and physical function that results in early mortality. There are currently 12 different NCLs genetically identified in humans (CLN1-CLN8, CLN10-CLN13), with four newly identified genes (CLN9, CLN14, CLCN6, and SGSH). This study specifically focused on the variant late-infantile NCL (vLINCL) CLN7, which is caused primarily by homozygous mutations in CLN7/MFSD8, a major facilitator superfamily gene. MFSD8 encodes a multispanning integral lysosomal membrane protein with 12 transmembrane domains and has recently been described as a potential chloride channel on endosomes and lysosomes. However, there is still no cure or treatment available for CLN7 disease. Additionally, there is strong evidence demonstrating that MFSD8 is involved in the pathogenesis and pathobiology of other adult dementias, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), as well as maculopathies and retinopathies, which share common disease-causing mutations in a heterozygosity manner. Considering the emerging relevance of the use of induced pluripotent stem cells (iPSCs) as a model for the investigation of neurodegenerative diseases, in this thesis, I studied CLN7 disease employing CLN7 patient-derived iPSCs. Specifically, two iPS cell lines were utilised, which were derived from a female patient diagnosed at the age of 2.5 years, who exhibited homozygosity for the common missense mutation p.T294K and a male patient diagnosed at the age of 4.5 years, who was also homozygous for a more severe missense mutation corresponding to p.R465W. These iPS cell lines were further differentiated into Neural Progenitor Cells (NPCs), constituting a novel approach to study the variant late-infantile NCL CLN7 and providing an opportunity to examine the disease using cell types that could more closely resemble those affected in vivo. In light of previous proteomic studies conducted in CLN7 patient-derived NPCs by our group, resulting in a downregulation of several nuclear proteins and, consistent with the observation of other studies, we identify the localisation of MFSD8 in the nucleus. These findings provide evidence of the potential existence of several co-existing MFSD8 variants within the cells, suggesting that MFSD8 might exert different functions depending on the different isoform expressed and its localisation. Additionally, this work also reveals an impairment in the autophagy-lysosomal pathway and mitochondria produced by disease-causing mutations in NPCs and the improvement of these phenotypes with the use of existing compounds. Furthermore, through the study of the post-translational modifications of MFSD8 and different protein stability assays, this work also provides more evidence of the intricacy of this protein. Therefore, further studies on the potential protein binding partners of MFSD8 were conducted to gain a deeper understanding of novel signalling pathways or molecular mechanisms in which MFSD8 might be involved. In summary, this thesis provides significant insights into the cellular and molecular biology of MFSD8 through the use of a clinically relevant model, which sheds new light on future directions for the study of CLN7 disease. These findings can contribute to the development of significant therapeutic strategies to ameliorate CLN7 disease and, as a consequence, improve other adult neurodegenerative diseases which share the same disease-causing mutations as CLN7 disease.
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.
2025-11-29 | First-in-human high dose AAV9 intrathecal gene therapy for paediatric CLN7 disease: a phase 1, open-label, single ascending dose, non-randomised clinical trial.
Neuronal Ceroid Lipofuscinoses type 7 (CLN7) is a paediatric lysosomal storage disease caused by mutations of the MFSD8 gene. Affected children have normal early development, but then suffer from progressive cognitive, motor, verbal, and visual decline. Ataxia and myoclonic epilepsy are predominant features of the condition, and there are no effective therapies. Death usually occurs by approximately age 11 years. While adeno-associated virus serotype 9 (AAV9) based gene therapy holds promise for treating monogenetic neurologic disorders, the impact of this intervention is limited by the maximum safe tolerable dose and the host immune response to the capsid and gene product. This study sought to confirm the safety of high dose intrathecal AAV-based gene therapy under a comprehensive immunosuppression regimen. This was a two-year open label, dose escalation, phase 1 first-in-human study of AAV9-based intrathecal gene therapy for CLN7. 4 participants (1 low dose, 3 high dose) were followed at regular intervals with blood work, CSF analysis, EEG, MRI, and measures of neurologic and neuropsychological function. This study provided evidence of safety for high dose intrathecal AAV9 based gene therapy in CLN7 disease under a specific immunosuppression regimen. Additionally, this study provides preliminary evidence of efficacy for this gene therapy. High dose intrathecal AAV based gene therapy can be pursued with adequate immunosuppression and monitoring for immune responses to the gene product. Additional long-term monitoring of the immune system during tapering of immunosuppression is needed to identify potential reactions to the gene product. This study was funded by The Batten's Hope Foundation, Mila's Miracle Foundation, Children's Health Dallas and Philanthropic Gifts to UT Southwestern. In addition, Emily R. Nettesheim received funding from NIH training grant 5T32GM131945-03 and Hamza Dahshi was supported in part by NIH award T32 GM152319.
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 CLN7 disease.
2 orphan drug designations for CLN7 disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adeno-associated viral vector serotype 9 encoding a codon-optimized human ceroid neuronal lipofuscinosis type 7 (CLN7) transgene | gene therapies | FDA | 2024-10-29 | — | Elpida Therapeutics SPC |
An adeno-associated virus serotype 9 (AAV9) vector with engineered transgene encoding the human CLN7/MFSD8 gene for expression of active human major facilitator superfamily domain containing 8 | gene therapies | FDA | 2020-07-31 | — | Neurogene Inc. |
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