cell therapies

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.

Open article ↗

2025-05-13 | Expanded Phenotype of the Cln6nclf Mouse Model.

Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurogenetic disorders caused by mutations in 14 different genes. CLN6 disease manifests as variant late-infantile NCL (vLINCL) or as an adult variant. In childhood, symptoms include speech delay, vision loss, cognitive and motor decline, seizures, and early death. An in-depth characterization of a naturally occurring Cln6 mutant mouse (Cln6nclf) is presented, with implications for translational research. The expanded phenotype provides data showing early death, vision loss, and motor deficits in male and female Cln6nclf mice. Diminished visual acuity in Cln6nclf mice was noted at 28 weeks of age, but the pathological loss of retinal layers began as early as 2 weeks or postnatal day 14 (P14). Apoptosis was confirmed by TUNEL staining in the Cln6nclf mouse brain at P8 and in the retina at P12. A peak in glial fibrillary acidic protein (GFAP) expression was established as a normal developmental phenomenon in the wild-type and Cln6nclf mouse brain cerebellum and the CA2-CA3 regions of the hippocampus at P8. In Cln6nclf mice, GFAP levels were elevated at P12 in the cerebellum and hippocampus. In the retina, a developmental peak in gliosis was absent, with increased astrogliosis noted at P6 and P8 in female and male Cln6nclf mice, respectively. This highlights the lack of a sex-dependent response in wild-type mice. These novel data position the Cln6nclf mouse model as a useful tool for screening potential therapeutics for human CLN6 disease.

Open article ↗

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.

Open article ↗

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.

Open article ↗

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.

Open article ↗

proteins

2026-09-19 | Conversion of a ventricular rickham reservoir to a subcutaneous chest port for repeated intraventricular enzyme replacement therapy: technical note and surgical considerations.

Cerliponase alfa enzyme replacement therapy has transformed the management of neuronal ceroid lipofuscinosis type 2 (CLN2) disease but requires lifelong cerebrospinal fluid (CSF) access for repeated intraventricular infusions. Conventional scalp-based ventricular reservoirs are associated with complications including infection, mechanical deterioration, and device revision related to repeated puncture. Chest port-mediated ventricular access has emerged as a potential alternative; however, detailed operative descriptions remain limited. We describe operative considerations and stepwise technique for establishing ventricular access using a Rickham reservoir connected via shunt tubing to a subcutaneous chest port system for repeated intraventricular cerliponase alfa infusion. Illustrative clinical experience demonstrates durable long-term use of this configuration. Key technical elements include neuronavigation-guided ventricular catheter placement, creation of a subcutaneous or subfascial chest pocket depending on patient body habitus, incorporation of strain-relief loops to reduce catheter tension, and systematic testing of the completed construct. The resulting system allows reliable ventricular access via a chest port while preserving ventricular catheter integrity. Chest port-mediated ventricular access represents a feasible and durable strategy for long-term intraventricular therapy in CLN2 disease. Dissemination of operative technique may facilitate broader adoption and support reliable delivery of enzyme replacement therapy for patients requiring lifelong treatment.

Open article ↗

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.

Open article ↗

2026-08-25 | K16ApoE-mediated delivery across the blood-brain barrier: mechanisms, applications, and translational challenges.

The blood-brain barrier (BBB) supporting the health of the central nervous system does this by limiting molecular exchange between circulation and brain tissue, although unfortunately this same restriction prevents therapeutically relevant macromolecules from entering the brain. Consequently, a number of protein-based therapies with success in peripheral tissues including enzymes, antibodies and biologics are unsuccessful in treating neurological disorders. The most recently described example is K16ApoE, a synthetic peptide that combines a polylysine-associated moiety with the receptor binding domain of apolipoprotein E (apoE), suggested to facilitate systemic delivery of large biomolecules across the BBB. Here, we review evidence that co-administration of K16ApoE with therapeutic proteins can mediate high concentrations of this protein in brain tissue, which can yield significant substrate clearance (pathological storage) and profound neurologic improvement and survival benefits in animal models of late-infantile neuronal ceroid lipofuscinosis (LINCL; CLN2 disease). In addition to applications in lysosomal storage disorders, the peptide has shown efficacy in promoting delivery of chemotherapeutic agents, antibodies and biologics related to brain tumors and neurodegenerative diseases. However, broad limitations persist including dose-dependent toxicity or nonspecific BBB permeability and immunogenicity as well high levels of uncertainty in referencing animal findings to humans. This review provides an integrated critical perspective on K16ApoE by connecting its proposed delivery mechanisms with therapeutic efficacy, toxicity, and translational barriers. In particular, we examine the unresolved balance between receptor-associated endothelial transport and transient BBB modulation and propose a mechanism-safety-translation framework to guide the rational development of K16ApoE and related peptide shuttles.

Open article ↗

2026-07-30 | Practical aspects of intracerebroventricular infusions of cerliponase alfa in patients with neuronal ceroid lipofuscinosis type 2

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare, autosomal recessive neurodegenerative disorder caused by mutations in the TPP1 gene, which lead to a decrease or complete loss of lysosomal tripeptidyl peptidase 1 enzyme activity. The classic form of CLN2 disease typically manifests between the ages of 2 and 4 years. Over time, there is a rapid and predictably severe progression of intellectual and motor deficits, loss of visual acuity, and an increased frequency of epileptic seizures refractory to antiepileptic therapy. In its natural course, the classic form of CLN2 disease leads to severe disability by 6–7 years of age and death on average during the 10th year of life. Currently, pathogenetic enzyme replacement therapy has been developed only for CLN2 disease, utilizing the drug cerliponase alfa. In Russia, children with CLN2 disease are provided with cerliponase alfa through funding from the “Circle of Kindness”, a state fund supporting children with severe life-threatening and chronic diseases, including rare (orphan) conditions. Cerliponase alfa cannot cross the blood-brain barrier and must be administered directly into the cerebrospinal fluid via intracerebroventricular (ICV) infusion through a surgically implanted reservoir and ventricular catheter. Infectious complications can result in missed ICV infusions, which, in turn, may adversely affect the efficacy of enzyme replacement therapy. To reduce the risk of infectious complications, strict adherence to aseptic rules is essential during patient preparation, as well as during and after the ICV infusion. These practical guidelines for performing ICV infusions of enzyme replacement therapy in patients with CLN2 disease have been developed to implement measures in clinical practice aimed at minimizing the risk of infectious complications and damage to ICV infusion devices.

Open article ↗

2026-03-28 | Patient and Family Perspective on Transition from Ventricular Access Device to Chest-Sited Port for Intracerebroventricular Infusion in CLN2 Disease.

Cerliponase alfa is currently the only approved disease-modifying therapy for neuronal ceroid lipofuscinosis type 2 (CLN2) disease and requires lifelong intracerebroventricular (ICV) infusion, traditionally via a scalp-sited ventricular access device (VAD). Chest-sited port (chest port) for intracerebroventricular access using a tunneled central venous access device is described as an alternative, though data remain limited. We present an anonymized caregiver narrative perspective describing two pediatric patients with CLN2 disease receiving cerliponase alfa infusions via different ICV access strategies: one patient who transitioned from a scalp-based ventricular access device to a chest port and one patient who initiated therapy with a chest port. A semi-structured caregiver interview was used to capture experiential insights related to decision-making, procedural burden, safety considerations, and psychosocial adaptation. The caregiver identified key advantages of chest ports for ICV infusion, including durability of the device, enhanced securement, and smooth long-term routine integration. The transition from a scalp VAD to a chest port was described as proactive, well-coordinated, and associated with high caregiver satisfaction. Noted considerations included increased visibility of the access needle to the child, proximity to oral secretions, and potential misidentification of the port by emergency medical services. Families implemented mitigation strategies through labeling, education, and coordination with the care team. This caregiver-centered case report highlights how access device choice meaningfully shapes treatment burden, safety planning, and daily life for families managing CLN2 disease. As chest-port methodologies become adopted, incorporating caregiver and patient perspectives is essential to developing patient-centered treatment options for long-term intracerebroventricular therapy.

Open article ↗

small molecules

2026-09-19 | Defective ATP13A2-ITCH-ALIX signaling impairs intraluminal vesicle biogenesis and increases neuronal vulnerability.

ATP13A2 is a lysosomal P5B-type ATPase whose loss-of-function mutations are associated with a spectrum of neurodegenerative disorders, including early-onset Parkinson's disease, Kufor-Rakeb syndrome, neuronal ceroid lipofuscinosis, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. Although ATP13A2 is known to contribute to lysosomal homeostasis and, thereby, to neuronal degeneration, emerging evidence suggests that it may also influence exosome biology. However, the mechanisms by which endogenous ATP13A2 regulates exosome biogenesis and the relevance of this process to neuronal vulnerability remain unclear. In the present study, using multiple ATP13A2-deficient human cell models, we demonstrated that ATP13A2 deficiency impairs intraluminal vesicle (ILV) biogenesis and reduces exosome secretion across diverse cellular contexts. Loss of ATP13A2 did not markedly affect endocytosis, early endosome abundance, or multivesicular body formation, but it consistently reduced ILV density within multivesicular bodies. Mechanistically, ATP13A2 deficiency promoted lysosome-associated accumulation of the E3 ubiquitin ligase ITCH, which enhanced ubiquitin-proteasome-dependent degradation of ALG-2-interacting protein X (ALIX), a critical adaptor of the endosomal sorting complex required for transport machinery that mediates ILV membrane remodeling. Restoration of ALIX expression or reduction of Itchy E3 ubiquitin-protein ligase (ITCH) activity rescued the ILV biogenesis defects in ATP13A2-deficient neuronal cells. Furthermore, dysregulation of the ATP13A2-ITCH-ALIX pathway increased neuronal susceptibility to mitochondrial stress, whereas restoration of ALIX or reduction of ITCH activity markedly improved neuronal survival. Together, these results identify an ATP13A2-ITCH-ALIX signaling axis linking lysosomal dysfunction to impaired ILV biogenesis and exosome regulation. Our study suggests that defective ILV biogenesis contributes to neuronal vulnerability and that modulation of the ATP13A2-ITCH-ALIX pathway may represent a therapeutic strategy for ATP13A2-associated neurodegeneration.

Open article ↗

2026-07-20 | Chronic oral cannabidiol delays seizure onset and reduces seizure burden in a mouse model of CLN2 disease.

A growing body of literature describes the anti-inflammatory, neuroprotective, and anti-epileptic properties of the cannabis sativa constituent cannabidiol, suggesting that it might play a useful role in the treatment of neurodegenerative diseases. Late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a rare pediatric neurodegenerative disorder resulting from an inherited dysfunction of the lysosome. CLN2 disease, and its representative animal models, display neuroimmune response, neuroinflammation, neurodegeneration, and epileptic seizures, and these symptoms are all touted as potential targets of cannabidiol therapeutic benefit. Here, we treated a valid model of CLN2 disease with long-term daily cannabidiol (300 mg/kg) from 1 month of age until disease end stage and evaluated epileptic seizures, lifespan, and markers of neuroimmune response. Chronic cannabidiol treatment significantly delayed or fully eliminated seizures in CLN2 model mice compared to those treated with vehicle only, and the treatment led to a non-significant extension of lifespan. These effects occurred in the absence of any therapeutic benefit to physiological markers of disease such as GFAP, CD68, and cytokine/chemokine reactivity. Taken together, we show that chronic treatment with cannabidiol confers significant anti-seizure benefit to the mouse model of CLN2 disease, and that it does not appear to do so by altering the inflammatory and neuroimmune markers traditionally used to track CLN2 disease progression.

Open article ↗

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.

Open article ↗

2026-06-17 | TGFb signaling promotes astroglial activation and TDP-43 proteinopathy in organoid models of frontotemporal lobar degeneration.

Dominant mutations in Progranulin (GRN) gene cause frontotemporal lobar degeneration (FTLD-GRN), whereas homozygous GRN mutations lead to neuronal ceroid lipofuscinosis, a childhood neurodegenerative disorder. While recent transcriptomic studies reveal profound glial and neuronal pathology in FTLD-GRN at the disease end stage, the mechanism that disrupts glia-neuron homeostasis remains unclear. Using induced pluripotent stem cell (iPSC)-derived cortical organoids, we showed that GRN-/- and GRNR493X mutations lead to precocious astrogliosis that promotes neuronal stress and synaptic loss. Single-cell transcriptomics and histopathology analyses revealed a robust activation in TGFb signaling pathway in GRN-/- and GRNR493X/R493X astrocytes, which was accompanied by features of immune activation, loss of synaptic support, and abundant pTDP-43+ fibrils in astroglial cytoplasm, a feature characteristic of FTLD-GRN. Intriguingly, blocking TGFb signaling mitigated astroglial activation and pTDP-43 proteinopathy in GRN-/- organoids. Together, these results provide new insights into the cell-autonomous role of astroglial activation in neurodegeneration caused by Progranulin deficiency.

Open article ↗

2026-05-26 | Topiramate-Responsive Myoclonic Status Epilepticus in a Child with Progressive Myoclonus Epilepsy Due to Neuronal Ceroid Lipofuscinosis Type 8: A Case Report.

Progressive myoclonus epilepsy (PME) is a severe developmental and epileptic encephalopathy characterized by drug-resistant seizures and progressive neurological regression. In the late stage, patients often develop myoclonic status epilepticus (MSE), for which an optimal treatment has not been established. Neuronal ceroid lipofuscinosis type 8 (NCL8), caused by pathogenic variants in the CLN8 gene, is a rare lysosomal disorder that can present with PME. However, published clinical experience is limited. We report the case of a boy with PME due to NCL8 who developed recurrent MSE with respiratory compromise and showed clinical improvement following the introduction of oral topiramate. He had developmental delays from late infancy, onset of epilepsy at three years of age, and multiple seizure types, including myoclonic seizures, generalized tonic-clonic seizures, and atypical absence seizures. Neurological regression progressed, and the patient became bedridden by 6 years of age. NCL8 was diagnosed based on the presence of a known pathogenic CLN8 variant and autofluorescent storage material in lysosomes identified on skin biopsy. At nine years of age, frequent and prolonged myoclonic seizures, confirmed by long-term video electroencephalography (EEG), occurred repeatedly with oxygen desaturation, requiring intensive care with continuous midazolam infusion. Despite escalation of antiseizure medication therapy, MSE persisted. After the initiation and titration of oral topiramate, the duration and frequency of myoclonic events decreased, allowing successful withdrawal of the continuous midazolam infusion. No further MSE occurred during an 8-month follow-up period, although occasional isolated myoclonic events persisted. Therefore, topiramate may be a useful therapeutic option for MSE in children with PME due to NCL8.

Open article ↗

gene therapies

2026-09-14 | Late infantile neuronal ceroid lipofuscinosis type 6 (CLN6) in Three Children from El salvador: a case series

Rationale Neuronal Ceroid Lipofuscinosis (NCL) is a group of rare, genetic, neurodegenerative disorders with fatal outcomes. Disease-causing variants occur in more than a dozen genes and produce distinct ages of onset and clinical courses. CLN6-related disease typically presents in the late-infantile period with motor regression, cognitive decline, progressive visual impairment, and drug-resistant epilepsy. We describe a case series of three children with genetically confirmed CLN6 disease from the Department of Morazán, El Salvador. Methods We retrospectively reviewed the clinical histories, examinations, EEGs, and brain MRIs of three patients (two brothers and one unrelated girl) from the Department of Morazán, El Salvador, evaluated jointly by child neurologists from the United States and El Salvador. Clinical data collected included age and character of disease onset, seizure semiology and treatment response, and ophthalmological findings. Diagnosis was suspected clinically and confirmed by next-generation sequencing (NGS) gene-panel testing (Invitae Epilepsy Panel, Invitae Corporation); there was no copy-number/deletion-duplication analysis included. Parental segregation testing was offered but could not be completed due to cost; segregation of the variant with disease was therefore not confirmed. Results Three patients were diagnosed with CLN6. All patients live in the Department of Morazan, located in the northeastern part of El Salvador (close to Honduras). All three patients had normal development, until the onset of unrelenting motor regression. The boys had an onset of symptoms at the age of 4 years and the girl at age of 5 years. This was followed by cognitive regression, progressive visual impairment, and the onset of drug-resistant epilepsy (DRE) 1 year after onset of symptoms. Initial MRI of the brain of one out of three patients was reviewed and reported as normal, and two out of three already showed cerebral atrophy. EEGs showed a slow background with fragmented and generalized spike wave discharges, and photoparoxysmal responses were present in all patients. Individual clinical, EEG, MRI, and genetic findings are summarized in Table 1. Genetic testing identified the same homozygous CLN6 missense variant, NM_017882.3:c.368G>A (p.Gly123Asp), in all three patients; American College of Medical Genetics and Genomics (ACMG) classification as likely pathogenic. Conclusion These three cases add clinical and molecular data on late-infantile CLN6 disease from a previously undocumented region of Central America. Based on a structured literature search, these appear to be the first molecularly confirmed cases of CLN6 disease reported from El Salvador; this cannot be considered a definitive claim given the possibility of undiagnosed or unpublished cases. Given the small sample size and the inclusion of two siblings, these findings cannot establish disease prevalence or a founder effect in this population; this remains a hypothesis for future investigation.

Open article ↗

2026-09-03 | Disruptions in speech, language and social communication in lysosomal storage diseases.

Communication enables social connection, autonomy and identity, making it a fundamental domain of human functioning. In lysosomal storage diseases (LSDs), progressive neurological dysfunction can severely disrupt speech, language and social communication, resulting in profound isolation and reduced quality of life. LSDs are a heterogeneous group of more than 70 inherited metabolic disorders caused by lysosomal dysfunction and substrate accumulation, leading to severe neurological consequences and multisystem pathology. LSDs are classified according to the biochemical nature of the accumulating substrate, reflecting both the underlying enzymatic defect and clinical phenotype. Disease groups include sphingolipidoses (e.g., Gaucher disease), mucopolysaccharidoses (e.g., Hurler syndrome [MPS I]), glycoproteinoses (e.g., aspartylglycosaminuria), gangliosidoses (e.g., Tay-Sachs disease), neuronal ceroid lipofuscinoses (e.g., Batten Disease [CLN3]) and other lipid storage disorders such as Pompe disease or Niemann Pick Type C. Clinical presentations are highly variable, with neurodevelopmental symptoms presenting in infancy or early childhood for many. In this review, we synthesize evidence on speech, language, and social communication phenotypes across lysosomal storage diseases, examining how they can mirror underlying neurodegenerative processes and provide insight into disease progression and neurological vulnerability. We discuss the potential of communication phenotyping to improve diagnosis and prognostic stratification, inform therapeutic monitoring, and guide timely, targeted interventions to preserve social connection and quality of life.

Open article ↗

2026-09-01 | A rare cause of variant late-infantile neuronal ceroid lipofuscinosis: CLN8-related disease

Neuronal Ceroid Lipofuscinosis (NCL) is a rare, inherited lysosomal storage disorder characterized by the accumulation of lipofuscin within neuronal cells, leading to progressive neurodegeneration. It is caused by pathogenic variants in at least 14 known genes, resulting in distinct clinical phenotypes. Neuronal ceroid lipofuscinosis presents with varying phenotypes depending on the age of onset and the underlying pathogenic gene variant. This case report highlights a 7-year-old boy with a variant form of late-infantile NCL, caused by a pathogenic variant in the CLN8 gene, who developed developmental regression, seizures, motor dysfunction, and vision loss. This case emphasizes the importance of early recognition, genetic testing, and MRI evaluation for timely diagnosis and management of NCL. It also underscores the need for interdisciplinary collaboration involving neurologists, geneticists, and radiologists in managing patients with neurodegenerative disorders like NCL. Early diagnosis can aid in genetic counseling, family planning, and potential intervention strategies.

Open article ↗

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.

Open article ↗

2026-04-16 | [Clinical features of 13 children with neuronal ceroid lipofuscinosis type 2].

Clinical data were retrospectively collected from 13 children with type 2 neuronal ceroid lipofuscinosis (CLN2) who underwent genetic testing for definitive diagnosis and were followed up at the Chinese PLA General Hospital from January 2018 to December 2023. The clinical features, disease progression, and prognosis were analyzed. The age at onset was [M(Q1, Q3)] 3.7 (3.2, 4.5) years, including 7 males and 6 females. The follow-up was conducted once every 3 months during the first 2 years after diagnosis, and once every 6 months starting from the 3rd year, with the last follow-up until December 2025. All patients presented with epilepsy as the initial manifestation, of whom 8 patients had myoclonic seizures. Psychomotor regression occurred in 10 patients shortly after seizure onset. Tripeptidyl peptidase 1 (TPP1) activity was below the normal reference range in all patients, and all harbored biallelic pathogenic or likely pathogenic variants in the TPP1 gene. Brain magnetic resonance imaging revealed cerebellar atrophy in all cases, and electroencephalography demonstrated generalized abnormalities in all patients. Disease progression exhibited relatively distinct stage-wise features. Within>1-2 years of onset, eleven patients developed ataxia and 10 experienced language regression. Within>2-3 years, ten patients had lost independent ambulation and 9 had lost language function. Within>3-5 years, all patients lost motor and language abilities, and 10 developed severe dysphagia. Five patients died during follow-up. In conclusion, CLN2 typically presents in early childhood with epilepsy as the predominant initial manifestation, followed by progressive neurofunctional decline and cerebellar atrophy. Markedly reduced TPP1 activity together with pathogenic TPP1 variants supports the diagnosis.

Open article ↗

other

2025-11-05 | Therapeutic antisense oligonucleotide mitigates retinal dysfunction in a pig model of CLN3 Batten disease.

CLN3 Batten disease is a lethal pediatric neurodegenerative disease caused by mutations in the CLN3 gene. Typically, the disease manifests as vision loss in early childhood and progresses to neurological dysfunction and death in young adulthood. Most therapeutic developments have focused on treating the brain and may not protect against vision loss, which greatly affects quality of life. We have previously 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 apply a similar ASO approach for treating retinal dysfunction in a pig model of CLN3 Batten 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 conserved in humans, making it a promising candidate for clinical translation. Our findings demonstrate the utility of an ASO-based approach to treat retinal dysfunction in CLN3 Batten disease and support broader ASO applications for treating ocular diseases.

Open article ↗

2025-09-01 | Discovery ofFunctionalized 1H‑Benzo[d]imidazoles That Confer Protective Effects in a PhenotypicCLN3 Disease Patient-Derived iPSC Model

The neuronal ceroid lipofuscinoses (NCLs) are rare and fatal autosomal pediatric neurodegenerative disorders. The most prevalent subtype, CLN3, arises from a mutation in the CLN3 gene. Common phenotypic hallmarks include lipofuscin and subunit c of mitochondrial ATP synthase accumulation, mitochondrial dysfunction, and reduced Bcl-2 expression, however the underlying pathophysiology is not well understood. No effective treatment option exists. Herein, we report the synthesis and characterization of bicyclic analogues of the bioisosteric non-opioid analgesics Flupirtine and Retigabine, previously shown to exhibit neuroprotective effects. These analogues were strategically modified to prevent formation of toxic reactive diamine/diimine intermediates characteristic of the parent compounds. Novel 1H-benzo­[d]­imidazoles that do not incur this metabolic liability are reported that possess enhanced protective effects in a highly phenotypic CLN3 patient-derived induced pluripotent stem cell (iPSC) model. Selected lead compounds 9b and 38b afforded significant protective effect and reduced phenotypic hallmarks of CLN3 pathology while also possessing “drug-like” pharmacokinetics.

Open article ↗

2025-07-28 | Milasen: The Emerging Era of Patient-Customized N-of-1 Antisense Oligonucleotides as Therapeutic Agents for Genetic Diseases.

Antisense oligonucleotide (AON) therapy has shown great promise in recent years for the treatment of numerous diseases, primarily in the neuromuscular field. While most often discussed in the context of diseases where AONs are already approved for use, AON therapy also serves as an ideal therapeutic modality for ultrarare N-of-1 genetic diseases given its sequence-specific nature and high degree of customization to an individual mutation. Batten disease is a debilitating and fatal neurodegenerative disease affecting children, characterized by impaired lysosomal storage and progressive neurodegeneration. No cure exists for this disease, and there remains an unmet medical need for effective therapeutics for Batten disease. In this chapter, we outline the landmark N-of-1 development of milasen, an antisense oligonucleotide therapy for a single patient with Batten disease. We highlight the development of milasen, as well as the suitability and limitations of antisense oligonucleotides for N-of-1 therapies and other personalized medicines. We also discuss the current state of N-of-1 therapy development, and how the history of milasen has contributed to the ongoing development of other N-of-1 therapies including atipeksen.

Open article ↗

2025-05-19 | Click-constructed modular signal aptamer chimeras enable receptor-independent degradation of membrane proteins.

Cell-membrane proteins are critical mediators of signal transduction, playing essential roles in disease occurrence and progression. The emerging LYTACs (Lysosome-targeting chimeras) technology combines drug-targeting strategies with lysosomal degradation, providing a novel approach to drug development and offering new possibilities for disease therapy. However, the clinical applicability of current LYTAC degraders is limited by the variable expression of lysosome-targeting receptors (LTRs) in tissues. To overcome this limitation, we herein hijacked a YXXØ sorting signal that derived from lysosome-associated membrane protein 2a (LAMP-2a) to develop a signal aptamer platform (SApt), which exhibits high specificity for targeting membrane proteins and inducing efficient lysosomal degradation. SApts were synthesized by conjugating the YXXØ signal peptide to the aptamer's terminus through a click reaction. Our study demonstrated that SApts efficiently degrade disease-associated membrane proteins, such as PTK7, Met, and NCL, based on the inherent signals rather than specific LTR. The potent antitumor efficacy of SApts was further confirmed in a xenograft tumor model, where in vivo degradation of PTK7 was observed. Collectively, our work provides insights into the development of a simple and universal lysosomal degradation platform with potential translational value in clinical treatment.

Open article ↗

2017-05-02 | A tailored mouse model of CLN2 disease: A nonsense mutant for testing personalized therapies

The Neuronal Ceroid Lipofuscinoses (NCLs), also known as Batten disease, result from mutations in over a dozen genes. Although, adults are susceptible, the NCLs are frequently classified as pediatric neurodegenerative diseases due to their greater pediatric prevalence. Initial clinical presentation usually consists of either seizures or retinopathy but develops to encompass both in conjunction with declining motor and cognitive function. The NCLs result in premature death due to the absence of curative therapies. Nevertheless, preclinical and clinical trials exist for various therapies. However, the genotypes of NCL animal models determine which therapeutic approaches can be assessed. Mutations of the CLN2 gene encoding a soluble lysosomal enzyme, tripeptidyl peptidase 1 (TPP1), cause late infantile NCL/CLN2 disease. The genotype of the original mouse model of CLN2 disease, Cln2-/-, excludes mutation guided therapies like antisense oligonucleotides and nonsense suppression. Therefore, the purpose of this study was to develop a model of CLN2 disease that allows for the assessment of all therapeutic approaches. Nonsense mutations in CLN2 disease are frequent, the most common being CLN2R208X. Thus, we created a mouse model that carries a mutation equivalent to the human p.R208X mutation. Molecular assessment of Cln2R207X/R207X tissues determined significant reduction in Cln2 transcript abundance and TPP1 enzyme activity. This reduction leads to the development of neurological impairment (e.g. tremors) and neuropathology (e.g. astrocytosis). Collectively, these assessments indicate that the Cln2R207X/R207X mouse is a valid CLN2 disease model which can be used for the preclinical evaluation of all therapeutic approaches including mutation guided therapies.

Open article ↗