RARE DISEASE
CLN2 disease
CLN2 disease
CLN2 disease
Synonyms: Neuronal ceroid cipofuscinosis type 2
Synonyms: Neuronal ceroid cipofuscinosis type 2
Synonyms: Neuronal ceroid cipofuscinosis type 2
Drug discovery
2
drugs
With orphan designations
Overview
CLN2 disease is a rare autosomal recessive neurodegenerative lysosomal disorder caused by TPP1 mutations, leading to tripeptidyl peptidase 1 deficiency. Classic presentation involves onset at 2–4 years with language delay, drug-resistant epilepsy, rapid motor/cognitive decline, vision loss, and death by early adolescence. Atypical forms show later onset and slower progression. Diagnosis requires TPP1 enzyme activity testing and genetic confirmation. Enzyme replacement therapy (cerliponase alfa) delays functional decline when initiated early [1][5][6][14].
Burden
Mortality: Median survival 10.1 years; rare survival past teens [8][13].
Caregiver impact: High caregiving hours (>12/day), reduced parental QoL, financial strain, and psychological distress [2][4].
Healthcare systems: Delayed diagnosis (average age 5 years), limited access to diagnostics/therapies in low-resource settings [1][5][18].
Therapies
Enzyme replacement therapy: Intracerebroventricular cerliponase α (approved in 2017) stabilizes motor/language function [1][3][14].
Supportive care: Multidisciplinary management (AEDs for seizures, mobility support, gastrostomy for dysphagia, palliative care) [4][7][16].
Emerging therapies: Gene therapy and substrate reduction therapies in clinical trials [3][11][14].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
225 drug discovery papers about CLN2 disease, with 5 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
225 drug discovery papers about CLN2 disease, with 5 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
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.
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.
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.
2025-11-18 | Chronic oral cannabidiol delays or prevents seizures in a mouse model of CLN2 disease
Abstract 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 (300mg/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 mice compared to those treated with vehicle only, and the treatment led to a nearly 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.
2025-08-27 | Whole-organism screening in a zebrafish model of CLN2 disease identifies pregnenolone as a modulator of lysosomal functions with anti-epileptic properties
Abstract Lysosomal storage disorders (LSDs), a group of inherited genetic diseases, are often associated with early-onset neurodegeneration and refractory epileptic seizures. In CLN2 disease, an LSD caused by recessively inherited dysfunction of lysosomal serine protease Tripeptidyl Peptidase 1 (TPP1), lysosomes are functionally impaired through a characteristic accumulation of subcellular materials. Here, we develop and apply a whole-organism screening workflow in tpp1 -/- zebrafish to identify small molecules that suppress epileptic seizures — a hallmark of the human disease — in this model. Among 640 US Food and Drug Administration-approved drugs, pregnenolone, an endogenous precursor for steroid biosynthesis, efficiently suppresses seizures and cell death in tpp1 -/- zebrafish. Using a semi-automated high-content workflow, we further show that pregnenolone normalizes lysosomal architecture in tpp1 -/- zebrafish. Pregnenolone stimulates steroid hormone biosynthesis and related gene expression, which is dysregulated in tpp1 -/- zebrafish. Taken together, tpp1 -/- zebrafish are a suitable model to study CLN2 disease, in which we have identified pregnenolone as a candidate with therapeutic properties.
cell therapies
2024-10-29 | 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.
2021-02-25 | Extracellular Vesicles as Drug Carriers for Enzyme Replacement Therapy to Treat CLN2 Batten Disease: Optimization of Drug Administration Routes.
CLN2 Batten disease (BD) is one of a broad class of lysosomal storage disorders that is characterized by the deficiency of lysosomal enzyme, TPP1, resulting in a build-up of toxic intracellular storage material in all organs and subsequent damage. A major challenge for BD therapeutics is delivery of enzymatically active TPP1 to the brain to attenuate progressive loss of neurological functions. To accomplish this daunting task, we propose the harnessing of naturally occurring nanoparticles, extracellular vesicles (EVs). Herein, we incorporated TPP1 into EVs released by immune cells, macrophages, and examined biodistribution and therapeutic efficacy of EV-TPP1 in BD mouse model, using various routes of administration. Administration through intrathecal and intranasal routes resulted in high TPP1 accumulation in the brain, decreased neurodegeneration and neuroinflammation, and reduced aggregation of lysosomal storage material in BD mouse model, CLN2 knock-out mice. Parenteral intravenous and intraperitoneal administrations led to TPP1 delivery to peripheral organs: liver, kidney, spleen, and lungs. A combination of intrathecal and intraperitoneal EV-TPP1 injections significantly prolonged lifespan in BD mice. Overall, the optimization of treatment strategies is crucial for successful applications of EVs-based therapeutics for BD.
2019-08-28 | Outcomes of Umbilical Cord Blood Transplantation in Children with Batten Disease
Introduction Neuronal ceroid lipofuscinoses (NCL, Batten Disease) are a class of lysosomal storage diseases caused by mutations in ceroid lipofuscinoses (CLN) genes. Neurological deterioration is influenced by the CLN subtype, but death typically occurs in childhood. Symptoms include visual impairment, behavioral changes, loss of motor and/or cognitive skills, and seizures. Umbilical cord blood transplant (UCBT) is effective in treating many lysosomal storage disorders but there is very limited experience in BD. Methods We retrospectively studied 6 patients (pt) with BD receiving UCBT between the ages of 4 months and 8.6 years at our center. All received myeloablative conditioning with busulfan, cyclophosphamide and ATG. Cyclosporine and mycophenolate were given for prophylaxis of GVHD. Pts 5 and 6 were concomitantly enrolled on clinical trial (NCT02254863) and also received intra-thecal injection of DUOC-01 cells after hematologic engraftment. Selected patient and donor characteristics are shown in Table 1: Results Patients received UCB grafts matching at 4/6-6/6 loci with a median pre-cryo cell dose of 7.2 (range, 5.1-35.1) x107 cells/kg. All pts engrafted neutrophil and platelets in a median of 25 (range, 12-34) and 39 days (range, 32-105), respectively. Four patients developed Grade 2-4 acute GvHD and 2 developed extensive chronic GvHD. Pt 1, the only patient transplanted after severe neurologic decline with advanced disease, died from progressive BD and aseptic shock 12 months post-UCBT. All others are alive at a median of 3.8 years (range, 0.5-5.5). Pt 2 has normal motor function, is nonverbal and was diagnosed with autism 2 years post UCBT. Her brain MRI is normal to date. Pt 3 is blind, has had occasional seizures, requires educational support and has no MRI evidence of BD. Pts 4 and 5 have age appropriate neurocognition, no seizures, and receive only visual support in school. Both have normal MRIs. It is too early to assess neurologic outcomes in Pt 6 (7 months post-UCBT). Conclusion UCBT is feasible in children with BD. At a median follow up of 3.8 years (range, 0.5-5.5), 5/6 patients are alive and 4/5 are neuro-cognitively stable and one developed new onset seizures post-transplant. All 5 surviving pts have no MRI evidence of disease. With the inherent variability of the different forms of BD, additional pts and continued follow-up is needed to fully understand the effect of UCBT on the natural history of BD.
2016-11-01 | Intravitreal implantation of TPP1-transduced stem cells delays retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis
The CLN2 form of neuronal ceroid lipofuscinosis is a neurodegenerative disease that results from mutations in the TPP1 gene. Affected children exhibit progressive declines in most neurological functions including vision. Functional declines are accompanied by progressive brain and retinal atrophy. TPP1 encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Dachshunds with a TPP1 null mutation exhibit a disorder very similar to human CLN2 disease. Periodic infusion of recombinant TPP1 protein or a single injection of a TPP1 gene therapy vector into the cerebrospinal fluid of affected dogs significantly delays the onset and progression of neurological signs but does not slow vision loss or retinal degeneration. Studies were conducted to determine whether intravitreal implantation of autologous bone marrow derived stem cells transduced with a TPP1 expression construct would inhibit retinal degeneration in the canine model. A single injection of the transduced cells at an early stage in the disease progression substantially inhibited the development of disease-related retinal function deficits and structural changes. No adverse effects of the treatment were detected. These findings indicate that ex vivo gene therapy using autologous stem cells is an effective means of achieving sustained delivery of therapeutic compounds to tissues such as the retina for which systemic administration would be ineffective.
2015-07-27 | Investigative and emerging treatments for Batten disease
Introduction: The neuronal ceroid lipofuscinoses (NCLs, or Batten disease) are a group of inherited neurodegenerative storage disorders that mostly affect children and young adults. Because no effective therapies are currently available, all prove fatal after a period of prolonged disability.Areas covered: This review details the progress toward devising experimental therapies for the different forms of NCL. These approaches differ according to whether the gene defects are in soluble lysosomal enzymes or transmembrane proteins, but include enzyme replacement, gene therapy, neural stem cell approaches and small-molecule treatments. Not knowing the function of many of the gene products hampers the ability to produce a mechanistic-based therapy, especially in transmembrane-deficient forms of NCL.Expert opinion: Promising progress has been made in preclinical studies for several forms of NCL, which has led to the initiation of clinical trials of several different experimental therapies. Nevertheless, challenges remain in how such preclinical advances can be translated successfully into a clinical setting. As new data about pathogenesis emerge it is likely that combination therapies that target different regions of the brain and/or body or different parts of the pathological cascade will be needed.
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.
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.
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.
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.
2026-03-01 | 4CPS-289 Disease is rare, suffering is for everyone: a case report
Background and Importance
CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. It has a devastating impact on children and families, leading to rapid functional decline and early death without effective treatment: early diagnosis and treatment of CLN2 disease are therefore vital to preserve function and slow decline for as long as possible. Cerliponase alfa, a recombinant form of the human TPP1 enzyme, is designed to replace the missing or deficient TPP1 enzyme in patients with CLN2 disease.
Aim and Objectives
This report will discuss the case of a patient who is responding to treatment, initiated in 2021.
Material and Methods
The patient is a little woman born in 2005. It was created of a custom pharmacological protocol, with continuous monitoring parameters vital, before during and after drug administration.
Results
The drug is stored at -20°C. Cerliponase alfa is administered, by clinician, by means of intracerebroventricular (ICV) infusion. The standard regimen involves a dose of 300 mg infused over approximately 4 hours, every 2 weeks. After verifying the clinical conditions, the doctor proceeds to prescribe the drug on the information system, on the date scheduled for administration. The treatment is taken care of and prepared at the Clinical Pharmacy laboratory. Once the chemical characteristics of the finished product have been verified, it is delivered to the department for subsequent administration.
Conclusion and Relevance
The Clinical Pharmacy Laboratory guarantees sterility and asepticity in the preparation of the drug. Administration is bimonthly, but temporary suspensions due to infections have occurred: the ICV delivery system, in fact, involves potential risks, in particular device-related complications, such as infections, which may require antibiotic treatment or device replacement. Despite this, the patient, in accordance with registered studies, appears to show a slower worsening of symptoms. This confirms the importance of encouraging and supporting clinical research, especially in rare diseases, which are often difficult to recognise and treat.
Conflict of Interest
No conflict of interest
gene therapies
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.
2025-12-08 | Incidence and timing of diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2): A nationwide study using the French hospital discharge database.
Neuronal ceroid lipofuscinoses (NCLs) are rare, progressive lysosomal neurodegenerative disorders. Among late-infantile onset forms (after 18 months of age), type 2 (CLN2 disease) is the most frequent. This study assessed the incidence and disease burden at diagnosis of CLN2 disease in France. This was a nationwide, population-based, retrospective study including all patients identified with CLN2 disease in the French Hospital Discharge Database (Programme de Médicalisation des Systèmes d'Information, PMSI) from January 2015 to December 2023. After a 2-year washout period to exclude prevalent patients, 51 children were considered to have been diagnosed with CLN2 disease over 7 years (2017-2023). Based on national birth statistics, this corresponds to an incidence of 0.99 cases of CLN2 disease per 100,000 live births. Median age at diagnosis was 5 years (interquartile range, 3-8), with a mean diagnostic delay of 19.1 ± 19.8 months from the first coded symptoms. Epilepsy (90.2 %) and intellectual disability (86.3 %) were the most frequently coded comorbidities. Of the 51 children, 84.3 % were hospitalized via emergency care, and 45.1 % required intensive care. Overall, 13 deaths (25.5 %) were reported, with median age at death of 9 years. This is the first nationwide epidemiological assessment of CLN2 disease in France. The results demonstrate substantial diagnostic delays and disease burden, underscoring the need for earlier diagnosis and referral to expert centers to optimize care and offer genetic counseling to parents before conceiving subsequent offspring.
2025-10-03 | Exploring Prime Editing strategies for genetic correction of a Ceroid Neuronal Lipofuscinosis type 2 disease causing variant
ABSTRACT Neuronal ceroid lipofuscinosis type 2 (CLN2) is a rare, fatal paediatric neurodegenerative genetic disease that causes progressive psychomotor decline, epilepsy, speech impairment, vision loss, and premature death by late childhood or early adolescence. It is caused by mutations in the TPP1 gene, which encodes the tripeptidyl peptidase 1 enzyme. To date, enzyme replacement therapy (ERT) with recombinant human TPP1 is the only approved treatment available and it does not appear to have a curative effect on disease progression or rescuing complex motor functions. This underscores the importance of developing more effective treatment strategies for CLN2 disease. In the quest for an alternative therapy, we here seek to utilise CRISPR based prime editing (PE) to correct one of the most frequent TPP1 mutations of c.622 C>T (p. Arg208Ter). In cultured mammalian HEK293a cells we screened 16 different PE and pegRNA combinations, achieving on-target editing efficiencies up to 27.36 %. To enable efficient in vivo gene editing, we packaged the most promising PE and pegRNA combination using engineered virus-like particles (eVLPs) which resulted in 12.6 % on-target editing. Given the robust on-target editing and reduced risk of bystander editing, PE is deemed suitable for in vivo testing in the pre-clinical models for CLN2 disease. Overall, our findings establish the proof of concept for CRISPR-based prime editing to correct pathogenic human TPP1 nonsense mutation of c.622 C>T (p. R208X) and provide a basis for further investigations of PE as a genetic treatment for CLN2 disease.
2025-07-25 | Recreating pathophysiology of CLN2 disease and demonstrating reversion by TPP1 gene therapy in hiPSC-derived retinal organoids and retina-on-chip.
Mutations in the tripeptidyl peptidase 1 (TPP1) gene lead to neuronal ceroid lipofuscinosis type 2 (CLN2), characterized by lysosomal accumulation of lipofuscins predominantly in the brain and retina. The ocular phenotype is characterized by outer retinal degeneration that leads to vision loss. Leveraging human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs), retinal pigmented epithelial cells, and the retina-on-chip system, we establish an in vitro CLN2 model that recreates the principal histological hallmarks, namely the accumulation of subunit C of mitochondrial ATP synthase (SCMAS) and lipids mainly in the outer retina. Furthermore, single-cell RNA sequencing reveals a dysregulation of translational and mitochondrial function in CLN2 cones. Finally, adeno-associated virus (AAV)-mediated TPP1 gene therapy can restore TPP1 expression and decrease and even prevent SCMAS accumulations. Our study uses an innovative human-relevant microphysiological retinal disease models, uncovers previously uncharacterized mechanisms of CLN2 pathophysiology, and demonstrates the potential of AAV9.hCLN2 gene therapy for CLN2 disease, potentially treating patient blindness.
2025-01-17 | Speech, Language and Non-verbal Communication in CLN2 and CLN3 Batten Disease.
CLN2 and CLN3 diseases, the most common types of Batten disease (also known as neuronal ceroid lipofuscinosis), are childhood dementias associated with progressive loss of speech, language and feeding skills. Here we delineate speech, language, non-verbal communication and feeding phenotypes in 33 individuals (19 females) with a median age of 9.5 years (range 3-28 years); 16 had CLN2 and 17 CLN3 disease; 8/15 (53%) participants with CLN2 and 8/17 (47%) participants with CLN3 disease had speech and language impairments prior to genetic diagnosis. At the time of study all participants, bar one, had language impairments. The remaining participant with typical language was tested at age 3 years, following pre-symptomatic enzyme replacement therapy (ERT) from age 9 months. CLN2 and CLN3 disease had different profiles. For CLN2 disease, all affected individuals showed language impairment with dysarthria; older individuals with classical disease progressively became non-verbal. For CLN3 disease, the presentation was more heterogeneous. Speech impairment was evident early in the disease course, with dysarthria (13/15, 87%), often manifesting as neurogenic stuttering (5/15, 33%). Participants with CLN2 disease had comparable expressive and receptive language skills (p > 0.99), yet participants with CLN3 disease had stronger expressive language than receptive language skills (p = 0.004). Speech, cognitive and language impairment and adaptive behaviour showed progressive decline in both diseases. Individuals with pre-symptomatic ERT or atypical CLN2 disease were less impaired. Challenging behaviours were common in CLN3 (11/17, 65%), but less frequent in CLN2 (4/16, 25%) disease. Individuals with Batten disease require tailored speech therapy incorporating communication partner training utilising environment adaptations and informal communication behaviours.
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.
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.
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.
2025-11-18 | Chronic oral cannabidiol delays or prevents seizures in a mouse model of CLN2 disease
Abstract 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 (300mg/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 mice compared to those treated with vehicle only, and the treatment led to a nearly 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.
2025-08-27 | Whole-organism screening in a zebrafish model of CLN2 disease identifies pregnenolone as a modulator of lysosomal functions with anti-epileptic properties
Abstract Lysosomal storage disorders (LSDs), a group of inherited genetic diseases, are often associated with early-onset neurodegeneration and refractory epileptic seizures. In CLN2 disease, an LSD caused by recessively inherited dysfunction of lysosomal serine protease Tripeptidyl Peptidase 1 (TPP1), lysosomes are functionally impaired through a characteristic accumulation of subcellular materials. Here, we develop and apply a whole-organism screening workflow in tpp1 -/- zebrafish to identify small molecules that suppress epileptic seizures — a hallmark of the human disease — in this model. Among 640 US Food and Drug Administration-approved drugs, pregnenolone, an endogenous precursor for steroid biosynthesis, efficiently suppresses seizures and cell death in tpp1 -/- zebrafish. Using a semi-automated high-content workflow, we further show that pregnenolone normalizes lysosomal architecture in tpp1 -/- zebrafish. Pregnenolone stimulates steroid hormone biosynthesis and related gene expression, which is dysregulated in tpp1 -/- zebrafish. Taken together, tpp1 -/- zebrafish are a suitable model to study CLN2 disease, in which we have identified pregnenolone as a candidate with therapeutic properties.
cell therapies
2024-10-29 | 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.
2021-02-25 | Extracellular Vesicles as Drug Carriers for Enzyme Replacement Therapy to Treat CLN2 Batten Disease: Optimization of Drug Administration Routes.
CLN2 Batten disease (BD) is one of a broad class of lysosomal storage disorders that is characterized by the deficiency of lysosomal enzyme, TPP1, resulting in a build-up of toxic intracellular storage material in all organs and subsequent damage. A major challenge for BD therapeutics is delivery of enzymatically active TPP1 to the brain to attenuate progressive loss of neurological functions. To accomplish this daunting task, we propose the harnessing of naturally occurring nanoparticles, extracellular vesicles (EVs). Herein, we incorporated TPP1 into EVs released by immune cells, macrophages, and examined biodistribution and therapeutic efficacy of EV-TPP1 in BD mouse model, using various routes of administration. Administration through intrathecal and intranasal routes resulted in high TPP1 accumulation in the brain, decreased neurodegeneration and neuroinflammation, and reduced aggregation of lysosomal storage material in BD mouse model, CLN2 knock-out mice. Parenteral intravenous and intraperitoneal administrations led to TPP1 delivery to peripheral organs: liver, kidney, spleen, and lungs. A combination of intrathecal and intraperitoneal EV-TPP1 injections significantly prolonged lifespan in BD mice. Overall, the optimization of treatment strategies is crucial for successful applications of EVs-based therapeutics for BD.
2019-08-28 | Outcomes of Umbilical Cord Blood Transplantation in Children with Batten Disease
Introduction Neuronal ceroid lipofuscinoses (NCL, Batten Disease) are a class of lysosomal storage diseases caused by mutations in ceroid lipofuscinoses (CLN) genes. Neurological deterioration is influenced by the CLN subtype, but death typically occurs in childhood. Symptoms include visual impairment, behavioral changes, loss of motor and/or cognitive skills, and seizures. Umbilical cord blood transplant (UCBT) is effective in treating many lysosomal storage disorders but there is very limited experience in BD. Methods We retrospectively studied 6 patients (pt) with BD receiving UCBT between the ages of 4 months and 8.6 years at our center. All received myeloablative conditioning with busulfan, cyclophosphamide and ATG. Cyclosporine and mycophenolate were given for prophylaxis of GVHD. Pts 5 and 6 were concomitantly enrolled on clinical trial (NCT02254863) and also received intra-thecal injection of DUOC-01 cells after hematologic engraftment. Selected patient and donor characteristics are shown in Table 1: Results Patients received UCB grafts matching at 4/6-6/6 loci with a median pre-cryo cell dose of 7.2 (range, 5.1-35.1) x107 cells/kg. All pts engrafted neutrophil and platelets in a median of 25 (range, 12-34) and 39 days (range, 32-105), respectively. Four patients developed Grade 2-4 acute GvHD and 2 developed extensive chronic GvHD. Pt 1, the only patient transplanted after severe neurologic decline with advanced disease, died from progressive BD and aseptic shock 12 months post-UCBT. All others are alive at a median of 3.8 years (range, 0.5-5.5). Pt 2 has normal motor function, is nonverbal and was diagnosed with autism 2 years post UCBT. Her brain MRI is normal to date. Pt 3 is blind, has had occasional seizures, requires educational support and has no MRI evidence of BD. Pts 4 and 5 have age appropriate neurocognition, no seizures, and receive only visual support in school. Both have normal MRIs. It is too early to assess neurologic outcomes in Pt 6 (7 months post-UCBT). Conclusion UCBT is feasible in children with BD. At a median follow up of 3.8 years (range, 0.5-5.5), 5/6 patients are alive and 4/5 are neuro-cognitively stable and one developed new onset seizures post-transplant. All 5 surviving pts have no MRI evidence of disease. With the inherent variability of the different forms of BD, additional pts and continued follow-up is needed to fully understand the effect of UCBT on the natural history of BD.
2016-11-01 | Intravitreal implantation of TPP1-transduced stem cells delays retinal degeneration in canine CLN2 neuronal ceroid lipofuscinosis
The CLN2 form of neuronal ceroid lipofuscinosis is a neurodegenerative disease that results from mutations in the TPP1 gene. Affected children exhibit progressive declines in most neurological functions including vision. Functional declines are accompanied by progressive brain and retinal atrophy. TPP1 encodes the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Dachshunds with a TPP1 null mutation exhibit a disorder very similar to human CLN2 disease. Periodic infusion of recombinant TPP1 protein or a single injection of a TPP1 gene therapy vector into the cerebrospinal fluid of affected dogs significantly delays the onset and progression of neurological signs but does not slow vision loss or retinal degeneration. Studies were conducted to determine whether intravitreal implantation of autologous bone marrow derived stem cells transduced with a TPP1 expression construct would inhibit retinal degeneration in the canine model. A single injection of the transduced cells at an early stage in the disease progression substantially inhibited the development of disease-related retinal function deficits and structural changes. No adverse effects of the treatment were detected. These findings indicate that ex vivo gene therapy using autologous stem cells is an effective means of achieving sustained delivery of therapeutic compounds to tissues such as the retina for which systemic administration would be ineffective.
2015-07-27 | Investigative and emerging treatments for Batten disease
Introduction: The neuronal ceroid lipofuscinoses (NCLs, or Batten disease) are a group of inherited neurodegenerative storage disorders that mostly affect children and young adults. Because no effective therapies are currently available, all prove fatal after a period of prolonged disability.Areas covered: This review details the progress toward devising experimental therapies for the different forms of NCL. These approaches differ according to whether the gene defects are in soluble lysosomal enzymes or transmembrane proteins, but include enzyme replacement, gene therapy, neural stem cell approaches and small-molecule treatments. Not knowing the function of many of the gene products hampers the ability to produce a mechanistic-based therapy, especially in transmembrane-deficient forms of NCL.Expert opinion: Promising progress has been made in preclinical studies for several forms of NCL, which has led to the initiation of clinical trials of several different experimental therapies. Nevertheless, challenges remain in how such preclinical advances can be translated successfully into a clinical setting. As new data about pathogenesis emerge it is likely that combination therapies that target different regions of the brain and/or body or different parts of the pathological cascade will be needed.
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.
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.
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.
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.
2026-03-01 | 4CPS-289 Disease is rare, suffering is for everyone: a case report
Background and Importance
CLN2 disease (Neuronal Ceroid Lipofuscinosis Type 2) is an ultra-rare, neurodegenerative lysosomal storage disease, caused by an enzyme deficiency of tripeptidyl peptidase 1 (TPP1). Lack of disease awareness and the non-specificity of presenting symptoms often leads to delayed diagnosis. It has a devastating impact on children and families, leading to rapid functional decline and early death without effective treatment: early diagnosis and treatment of CLN2 disease are therefore vital to preserve function and slow decline for as long as possible. Cerliponase alfa, a recombinant form of the human TPP1 enzyme, is designed to replace the missing or deficient TPP1 enzyme in patients with CLN2 disease.
Aim and Objectives
This report will discuss the case of a patient who is responding to treatment, initiated in 2021.
Material and Methods
The patient is a little woman born in 2005. It was created of a custom pharmacological protocol, with continuous monitoring parameters vital, before during and after drug administration.
Results
The drug is stored at -20°C. Cerliponase alfa is administered, by clinician, by means of intracerebroventricular (ICV) infusion. The standard regimen involves a dose of 300 mg infused over approximately 4 hours, every 2 weeks. After verifying the clinical conditions, the doctor proceeds to prescribe the drug on the information system, on the date scheduled for administration. The treatment is taken care of and prepared at the Clinical Pharmacy laboratory. Once the chemical characteristics of the finished product have been verified, it is delivered to the department for subsequent administration.
Conclusion and Relevance
The Clinical Pharmacy Laboratory guarantees sterility and asepticity in the preparation of the drug. Administration is bimonthly, but temporary suspensions due to infections have occurred: the ICV delivery system, in fact, involves potential risks, in particular device-related complications, such as infections, which may require antibiotic treatment or device replacement. Despite this, the patient, in accordance with registered studies, appears to show a slower worsening of symptoms. This confirms the importance of encouraging and supporting clinical research, especially in rare diseases, which are often difficult to recognise and treat.
Conflict of Interest
No conflict of interest
gene therapies
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.
2025-12-08 | Incidence and timing of diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2): A nationwide study using the French hospital discharge database.
Neuronal ceroid lipofuscinoses (NCLs) are rare, progressive lysosomal neurodegenerative disorders. Among late-infantile onset forms (after 18 months of age), type 2 (CLN2 disease) is the most frequent. This study assessed the incidence and disease burden at diagnosis of CLN2 disease in France. This was a nationwide, population-based, retrospective study including all patients identified with CLN2 disease in the French Hospital Discharge Database (Programme de Médicalisation des Systèmes d'Information, PMSI) from January 2015 to December 2023. After a 2-year washout period to exclude prevalent patients, 51 children were considered to have been diagnosed with CLN2 disease over 7 years (2017-2023). Based on national birth statistics, this corresponds to an incidence of 0.99 cases of CLN2 disease per 100,000 live births. Median age at diagnosis was 5 years (interquartile range, 3-8), with a mean diagnostic delay of 19.1 ± 19.8 months from the first coded symptoms. Epilepsy (90.2 %) and intellectual disability (86.3 %) were the most frequently coded comorbidities. Of the 51 children, 84.3 % were hospitalized via emergency care, and 45.1 % required intensive care. Overall, 13 deaths (25.5 %) were reported, with median age at death of 9 years. This is the first nationwide epidemiological assessment of CLN2 disease in France. The results demonstrate substantial diagnostic delays and disease burden, underscoring the need for earlier diagnosis and referral to expert centers to optimize care and offer genetic counseling to parents before conceiving subsequent offspring.
2025-10-03 | Exploring Prime Editing strategies for genetic correction of a Ceroid Neuronal Lipofuscinosis type 2 disease causing variant
ABSTRACT Neuronal ceroid lipofuscinosis type 2 (CLN2) is a rare, fatal paediatric neurodegenerative genetic disease that causes progressive psychomotor decline, epilepsy, speech impairment, vision loss, and premature death by late childhood or early adolescence. It is caused by mutations in the TPP1 gene, which encodes the tripeptidyl peptidase 1 enzyme. To date, enzyme replacement therapy (ERT) with recombinant human TPP1 is the only approved treatment available and it does not appear to have a curative effect on disease progression or rescuing complex motor functions. This underscores the importance of developing more effective treatment strategies for CLN2 disease. In the quest for an alternative therapy, we here seek to utilise CRISPR based prime editing (PE) to correct one of the most frequent TPP1 mutations of c.622 C>T (p. Arg208Ter). In cultured mammalian HEK293a cells we screened 16 different PE and pegRNA combinations, achieving on-target editing efficiencies up to 27.36 %. To enable efficient in vivo gene editing, we packaged the most promising PE and pegRNA combination using engineered virus-like particles (eVLPs) which resulted in 12.6 % on-target editing. Given the robust on-target editing and reduced risk of bystander editing, PE is deemed suitable for in vivo testing in the pre-clinical models for CLN2 disease. Overall, our findings establish the proof of concept for CRISPR-based prime editing to correct pathogenic human TPP1 nonsense mutation of c.622 C>T (p. R208X) and provide a basis for further investigations of PE as a genetic treatment for CLN2 disease.
2025-07-25 | Recreating pathophysiology of CLN2 disease and demonstrating reversion by TPP1 gene therapy in hiPSC-derived retinal organoids and retina-on-chip.
Mutations in the tripeptidyl peptidase 1 (TPP1) gene lead to neuronal ceroid lipofuscinosis type 2 (CLN2), characterized by lysosomal accumulation of lipofuscins predominantly in the brain and retina. The ocular phenotype is characterized by outer retinal degeneration that leads to vision loss. Leveraging human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs), retinal pigmented epithelial cells, and the retina-on-chip system, we establish an in vitro CLN2 model that recreates the principal histological hallmarks, namely the accumulation of subunit C of mitochondrial ATP synthase (SCMAS) and lipids mainly in the outer retina. Furthermore, single-cell RNA sequencing reveals a dysregulation of translational and mitochondrial function in CLN2 cones. Finally, adeno-associated virus (AAV)-mediated TPP1 gene therapy can restore TPP1 expression and decrease and even prevent SCMAS accumulations. Our study uses an innovative human-relevant microphysiological retinal disease models, uncovers previously uncharacterized mechanisms of CLN2 pathophysiology, and demonstrates the potential of AAV9.hCLN2 gene therapy for CLN2 disease, potentially treating patient blindness.
2025-01-17 | Speech, Language and Non-verbal Communication in CLN2 and CLN3 Batten Disease.
CLN2 and CLN3 diseases, the most common types of Batten disease (also known as neuronal ceroid lipofuscinosis), are childhood dementias associated with progressive loss of speech, language and feeding skills. Here we delineate speech, language, non-verbal communication and feeding phenotypes in 33 individuals (19 females) with a median age of 9.5 years (range 3-28 years); 16 had CLN2 and 17 CLN3 disease; 8/15 (53%) participants with CLN2 and 8/17 (47%) participants with CLN3 disease had speech and language impairments prior to genetic diagnosis. At the time of study all participants, bar one, had language impairments. The remaining participant with typical language was tested at age 3 years, following pre-symptomatic enzyme replacement therapy (ERT) from age 9 months. CLN2 and CLN3 disease had different profiles. For CLN2 disease, all affected individuals showed language impairment with dysarthria; older individuals with classical disease progressively became non-verbal. For CLN3 disease, the presentation was more heterogeneous. Speech impairment was evident early in the disease course, with dysarthria (13/15, 87%), often manifesting as neurogenic stuttering (5/15, 33%). Participants with CLN2 disease had comparable expressive and receptive language skills (p > 0.99), yet participants with CLN3 disease had stronger expressive language than receptive language skills (p = 0.004). Speech, cognitive and language impairment and adaptive behaviour showed progressive decline in both diseases. Individuals with pre-symptomatic ERT or atypical CLN2 disease were less impaired. Challenging behaviours were common in CLN3 (11/17, 65%), but less frequent in CLN2 (4/16, 25%) disease. Individuals with Batten disease require tailored speech therapy incorporating communication partner training utilising environment adaptations and informal communication behaviours.
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 CLN2 disease.
2 orphan drug designations for CLN2 disease.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
AAV composed of an engineered viral capsid variant and a single-stranded DNA (ssDNA) expression cassette containing human tripeptidyl peptidase 1 (hTPP1) cDNA | gene therapies | FDA | — | Latus Bio |
adeno-associated viral serotype 2 vector under the regulatory control of a CMV promoter encoding the human tripeptidyl peptidase-1 (hTPP1) cDNA | gene therapies | FDA | — | Spark Therapeutics, Inc. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.