Current therapies for the soluble lysosomal forms of neuronal ceroid lipofuscinosis

The NCLs (neuronal ceroid lipofuscinoses) are the most common inherited paediatric neurodegenerative disorder. Although genetically distinct, NCLs can be broadly divided into two categories: one in which the mutation results in a defect in a transmembrane protein, and the other where the defect lies in a soluble lysosomal enzyme. A number of therapeutic approaches are applicable to the soluble lysosomal forms of NCL based on the phenomenon of cross-correction, whereby the ubiquitously expressed mannose 6-phosphate/IGF (insulin-like growth factor) II receptor provides an avenue for endocytosis, trafficking and lysosomal processing of extracellularly delivered enzyme. The present review discusses therapeutic utilization of cross-correction by enzyme-replacement therapy, gene therapy and stem cell therapy for the NCLs, along with an overview of the recent progress in translating these treatments into the clinic.

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Current Insights in Elucidation of Possible Molecular Mechanisms of the Juvenile Form of Batten Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21218055 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8055

Author(s):

Elena K. Shematorova ◽

George V. Shpakovski

Keyword(s):

Molecular Mechanisms ◽

Neuronal Ceroid Lipofuscinosis ◽

Transmembrane Protein ◽

Mammalian Species ◽

Disease Onset ◽

In Vivo Studies ◽

Neuronal Ceroid Lipofuscinoses ◽

Juvenile Form ◽

Molecular Features ◽

Human Specific

The neuronal ceroid lipofuscinoses (NCLs) collectively constitute one of the most common forms of inherited childhood-onset neurodegenerative disorders. They form a heterogeneous group of incurable lysosomal storage diseases that lead to blindness, motor deterioration, epilepsy, and dementia. Traditionally the NCL diseases were classified according to the age of disease onset (infantile, late-infantile, juvenile, and adult forms), with at least 13 different NCL varieties having been described at present. The current review focuses on classic juvenile NCL (JNCL) or the so-called Batten (Batten-Spielmeyer-Vogt; Spielmeyer-Sjogren) disease, which represents the most common and the most studied form of NCL, and is caused by mutations in the CLN3 gene located on human chromosome 16. Most JNCL patients carry the same 1.02-kb deletion in this gene, encoding an unusual transmembrane protein, CLN3, or battenin. Accordingly, the names CLN3-related neuronal ceroid lipofuscinosis or CLN3-disease sometimes have been used for this malady. Despite excessive in vitro and in vivo studies, the precise functions of the CLN3 protein and the JNCL disease mechanisms remain elusive and are the main subject of this review. Although the CLN3 gene is highly conserved in evolution of all mammalian species, detailed analysis of recent genomic and transcriptomic data indicates the presence of human-specific features of its expression, which are also under discussion. The main recorded to date changes in cell metabolism, to some extent contributing to the emergence and progression of JNCL disease, and human-specific molecular features of CLN3 gene expression are summarized and critically discussed with an emphasis on the possible molecular mechanisms of the malady appearance and progression.

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Congenital Neuronal Ceroid Lipofuscinosis with a Novel CTSD Gene Mutation: A Rare Cause of Neonatal-Onset Neurodegenerative Disorder

Neuropediatrics ◽

10.1055/s-0037-1613681 ◽

2017 ◽

Vol 49 (02) ◽

pp. 150-153 ◽

Cited By ~ 6

Author(s):

K. Varvagiannis ◽

S. Hanquinet ◽

M. Billieux ◽

R. De Luca ◽

P. Rimensberger ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Age Of Onset ◽

Neuronal Ceroid Lipofuscinosis ◽

Molecular Genetic ◽

Bioinformatic Analysis ◽

Neuronal Ceroid Lipofuscinoses ◽

Gene Encoding ◽

Functional Studies ◽

Ceroid Lipofuscinosis ◽

Similar Phenotype

AbstractNeuronal ceroid lipofuscinoses represent a heterogeneous group of early onset neurodegenerative disorders that are characterized by progressive cognitive and motor function decline, visual loss, and epilepsy. The age of onset has been historically used for the phenotypic classification of this group of disorders, but their molecular genetic delineation has now enabled a better characterization, demonstrating significant genetic heterogeneity even among individuals with a similar phenotype. The rare Congenital Neuronal Ceroid Lipofuscinosis (CLN10) caused by mutations in the CTSD gene encoding for cathepsin D is associated with a dramatic presentation with onset before or around birth. We report on a female born to consanguineous parents who presented at birth with severe neonatal encephalopathy with massive cerebral and cerebellar shrinking on magnetic resonance imaging. Whole exome sequencing with targeted bioinformatic analysis of a panel of genes associated with prenatal/perinatal onset of neurodegenerative disease was performed and revealed the presence of a novel homozygous in-frame deletion in CTSD. Additional functional studies further confirmed the pathogenic character of this variant and established the diagnosis of CLN10 in the patient.

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Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease

Human Molecular Genetics ◽

10.1093/hmg/ddz210 ◽

2019 ◽

Vol 28 (23) ◽

pp. 3867-3879 ◽

Cited By ~ 6

Author(s):

Sophia-Martha kleine Holthaus ◽

Saul Herranz-Martin ◽

Giulia Massaro ◽

Mikel Aristorena ◽

Justin Hoke ◽

...

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Motor Coordination ◽

Transmembrane Protein ◽

Batten Disease ◽

Premature Death ◽

Neuronal Ceroid Lipofuscinoses ◽

Therapeutic Effects ◽

Lysosomal Storage ◽

Enzyme Replacement

Abstract The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and pre-clinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.

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Experience in Diagnosing Neuronal Ceroid Lipofuscinosis Type-2

Journal Of The Indonesian Medical Association ◽

10.47830/jinma-vol.71.5-2021-452 ◽

2021 ◽

Vol 71 (5) ◽

pp. 234-240

Author(s):

Lanny Christine Gultom ◽

Valensia Vivian The

Keyword(s):

Neurodegenerative Disorder ◽

Neuronal Ceroid Lipofuscinosis ◽

Early Stage ◽

Diagnostic Delay ◽

Compound Heterozygous ◽

Recurrent Seizure ◽

Enzyme Replacement ◽

Ceroid Lipofuscinosis ◽

Developmental Regression

Introduction: Developmental regression is always an alarming symptom in children as it is an early sign of some genetic disorders, one of which is neuronal ceroid lipofuscinosis (NCL). NCL is a group of rare neurodegenerative disorder caused by accumulation of intracellular ceroid lipofuscin. Since 2017 an enzyme replacement therapy (ERT) has been approved by Food and Drug Administration (FDA) for this disease. The symptoms of NCL could be managed by ERT if detected early, and the child could live normally.Case: We present a case of a 6-year-and-5-month-old boy with developmental regression, speech delay, recurrent seizure, and visual impairment, who was diagnosed with NCL type 2 after genetic testing. Compound heterozygous mutations in tripeptidyl-peptidase 1 (TPP1) gene was revealed, consistent with very low level of TPP1 enzyme in this patient.Discussion: NCL is a fatal disease which is often misdiagnosed in early stage. Diagnostic delay of NCL often occurs due to lack of awareness which often leads to premature death.Conclusion: Knowledge regarding the disease is important for early detection and to slow down the disease progression.

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Neuronal Ceroid Lipofuscinoses

10.1093/med/9780199972135.003.0059 ◽

2016 ◽

Author(s):

Catherine Caillaud ◽

Frédéric Sedel

Keyword(s):

Gene Transfer ◽

Neurodegenerative Disorders ◽

Direct Sequencing ◽

Neuronal Ceroid Lipofuscinoses ◽

Clinical Heterogeneity ◽

Therapeutic Approaches ◽

Huge Number ◽

Enzyme Replacement ◽

Number Of Genes ◽

Or Gene

Neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative disorders beginning mainly in childhood, rarely in adults. They are characterized by the accumulation of autofluorescent lipopigments in brain, especially in neurons. Their clinical heterogeneity is now explained by the huge number of genes (from CLN1 to CLN14) involved in their pathogenesis. Their diagnosis is possible using enzymatic tests and/or direct sequencing of the corresponding genes. Different therapeutic approaches are in development for these diseases such as enzyme replacement therapy or gene transfer.

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Central nervous system stem cell transplantation for children with neuronal ceroid lipofuscinosis

Journal of Neurosurgery Pediatrics ◽

10.3171/2013.3.peds12397 ◽

2013 ◽

Vol 11 (6) ◽

pp. 643-652 ◽

Cited By ~ 81

Author(s):

Nathan R. Selden ◽

Amira Al-Uzri ◽

Stephen L. Huhn ◽

Thomas K. Koch ◽

Darryn M. Sikora ◽

...

Keyword(s):

Clinical Trial ◽

Stem Cells ◽

Adverse Events ◽

Cell Transplantation ◽

Neurodegenerative Disorder ◽

Neuronal Ceroid Lipofuscinosis ◽

Neuronal Ceroid Lipofuscinoses ◽

Potential Treatment ◽

Serious Adverse Events ◽

Clinical Trial Registration

Object Infantile and late-infantile neuronal ceroid lipofuscinoses (NCLs) are invariably fatal lysosomal storage diseases associated with defects in lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT-1) or tripeptidyl peptidase 1 (TPP1) activity. Previous preclinical studies have demonstrated that human CNS stem cells (HuCNS-SCs) produce both PPT-1 and TPP1 and result in donor cell engraftment and reduced accumulation of storage material in the brain when tested in an NCL mouse model. Methods HuCNS-SC transplantation was tested in an open-label dose-escalation Phase I clinical trial as a potential treatment for infantile and late-infantile NCL. Study design included direct neurosurgical transplantation of allogeneic HuCNS-SCs into the cerebral hemispheres and lateral ventricles accompanied by 12 months of immunosuppression. Results Six children with either the infantile or late-infantile forms of NCL underwent low- (3 patients) and high- (3 patients) dose transplantation of HuCNS-SCs followed by immunosuppression. The surgery, immunosuppression, and cell transplantation were well tolerated. Adverse events following transplantation were consistent with the underlying disease, and none were directly attributed to the donor cells. Observations regarding efficacy of the intervention were limited by the enrollment criteria requiring that patients be in advanced stages of disease. Conclusions This study represents the first-in-human clinical trial involving transplantation of a purified population of human neural stem cells for a neurodegenerative disorder. The feasibility of this approach and absence of transplantation-related serious adverse events support further exploration of HuCNS-SC transplantation as a potential treatment for select subtypes of NCL, and possibly for other neurodegenerative disorders. Clinical trial registration no.: NCT00337636 (ClinicalTrials.gov).

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A Novel CLN6 Variant Associated With Juvenile Neuronal Ceroid Lipofuscinosis in Patients With Absence of Visual Loss as a Presenting Feature

Frontiers in Genetics ◽

10.3389/fgene.2021.746101 ◽

2021 ◽

Vol 12 ◽

Author(s):

Paschalis Nicolaou ◽

George A. Tanteles ◽

Christina Votsi ◽

Eleni Zamba-Papanicolaou ◽

Savvas S. Papacostas ◽

...

Keyword(s):

In Silico ◽

De Novo ◽

Neuronal Ceroid Lipofuscinosis ◽

Transmembrane Protein ◽

Structural Modeling ◽

Neuronal Ceroid Lipofuscinoses ◽

Lysosomal Storage ◽

Structural Differentiation ◽

Prediction Analysis ◽

Loss Of Vision

The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of autosomal recessive lysosomal storage disorders that are characterized by neurodegeneration, progressive cognitive decline, motor impairment, ataxia, loss of vision, seizures, and premature death. To date, pathogenic variants in more than 13 genes have been associated with NCLs. CLN6 encodes an endoplasmic reticulum non-glycosylated transmembrane protein, which is involved in lysosomal acidification. Mutations in CLN6 cause late-infantile juvenile NCL (JNCL) adult-onset NCL, and Kufs disease. Members from two available families with JNCL were clinically evaluated, and samples were collected from consenting individuals. The molecular investigation was performed by whole-exome sequencing, Sanger sequencing, and family segregation analysis. Furthermore, in silico prediction analysis and structural modeling of the identified CLN6 variants were performed. We report clinical and genetic findings of three patients from two Greek-Cypriot families (families 915 and 926) with JNCL. All patients were males, and the first symptoms appeared at the age of 6 years. The proband of family 926 presented with loss of motor abilities, ataxia, spasticity, seizure, and epilepsy. The proband of family 915 had ataxia, spasticity, dysarthria, dystonia, and intellectual disability. Both probands did not show initial signs of vision and/or hearing loss. Molecular analysis of family 926 revealed two CLN6 biallelic variants: the novel, de novo p.Tyr295Cys and the known p.Arg136His variants. In family 915, both patients were homozygous for the p.Arg136His CLN6 variant. Prediction analysis of the two CLN6 variants characterized them as probably damaging and disease-causing. Structural modeling of the variants predicted that they probably cause protein structural differentiation. In conclusion, we describe two unrelated Cypriot families with JNCL. Both families had variants in the CLN6 gene; however, they presented with slightly different symptoms, and notably none of the patients has loss of vision. In silico prediction and structural analyses indicate that both variants are most likely pathogenic.

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Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease

10.1101/673848 ◽

2019 ◽

Author(s):

Sophia-Martha kleine Holthaus ◽

Saul Martin-Herranz ◽

Giulia Massaro ◽

Mikel Aristorena ◽

Justin Hoke ◽

...

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Motor Coordination ◽

Transmembrane Protein ◽

Batten Disease ◽

Premature Death ◽

Neuronal Ceroid Lipofuscinoses ◽

Therapeutic Effects ◽

Lysosomal Storage ◽

Enzyme Replacement

The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and preclinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.

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Development of the “Hamburg Best Practice Guidelines for ICV−Enzyme Replacement therapy (ERT) in CLN2 Disease” Based on 6 Years Treatment Experience in 48 Patients

Journal of Child Neurology ◽

10.1177/0883073821989154 ◽

2021 ◽

pp. 088307382198915

Author(s):

Christoph Schwering ◽

Gertrud Kammler ◽

Eva Wibbeler ◽

Martin Christner ◽

Johannes K.-M. Knobloch ◽

...

Keyword(s):

Patient Safety ◽

Adverse Events ◽

Enzyme Replacement Therapy ◽

Replacement Therapy ◽

Practice Guidelines ◽

Best Practice ◽

Vision Loss ◽

Neuronal Ceroid Lipofuscinosis ◽

Enzyme Replacement ◽

Best Practice Guidelines

Intracerebroventricular enzyme replacement therapy (ICV-ERT) for CLN2 disease represents the first approved treatment for neuronal ceroid lipofuscinosis (NCL) diseases. It is the first treatment where a recombinant lysosomal enzyme, cerliponase alfa, is administered into the lateral cerebral ventricles to reach the central nervous system, the organ affected in CLN2 disease. If untreated, CLN2 children show first symptoms such as epilepsy and language developmental delay at 2-4 years followed by rapid loss of motor and language function, vision loss, and early death. Treatment with cerliponase alfa has shown to slow the rapid neurologic decline. However, the mode of administration by 4 hour-long intracerebroventricular infusions every 14 days represents a potentially greater risk of infection compared to intravenous enzyme replacement therapies. The Hamburg NCL Specialty Clinic was the first site worldwide to perform intracerebroventricular enzyme replacement therapy in children with CLN2 disease. In order to ensure maximum patient safety, we analysed data from our center from more than 3000 intracerebroventricular enzyme replacement therapies in 48 patients over 6 years with regard to the occurrence of device-related adverse events and device infections. Since starting intracerebroventricular enzyme replacement therapy, we have also developed and continuously improved the “Hamburg Best Practice Guidelines for ICV–Enzyme Replacement Therapy (ERT) in CLN2 Disease.” Results from this study showed low rates for device-related adverse events and infections with 0.27% and 0.33%, respectively. Therefore, following our internal procedural guidelines has shown to improve standardization and patient safety of intracerebroventricular enzyme replacement therapy for CLN2 disease.

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