Future perspectives: Moving towards NCL treatments

Cotman, Susan L.; Mole, Sara; Kohan, Romina

doi:10.1016/j.bbadis.2015.04.001

Cited by 7 publications

(5 citation statements)

References 19 publications

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“…3 The combination of data collected in DEMCHILD, 9,10 NCL Mutation Database, and application of NCL disease rating scales 11,12 allows correlations to be made between the disease and under lying mutations to provide some guid ance to the expected disease course, and to give an approxi mation of frequency and occurrence in specific ethnic groups. As the pheno typic spectrum broadens, increasing overlap with other rare (eg, inborn errors of metabolism) and common diseases (eg, retinal dystrophies) that share similar disease mechanisms is expected, 37 which could lead to better understanding of all these diseases.…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis

Mole

Anderson

Band³

et al. 2019

The Lancet Neurology

153

161

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Treatment of the neuronal ceroid lipofuscinoses, also known as Batten disease, is at the start of a new era because of diagnostic and therapeutic advances relevant to this group of inherited neurodegenerative and life-limiting disorders that affect children. Diagnosis has improved with the use of comprehensive DNA-based tests that simultaneously screen for many genes. The identification of disease-causing mutations in 13 genes provides a basis for understanding the molecular mechanisms underlying neuronal ceroid lipofuscinoses, and for the development of targeted therapies. These targeted therapies include enzyme replacement therapies, gene therapies targeting the brain and the eye, cell therapies, and pharmacological drugs that could modulate defective molecular pathways. Such therapeutic developments have the potential to enable earlier diagnosis and better targeted therapeutic management. The first approved treatment is an intracerebroventricularly administered enzyme for neuronal ceroid lipofuscinosis type 2 disease that delays symptom progression. Efforts are underway to make similar progress for other forms of the disorder.

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Section: Genotype-phenotype Correlationsmentioning

confidence: 99%

Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis

Mole

Anderson

Band³

et al. 2019

The Lancet Neurology

153

161

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“…The standard of care is generally to minimize symptoms, especially seizures. Many new therapies are emerging and hopefully some will halt or slow disease progression but none are likely to reverse the damage [ 7 – 9 ]. Based on a systematic search of the literature and clinicaltrials.gov , several approaches offer promising therapeutic strategies, including gene therapy, stem cell therapy, enzyme replacement therapy, anti-inflammatories, and small molecules.…”

Section: Therapeutic Approaches For Nclsmentioning

confidence: 99%

Safety and potential efficacy of gemfibrozil as a supportive treatment for children with late infantile neuronal ceroid lipofuscinosis and other lipid storage disorders

Kim

Kleinman

Lee³

et al. 2017

Orphanet J Rare Dis

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Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is a group of genetically distinct lysosomal disorders that mainly affect the central nervous system, resulting in progressive motor and cognitive decline primarily in children. Multiple distinct genes involved in the metabolism of lipids have been identified to date with various mutations in this family of diseases. There is no cure for these diseases but some new therapeutic approaches have been tested that offer more hope than the standard palliative care. Many of the therapeutic advances require invasive procedures but some progress in slowing the disease has been found and more options can be expected in the future. We also review the literature on children with disease/conditions other than NCL for the non-invasive use, safety, and tolerability of a lipid-lowering drug, gemfibrozil, as a potential treatment for NCLs. Gemfibrozil has shown efficacy in an animal model of NCL known as CLN2 (late infantile classic juvenile) and has been shown to be safe for lowering lipids in children. Among the 200 non-NCL children found in the published literature who were treated with gemfibrozil for NCL-related problems, only 3 experienced adverse events, including 2 with muscle pain and 1 with localized linear IgA bullous dermatitis. We conclude that gemfibrozil is safe for long-term use in children, causes minimal adverse events, is well tolerated, and may delay the progression of NCLs. Gemfibrozil may potentially be an alternative to more invasive therapeutic approaches currently under investigation and has the potential to be used in combination with other therapeutic approaches.

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“…The functions of all NCL genes and thereby disease mechanisms are not yet known. As understanding increases overlap with other rare and common diseases, such as retinal dystrophies may indicate shared disease mechanisms ( 82 ).…”

Section: Discussionmentioning

confidence: 99%

The Genetic Basis of Phenotypic Heterogeneity in the Neuronal Ceroid Lipofuscinoses

Gardner

Mole

2021

Front. Neurol.

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The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders that affect children and adults. They share some similar clinical features and the accumulation of autofluorescent storage material. Since the discovery of the first causative genes, more than 530 mutations have been identified across 13 genes in cases diagnosed with NCL. These genes encode a variety of proteins whose functions have not been fully defined; most are lysosomal enzymes, or transmembrane proteins of the lysosome or other organelles. Many mutations in these genes are associated with a typical NCL disease phenotype. However, increasing numbers of variant disease phenotypes are being described, affecting age of onset, severity or progression, and including some distinct clinical phenotypes. This data is collated by the NCL Mutation Database which allows analysis from many perspectives. This article will summarise and interpret current knowledge and understanding of their genetic basis and phenotypic heterogeneity.

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Future perspectives: Moving towards NCL treatments

Cited by 7 publications

References 19 publications

Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis

Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis

Safety and potential efficacy of gemfibrozil as a supportive treatment for children with late infantile neuronal ceroid lipofuscinosis and other lipid storage disorders

The Genetic Basis of Phenotypic Heterogeneity in the Neuronal Ceroid Lipofuscinoses

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