scholarly journals Towards Splicing Therapy for Lysosomal Storage Disorders: Methylxanthines and Luteolin Ameliorate Splicing Defects in Aspartylglucosaminuria and Classic Late Infantile Neuronal Ceroid Lipofuscinosis

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2813
Author(s):  
Antje Banning ◽  
Ritva Tikkanen
Keyword(s):  
Small Molecules ◽  
Splice Site ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Lysosomal Storage Disorders ◽  
Specific Gene ◽  
Lysosomal Storage ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Ceroid Lipofuscinosis ◽  
Splicing Defects ◽  
Storage Disorders

Splicing defects caused by mutations in the consensus sequences at the borders of introns and exons are common in human diseases. Such defects frequently result in a complete loss of function of the protein in question. Therapy approaches based on antisense oligonucleotides for specific gene mutations have been developed in the past, but they are very expensive and require invasive, life-long administration. Thus, modulation of splicing by means of small molecules is of great interest for the therapy of genetic diseases resulting from splice-site mutations. Using minigene approaches and patient cells, we here show that methylxanthine derivatives and the food-derived flavonoid luteolin are able to enhance the correct splicing of the AGA mRNA with a splice-site mutation c.128-2A>G in aspartylglucosaminuria, and result in increased AGA enzyme activity in patient cells. Furthermore, we also show that one of the most common disease causing TPP1 gene variants in classic late infantile neuronal ceroid lipofuscinosis may also be amenable to splicing modulation using similar substances. Therefore, our data suggest that splice-modulation with small molecules may be a valid therapy option for lysosomal storage disorders.

scholarly journals Fronto-temporal dementia risk gene TMEM106B has opposing effects in different lysosomal storage disorders

2020 ◽  
Author(s):  
Azucena Perez-Canamas ◽  
Hideyuki Takahashi ◽  
Jane A Lindborg ◽  
Stephen M Strittmatter
Keyword(s):  
Gaucher Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Vacuolar Atpase ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Lysosomal Compartment ◽  
Lysosomal Ph ◽  
Ceroid Lipofuscinosis ◽  
Storage Disorders

Abstract TMEM106B is a transmembrane protein localized to the endo-lysosomal compartment. Genome-wide association studies have identified TMEM106B as a risk modifier of Alzheimer’s disease and frontotemporal lobar degeneration, especially with progranulin haploinsufficiency. We recently demonstrated that TMEM106B loss rescues progranulin null mouse phenotypes including lysosomal enzyme dysregulation, neurodegeneration and behavioural alterations. However, the reason whether TMEM106B is involved in other neurodegenerative lysosomal diseases is unknown. Here, we evaluate the potential role of TMEM106B in modifying the progression of lysosomal storage disorders using progranulin-independent models of Gaucher disease and neuronal ceroid lipofuscinosis. To study Gaucher disease, we employ a pharmacological approach using the inhibitor conduritol B epoxide in wild-type and hypomorphic Tmem106b−/− mice. TMEM106B depletion ameliorates neuronal degeneration and some behavioural abnormalities in the pharmacological model of Gaucher disease, similar to its effect on certain progranulin null phenotypes. In order to examine the role of TMEM106B in neuronal ceroid lipofuscinosis, we crossbred Tmem106b−/− mice with Ppt1−/−, a genetic model of the disease. In contrast to its conduritol B epoxide-rescuing effect, TMEM106B loss exacerbates Purkinje cell degeneration and motor deficits in Ppt1−/− mice. Mechanistically, TMEM106B is known to interact with subunits of the vacuolar ATPase and influence lysosomal acidification. In the pharmacological Gaucher disease model, the acidified lysosomal compartment is enhanced and TMEM106B loss rescues in vivo phenotypes. In contrast, gene-edited neuronal loss of Ppt1 causes a reduction in vacuolar ATPase levels and impairment of the acidified lysosomal compartment, and TMEM106B deletion exacerbates the mouse Ppt1−/− phenotype. Our findings indicate that TMEM106B differentially modulates the progression of the lysosomal storage disorders Gaucher disease and neuronal ceroid lipofuscinosis. The effect of TMEM106B in neurodegeneration varies depending on vacuolar ATPase state and modulation of lysosomal pH. These data suggest TMEM106B as a target for correcting lysosomal pH alterations, and in particular for therapeutic intervention in Gaucher disease and neuronal ceroid lipofuscinosis.

Pharmacological small molecules for the treatment of lysosomal storage disorders

2010 ◽  
Vol 19 (11) ◽  
pp. 1367-1379 ◽  
Author(s):  
BE Smid ◽  
JMFG Aerts ◽  
RG Boot ◽  
GE Linthorst ◽  
CEM Hollak
Keyword(s):  
Small Molecules ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Storage Disorders

scholarly journals Glial fibrillary acidic protein is elevated in the lysosomal storage disease classical late-infantile neuronal ceroid lipofuscinosis, but is not a component of the storage material

2010 ◽  
Vol 428 (3) ◽  
pp. 355-362 ◽  
Author(s):  
Su Xu ◽  
David E. Sleat ◽  
Michel Jadot ◽  
Peter Lobel
Keyword(s):  
Glial Fibrillary Acidic Protein ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Subcellular Fractionation ◽  
Acidic Protein ◽  
Lysosomal Storage ◽  
Storage Material ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Lysosomal Protease ◽  
Ceroid Lipofuscinosis ◽  
Mitochondrial Atp Synthase

Classical late-infantile neuronal ceroid lipofuscinosis (LINCL) is a fatal neurodegenerative disease of children caused by mutations in TPP1, the gene encoding the lysosomal protease tripeptidyl peptidase 1. LINCL is characterized by lysosomal accumulation of storage material of which only a single protein component, subunit c of mitochondrial ATP synthase, has been well established to date. Identification of other protein constituents of the storage material could provide useful insights into the pathophysiology of disease and the natural substrates for TPP1. We have therefore initiated a proteomic analysis of storage material in brain from a LINCL mouse model. One protein, GFAP (glial fibrillary acidic protein), was found to be elevated in the LINCL mice compared with normal controls in both isolated storage bodies and a lysosome-enriched subcellular fraction that contains storage material. To determine whether GFAP accumulates within the lysosome in LINCL, we examined its intracellular distribution using subcellular fractionation and morphological methods. These experiments demonstrate that GFAP is not a component of the storage material in LINCL, suggesting that reports of GFAP storage in other NCLs may need to be re-examined. A number of other proteins were elevated in the storage material and/or lysosome-enriched fraction from the LINCL mice, but it remains unclear whether these proteins are true constituents of the storage material or, like GFAP, whether they associate with this material upon purification.

scholarly journals FDA orphan drug designations for lysosomal storage disorders – a cross sectional analysis

2020 ◽  
Author(s):  
Sven F. Garbade ◽  
Matthias Zielonka ◽  
Konstantin Mechler ◽  
Stefan Kölker ◽  
Georg F. Hoffmann ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Small Molecules ◽  
Orphan Drug ◽  
Pompe Disease ◽  
Gaucher Disease ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Mps I ◽  
Storage Disorders

AbstractPurposeTo provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat lysosomal storage disorders (LSD’s).MethodsAssessment of the drug pipeline through analysis of the FDA database for orphan drug designations with descriptive and comparative statistics.ResultsBetween 1983 and 2019, 124 orphan drug designations were granted by the FDA for compounds intended to treat 28 lysosomal storage diseases. Orphan drug designations focused on Gaucher disease (N=16), Pompe disease (N=16), Fabry disease (N=10), MPS II (N=10), MPS I (N=9), and MPS IIIA (N=9), and included enzyme replacement therapies, gene therapies, and small molecules, and others. Twenty-three orphan drugs were approved for the treatment of 11 LSDs. Gaucher disease (N=6), cystinosis (N=5), Pompe disease (N=3), and Fabry disease (N=2) had multiple approvals, CLN2, LAL-D, MPS I, II, IVA, VI, and VII one approval each. This is an increase of nine more approved drugs and four more treatable LSD’s (CLN2, MPS VII, LAL-D, and MPS IVA) since 2013. Mean time between orphan drug designation and FDA approval was 89.7 SD 55.00 (range 8-203, N=23) months.ConclusionsThe development pipeline is growing and evolving into diversified small molecules and gene therapy. CLN2 was the first and only LSD with an approved therapy directly targeted to the brain. Newly approved products included “me-too” – enzymes and innovative compounds such as the first pharmacological chaperone for the treatment of Fabry disease.

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