scholarly journals Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders

2021 ◽  
Vol 17 (9) ◽  
pp. e1009370
Author(s):  
Jaie Woodard ◽  
Wei Zheng ◽  
Yang Zhang
Keyword(s):  
Gaucher Disease ◽  
Three Dimensional ◽  
Structural Features ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Pharmacological Chaperone ◽  
Protein Residues ◽  
Cellular Kinetics ◽  
Machine Learning Approach ◽  
Storage Disorders

Three-dimensional structures of proteins can provide important clues into the efficacy of personalized treatment. We perform a structural analysis of variants within three inherited lysosomal storage disorders, comparing variants responsive to pharmacological chaperone treatment to those unresponsive to such treatment. We find that predicted ΔΔG of mutation is higher on average for variants unresponsive to treatment, in the case of datasets for both Fabry disease and Pompe disease, in line with previous findings. Using both a single decision tree and an advanced machine learning approach based on the larger Fabry dataset, we correctly predict responsiveness of three Gaucher disease variants, and we provide predictions for untested variants. Many variants are predicted to be responsive to treatment, suggesting that drug-based treatments may be effective for a number of variants in Gaucher disease. In our analysis, we observe dependence on a topological feature reporting on contact arrangements which is likely connected to the order of folding of protein residues, and we provide a potential justification for this observation based on steady-state cellular kinetics.

scholarly journals Protein structural features predict responsiveness to pharmacological chaperone treatment for three lysosomal storage disorders

2021 ◽  
Author(s):  
Jaie C. Woodard ◽  
Wei Zheng ◽  
Yang Zhang
Keyword(s):  
Gaucher Disease ◽  
Three Dimensional ◽  
Structural Features ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Pharmacological Chaperone ◽  
Protein Residues ◽  
Cellular Kinetics ◽  
Machine Learning Approach ◽  
Storage Disorders

Three-dimensional structures of proteins can provide important clues into the efficacy of personalized treatment. We perform a structural analysis of variants within three inherited lysosomal storage disorders, comparing variants responsive to pharmacological chaperone treatment to those unresponsive to such treatment. We find that predicted ∆∆G of mutation is higher on average for variants unresponsive to treatment, in the case of datasets for both Fabry disease and Pompe disease, in line with previous findings. Using both a single decision tree and an advanced machine learning approach based on the larger Fabry dataset, we correctly predict responsiveness of three Gaucher disease variants, and we provide predictions for untested variants. Many variants are predicted to be responsive to treatment, suggesting that drug-based treatments may be effective for a number of variants in Gaucher disease. In our analysis, we observe dependence on a topological feature reporting on contact arrangements which is likely connected to the order of folding of protein residues, and we provide a potential justification for this observation based on steady-state cellular kinetics.

scholarly journals Efficacy of pentosan polysulfate in in vitro models of lysosomal storage disorders: Fabry and Gaucher Disease

PLoS ONE ◽  
2019 ◽  
Vol 14 (5) ◽  
pp. e0217780 ◽  
Author(s):  
Andrea N. Crivaro ◽  
Juan M. Mucci ◽  
Constanza M. Bondar ◽  
Maximiliano E. Ormazabal ◽  
Romina Ceci ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
In Vitro Models ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Pentosan Polysulfate ◽  
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.

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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