How close are we to therapies for Sanfilippo disease?

Gaffke, Lidia; Pierzynowska, Karolina; Piotrowska, Ewa; Węgrzyn, Grzegorz

doi:10.1007/s11011-017-0111-4

Cited by 48 publications

(41 citation statements)

References 49 publications

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“…The highest number of behavior-related genes with changed expression (relative to HDFa control) was found in MPS IIIA (39 genes), and the lowest number was detected in MPS VI (8 genes). It is worth to note that Sanfilippo disease (MPS III, including the MPS IIIA subtype) is the MPS type in which the most severe behavioral disturbances are described [13][14][15], while no behavioral abnormalities occur in MPS VI [16]. Therefore, we assume that, although our transcriptomic experiments were performed with RNA isolated from fibroblasts, not neurons, information about the expression of genes involved in behavioral processes gained from such studies can be accurate.…”

Section: Resultsmentioning

confidence: 99%

Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies

Pierzynowska

Gaffke

Podlacha

et al. 2020

IJMS

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Mucopolysaccharidoses (MPS) are a group of inherited metabolic diseases caused by mutations leading to defective degradation of glycosaminoglycans (GAGs) and their accumulation in cells. Among 11 known types and subtypes of MPS, neuronopathy occurs in seven (MPS I, II, IIIA, IIIB, IIIC, IIID, VII). Brain dysfunctions, occurring in these seven types/subtypes include various behavioral disorders. Intriguingly, behavioral symptoms are significantly different between patients suffering from various MPS types. Molecular base of such differences remains unknown. Here, we asked if expression of genes considered as connected to behavior (based on Gene Ontology, GO terms) is changed in MPS. Using cell lines of all MPS types, we have performed transcriptomic (RNA-seq) studies and assessed expression of genes involved in behavior. We found significant differences between MPS types in this regard, with the most severe changes in MPS IIIA (the type considered as the behaviorally most severely affected), while the lowest changes in MPS IVA and MPS VI (types in which little or no behavioral disorders are known). Intriguingly, relatively severe changes were found also in MPS IVB (in which, despite no behavioral disorder noted, the same gene is mutated as in GM1 gangliosidosis, a severe neurodegenerative disease) and MPS IX (in which only a few patients were described to date, thus, behavioral problems are not well recognized). More detailed analyses of expression of certain genes allowed us to propose an association of specific changes in the levels of transcripts in specific MPS types to certain behavioral disorders observed in patients. Therefore, this work provides a principle for further studies on the molecular mechanism of behavioral changes occurring in MPS patients.

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Section: Resultsmentioning

confidence: 99%

Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies

Pierzynowska

Gaffke

Podlacha

et al. 2020

IJMS

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“…Recent findings generated in a small number of patients have suggested a possible link between PD and FD 287 , which also exists between patients with PD and Gaucher disease who have GBA mutations (see above). Finally, genistein, a pleotropic natural product that inhibits kinases involved in the regulation of proteo glycan biosynthesis and also affects TFEB function, is in a phase III trial for Sanfilippo syndrome 288 .…”

Section: Substrate Reduction Therapies and Small-molecule Chaperonesmentioning

confidence: 99%

Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

452

312

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| Lysosomes are membrane-bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in genes encoding lysosomal proteins cause lysosomal storage disorders, in which enzyme replacement therapy has proved successful. Growing evidence also implicates roles for lysosomal dysfunction in more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. With a focus on lysosomal dysfunction in autoimmune disorders and neurodegenerative diseases -including lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer disease and Parkinson disease -this Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs.

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“…There is no cure for MPS III. Recent studies represent interesting approaches for enzyme replacement therapy, gene therapy, and substrate reduction therapy (reviewed in [137]).…”

Section: Mps III (Sanfilippo Syndrome)mentioning

confidence: 99%

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Breiden

Sandhoff

2020

IJMS

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Gangliosidoses are caused by monogenic defects of a specific hydrolase or an ancillary sphingolipid activator protein essential for a specific step in the catabolism of gangliosides. Such defects in lysosomal function cause a primary accumulation of multiple undegradable gangliosides and glycosphingolipids. In reality, however, predominantly small gangliosides also accumulate in many lysosomal diseases as secondary storage material without any known defect in their catabolic pathway. In recent reconstitution experiments, we identified primary storage materials like sphingomyelin, cholesterol, lysosphingolipids, and chondroitin sulfate as strong inhibitors of sphingolipid activator proteins (like GM2 activator protein, saposin A and B), essential for the catabolism of many gangliosides and glycosphingolipids, as well as inhibitors of specific catabolic steps in lysosomal ganglioside catabolism and cholesterol turnover. In particular, they trigger a secondary accumulation of ganglioside GM2, glucosylceramide and cholesterol in Niemann-Pick disease type A and B, and of GM2 and glucosylceramide in Niemann-Pick disease type C. Chondroitin sulfate effectively inhibits GM2 catabolism in mucopolysaccharidoses like Hurler, Hunter, Sanfilippo, and Sly syndrome and causes a secondary neuronal ganglioside GM2 accumulation, triggering neurodegeneration. Secondary ganglioside and lipid accumulation is furthermore known in many more lysosomal storage diseases, so far without known molecular basis.

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How close are we to therapies for Sanfilippo disease?

Cited by 48 publications

References 49 publications

Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies

Genetic Base of Behavioral Disorders in Mucopolysaccharidoses: Transcriptomic Studies

Lysosomes as a therapeutic target

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

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