114. Pharmacological chaperone therapy for Gaucher disease: Mechanism of action, a survey of responsive mutations and phase I clinical trial results

Wustman, Brandon A.; Pine, C.W.; Ranes, Brian; Flanagan, John F.; Palling, David J.; Do, Hung; Insinga, Frank; Grabowski, Gregory A.; Weinreb, Neal J.; Pastores, Gregory M.; Fernhoff, Paul M.; Kaplan, Paige; Lockhart, David J.

doi:10.1016/j.ymgme.2007.10.126

Cited by 4 publications

(2 citation statements)

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“…6B). 133 GCase levels were elevated up to 3.5-fold compared with baseline levels, and remained elevated for up to 7 days after withdrawal of IFG. These data clearly indicate that IFG can interact with its intended target in humans, and that this interaction results in stabilization and increased GCase levels in vivo.…”

Section: Pharmacokinetics Tissue Distribution and Effects On Wild-tmentioning

confidence: 87%

Identification and Characterization of Pharmacological Chaperones to Correct Enzyme Deficiencies in Lysosomal Storage Disorders

Valenzano

Khanna

Powe

et al. 2011

ASSAY and Drug Development Technologies

141

135

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Many human diseases result from mutations in specific genes. Once translated, the resulting aberrant proteins may be functionally competent and produced at near-normal levels. However, because of the mutations, the proteins are recognized by the quality control system of the endoplasmic reticulum and are not processed or trafficked correctly, ultimately leading to cellular dysfunction and disease. Pharmacological chaperones (PCs) are small molecules designed to mitigate this problem by selectively binding and stabilizing their target protein, thus reducing premature degradation, facilitating intracellular trafficking, and increasing cellular activity. Partial or complete restoration of normal function by PCs has been shown for numerous types of mutant proteins, including secreted proteins, transcription factors, ion channels, G protein-coupled receptors, and, importantly, lysosomal enzymes. Collectively, lysosomal storage disorders (LSDs) result from genetic mutations in the genes that encode specific lysosomal enzymes, leading to a deficiency in essential enzymatic activity and cellular accumulation of the respective substrate. To date, over 50 different LSDs have been identified, several of which are treated clinically with enzyme replacement therapy or substrate reduction therapy, although insufficiently in some cases. Importantly, a wide range of in vitro assays are now available to measure mutant lysosomal enzyme interaction with and stabilization by PCs, as well as subsequent increases in cellular enzyme levels and function. The application of these assays to the identification and characterization of candidate PCs for mutant lysosomal enzymes will be discussed in this review. In addition, considerations for the successful in vivo use and development of PCs to treat LSDs will be discussed.

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Section: Pharmacokinetics Tissue Distribution and Effects On Wild-tmentioning

confidence: 87%

Identification and Characterization of Pharmacological Chaperones to Correct Enzyme Deficiencies in Lysosomal Storage Disorders

Valenzano

Khanna

Powe

et al. 2011

ASSAY and Drug Development Technologies

141

135

View full text Add to dashboard Cite

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“…Fibroblasts derived from healthy subjects (CRL1509, CRL2076 and CRL2097) were purchased from the American Type Culture Collection (Manasses, VA, USA); fibroblasts derived from patients with Gaucher disease homozygous for L444P GCase (GM07968, GM10915, GM08760 and GM00877) or N370S GCase (DMN89.45) were purchased from Coriell (Camden, NJ, USA). LCLs (GS0501, GS0502, GS0503, GS0504 and GS0505) were derived from the blood of patients with Gaucher disease collected in the laboratory of Dr Raphael Schiffmann (National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA) [50]; patient GS501 received a bone marrow tranplantation during infancy. LCLs from healthy volunteers (GM02184 and GM03201, WT0003) were obtained from Coriell.…”

Section: Methodsmentioning

confidence: 99%

The pharmacological chaperone isofagomine increases the activity of the Gaucher disease L444P mutant form of β‐glucosidase

et al. 2010

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Gaucher disease is caused by mutations in the gene that encodes the lysosomal enzyme acid b-glucosidase (GCase). We have shown previously that the small molecule pharmacological chaperone isofagomine (IFG) binds and stabilizes N370S GCase, resulting in increased lysosomal trafficking and cellular activity. In this study, we investigated the effect of IFG on L444P GCase. Incubation of Gaucher patient-derived lymphoblastoid cell lines (LCLs) or fibroblasts with IFG led to approximately 3.5-and 1.3-fold increases in L444P GCase activity, respectively, as measured in cell lysates. The effect in fibroblasts was increased approximately 2-fold using glycoprotein-enrichment, GCase-immunocapture, or by incubating cells overnight in IFG-free media prior to assay, methods designed to maximize GCase activity by reducing IFG carryover and inhibition in the enzymatic assay. IFG incubation also increased the lysosomal trafficking and in situ activity of L444P GCase in intact cells, as measured by reduction in endogenous glucosylceramide levels. Importantly, this reduction was seen only following three-day incubation in IFG-free media, underscoring the importance of IFG removal to restore lysosomal GCase activity. In mice expressing murine L444P GCase, oral administration of IFG resulted in significant increases (2-to 5-fold) in GCase activity in disease-relevant tissues, including brain. Additionally, eight-week IFG administration significantly lowered plasma chitin III and IgG levels, and 24-week administration significantly reduced spleen and liver weights. Taken together, these data suggest that IFG can increase the lysosomal activity of L444P GCase in cells and tissues. Moreover, IFG is orally available and distributes into multiple tissues, including brain, and may thus merit therapeutic evaluation for patients with neuronopathic and non-neuronopathic Gaucher disease.

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Lysosomal Proteins as a Therapeutic Target in Neurodegeneration

Donald

Krainc

2017

Annu. Rev. Med.

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Several proteins that are mutated in lysosomal storage diseases are linked to neurodegenerative disease. This review focuses on some of these lysosomal enzymes and transporters, as well as current therapies that have emerged from the lysosomal storage disease field. Given the deeper genetic understanding of lysosomal defects in neurodegeneration, we explore why some of these orphan disease drug candidates are also attractive targets in subpopulations of individuals with neurodegenerative disease.

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114. Pharmacological chaperone therapy for Gaucher disease: Mechanism of action, a survey of responsive mutations and phase I clinical trial results

Cited by 4 publications

References 0 publications

Identification and Characterization of Pharmacological Chaperones to Correct Enzyme Deficiencies in Lysosomal Storage Disorders

Identification and Characterization of Pharmacological Chaperones to Correct Enzyme Deficiencies in Lysosomal Storage Disorders

The pharmacological chaperone isofagomine increases the activity of the Gaucher disease L444P mutant form of β‐glucosidase

Lysosomal Proteins as a Therapeutic Target in Neurodegeneration

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