Dataset Information

Macrophage models of Gaucher disease for evaluating disease pathogenesis and candidate drugs.

ABSTRACT: Gaucher disease is caused by an inherited deficiency of glucocerebrosidase that manifests with storage of glycolipids in lysosomes, particularly in macrophages. Available cell lines modeling Gaucher disease do not demonstrate lysosomal storage of glycolipids; therefore, we set out to develop two macrophage models of Gaucher disease that exhibit appropriate substrate accumulation. We used these cellular models both to investigate altered macrophage biology in Gaucher disease and to evaluate candidate drugs for its treatment. We generated and characterized monocyte-derived macrophages from 20 patients carrying different Gaucher disease mutations. In addition, we created induced pluripotent stem cell (iPSC)-derived macrophages from five fibroblast lines taken from patients with type 1 or type 2 Gaucher disease. Macrophages derived from patient monocytes or iPSCs showed reduced glucocerebrosidase activity and increased storage of glucocerebroside and glucosylsphingosine in lysosomes. These macrophages showed efficient phagocytosis of bacteria but reduced production of intracellular reactive oxygen species and impaired chemotaxis. The disease phenotype was reversed with a noninhibitory small-molecule chaperone drug that enhanced glucocerebrosidase activity in the macrophages, reduced glycolipid storage, and normalized chemotaxis and production of reactive oxygen species. Macrophages differentiated from patient monocytes or patient-derived iPSCs provide cellular models that can be used to investigate disease pathogenesis and facilitate drug development.

SUBMITTER: Aflaki E

PROVIDER: S-EPMC4161206 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Macrophage models of Gaucher disease for evaluating disease pathogenesis and candidate drugs.

Aflaki Elma E Stubblefield Barbara K BK Maniwang Emerson E Lopez Grisel G Moaven Nima N Goldin Ehud E Marugan Juan J Patnaik Samarjit S Dutra Amalia A Southall Noel N Zheng Wei W Tayebi Nahid N Sidransky Ellen E

Science translational medicine 20140601 240

Gaucher disease is caused by an inherited deficiency of glucocerebrosidase that manifests with storage of glycolipids in lysosomes, particularly in macrophages. Available cell lines modeling Gaucher disease do not demonstrate lysosomal storage of glycolipids; therefore, we set out to develop two macrophage models of Gaucher disease that exhibit appropriate substrate accumulation. We used these cellular models both to investigate altered macrophage biology in Gaucher disease and to evaluate candi ...[more]

PMID: 24920659

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Project description:The Disease Severity Scoring System (DS3) is a validated measure for evaluating Gaucher disease type 1 (GD1) severity. We developed a new framework, consisting of health states, transition probabilities between those states, and preferences for those states (utilities) based on the DS3 to predict long-term outcomes of patients starting treatment. We defined nine mutually exclusive (alive) health states based on three DS3 categories: mild (0 ? DS3 ? 3.5) without symptoms of bone disease; mild with bone pain, mild with severe skeletal complications (SSC) defined as lytic lesions, avascular necrosis, or fracture; moderate (3.5?<?DS3 ? 6.5) without SSC; moderate with SSC; marked (6.5?<?DS3 ? 9.5) without SSC; marked with SSC; severe (9.5?<?DS3 ? 19) without SSC; and severe with SSC. Health-state transition probabilities and utilities were estimated from a longitudinal sample of patients with GD1 who started enzyme replacement therapy (the DS3 Score Study). Age dependent GD1-specific mortality was derived from published data. We used a Markov state-transition model to illustrate how to estimate time spent in each health state.The average predicted utilities for each health state ranged from 0.76 for mild disease with no clinical symptoms of bone disease to 0.52 with severe disease with SSC. Transition probabilities depended on disease severity (DS3 score) at treatment initiation and whether patients had undergone a total splenectomy or had an intact spleen/partial splenectomy prior to starting treatment. Patients who started treatment with intact or residual spleens spent more time in better health states than those who started treatment with total splenectomy.This new framework, which is based on the DS3, can be used to project the long-term outcomes of GD1 patients starting treatment. The framework could also be used to compare the long-term outcomes of different GD1 treatment options.NCT01136304 . Registered: May 31, 2010 (retrospectively registered).

Dataset Information

Macrophage models of Gaucher disease for evaluating disease pathogenesis and candidate drugs.

Publications

Macrophage models of Gaucher disease for evaluating disease pathogenesis and candidate drugs.

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