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Fibrosis: a key feature of Fabry disease with potential therapeutic implications.

Weidemann F, Sanchez-Niño MD, Politei J, Oliveira JP, Wanner C, Warnock DG, Ortiz A - Orphanet J Rare Dis (2013)

Bottom Line: Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature.However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis.Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Divisions of Cardiology and Nephrology, The Comprehensive Heart Failure Center at the University of Würzburg.

ABSTRACT
Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease.

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Conceptual framework for the design of novel therapeutic approaches to Fabry disease: lessons from diabetic nephropathy. A) Pathogenesis of Fabry fibrosis. The traditional view is that this is a late event secondary to endothelial glycolipid deposition leading to luminal obstruction and ischemia. However, fibrosis in other metabolic disorders, such as diabetes, is known to result from recruitment of secondary mediators of injury by both direct actions of accumulated metabolites (in this case glucose) on target organ cells and also by ischemia. Recent evidence suggests that certain metabolites that accumulate in Fabry disease may recruit secondary mediators of injury in target organ cells. Such pathways might be amenable to therapeutic targeting by preventing the effects of accumulated metabolites on target cell or by targeting the secondary mediators that are recruited. B) Potential impact on therapy of an improved understanding of the pathogenesis of fibrosis in Fabry disease. Current therapy of Fabry disease consists of enzyme replacement therapy (ERT). Substrate reduction therapy (SRT) in under investigation and may further decrease the levels of certain metabolites identified as pro-fibrotic. Identification of metabolites recruiting secondary mediators of injury may eventually lead to therapies preventing their binding to receptors. In addition, anti-proteinuric therapy may decrease the pro-inflammatory, pro-fibrotic effects of proteinuria in the kidney. Certain anti-proteinuric agents have additional anti-fibrotic actions in the kidney and vasculature. Finally, targeting of secondary mediators of fibrosis may further prevent fibrosis progression in patients with more advanced disease for whom correction of the initial metabolic defect may not be sufficient.
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Figure 1: Conceptual framework for the design of novel therapeutic approaches to Fabry disease: lessons from diabetic nephropathy. A) Pathogenesis of Fabry fibrosis. The traditional view is that this is a late event secondary to endothelial glycolipid deposition leading to luminal obstruction and ischemia. However, fibrosis in other metabolic disorders, such as diabetes, is known to result from recruitment of secondary mediators of injury by both direct actions of accumulated metabolites (in this case glucose) on target organ cells and also by ischemia. Recent evidence suggests that certain metabolites that accumulate in Fabry disease may recruit secondary mediators of injury in target organ cells. Such pathways might be amenable to therapeutic targeting by preventing the effects of accumulated metabolites on target cell or by targeting the secondary mediators that are recruited. B) Potential impact on therapy of an improved understanding of the pathogenesis of fibrosis in Fabry disease. Current therapy of Fabry disease consists of enzyme replacement therapy (ERT). Substrate reduction therapy (SRT) in under investigation and may further decrease the levels of certain metabolites identified as pro-fibrotic. Identification of metabolites recruiting secondary mediators of injury may eventually lead to therapies preventing their binding to receptors. In addition, anti-proteinuric therapy may decrease the pro-inflammatory, pro-fibrotic effects of proteinuria in the kidney. Certain anti-proteinuric agents have additional anti-fibrotic actions in the kidney and vasculature. Finally, targeting of secondary mediators of fibrosis may further prevent fibrosis progression in patients with more advanced disease for whom correction of the initial metabolic defect may not be sufficient.

Mentions: Initial symptoms of Fabry disease usually appear in childhood and reduce the quality of life but are not life-threatening[1]. These include angiokeratoma, neuropathic pain, hypohydrosis and digestive tract symptoms. During the second decade of life, potentially life-threatening involvement may develop, including the central nervous system (CNS), including stroke, chronic kidney disease (CKD) usually associated with proteinuria and progressive loss of glomerular filtration rate (GFR), and left ventricular (LV) hypertrophy, arrhythmia and heart failure. Fibrosis of these organs is a key feature of Fabry disease. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management[1,4,5] (Figure 1). ERT is less efficacious when started after the development of tissue injury and specifically, of tissue fibrosis[6]. ERT should be complemented by symptomatic therapy and by adjuvant therapy aimed at modifying the underlying pathogenic mechanisms of tissue injury, such as targeting the renin-angiotensin-aldosterone system (RAAS) to reduce proteinuria[4,5,7]. Novel therapeutic approaches based on a better understanding of pathogenic events are needed to complement ERT and optimize patient outcomes. In this review we discuss the current understanding of fibrosis in Fabry disease, and address following questions: What is the contribution of fibrosis to disease burden in Fabry disease? What are the cellular and molecular mechanisms of fibrosis? How can fibrosis be assessed? And what are the prospects for fibrosis-guided therapy?


Fibrosis: a key feature of Fabry disease with potential therapeutic implications.

Weidemann F, Sanchez-Niño MD, Politei J, Oliveira JP, Wanner C, Warnock DG, Ortiz A - Orphanet J Rare Dis (2013)

Conceptual framework for the design of novel therapeutic approaches to Fabry disease: lessons from diabetic nephropathy. A) Pathogenesis of Fabry fibrosis. The traditional view is that this is a late event secondary to endothelial glycolipid deposition leading to luminal obstruction and ischemia. However, fibrosis in other metabolic disorders, such as diabetes, is known to result from recruitment of secondary mediators of injury by both direct actions of accumulated metabolites (in this case glucose) on target organ cells and also by ischemia. Recent evidence suggests that certain metabolites that accumulate in Fabry disease may recruit secondary mediators of injury in target organ cells. Such pathways might be amenable to therapeutic targeting by preventing the effects of accumulated metabolites on target cell or by targeting the secondary mediators that are recruited. B) Potential impact on therapy of an improved understanding of the pathogenesis of fibrosis in Fabry disease. Current therapy of Fabry disease consists of enzyme replacement therapy (ERT). Substrate reduction therapy (SRT) in under investigation and may further decrease the levels of certain metabolites identified as pro-fibrotic. Identification of metabolites recruiting secondary mediators of injury may eventually lead to therapies preventing their binding to receptors. In addition, anti-proteinuric therapy may decrease the pro-inflammatory, pro-fibrotic effects of proteinuria in the kidney. Certain anti-proteinuric agents have additional anti-fibrotic actions in the kidney and vasculature. Finally, targeting of secondary mediators of fibrosis may further prevent fibrosis progression in patients with more advanced disease for whom correction of the initial metabolic defect may not be sufficient.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750297&req=5

Figure 1: Conceptual framework for the design of novel therapeutic approaches to Fabry disease: lessons from diabetic nephropathy. A) Pathogenesis of Fabry fibrosis. The traditional view is that this is a late event secondary to endothelial glycolipid deposition leading to luminal obstruction and ischemia. However, fibrosis in other metabolic disorders, such as diabetes, is known to result from recruitment of secondary mediators of injury by both direct actions of accumulated metabolites (in this case glucose) on target organ cells and also by ischemia. Recent evidence suggests that certain metabolites that accumulate in Fabry disease may recruit secondary mediators of injury in target organ cells. Such pathways might be amenable to therapeutic targeting by preventing the effects of accumulated metabolites on target cell or by targeting the secondary mediators that are recruited. B) Potential impact on therapy of an improved understanding of the pathogenesis of fibrosis in Fabry disease. Current therapy of Fabry disease consists of enzyme replacement therapy (ERT). Substrate reduction therapy (SRT) in under investigation and may further decrease the levels of certain metabolites identified as pro-fibrotic. Identification of metabolites recruiting secondary mediators of injury may eventually lead to therapies preventing their binding to receptors. In addition, anti-proteinuric therapy may decrease the pro-inflammatory, pro-fibrotic effects of proteinuria in the kidney. Certain anti-proteinuric agents have additional anti-fibrotic actions in the kidney and vasculature. Finally, targeting of secondary mediators of fibrosis may further prevent fibrosis progression in patients with more advanced disease for whom correction of the initial metabolic defect may not be sufficient.
Mentions: Initial symptoms of Fabry disease usually appear in childhood and reduce the quality of life but are not life-threatening[1]. These include angiokeratoma, neuropathic pain, hypohydrosis and digestive tract symptoms. During the second decade of life, potentially life-threatening involvement may develop, including the central nervous system (CNS), including stroke, chronic kidney disease (CKD) usually associated with proteinuria and progressive loss of glomerular filtration rate (GFR), and left ventricular (LV) hypertrophy, arrhythmia and heart failure. Fibrosis of these organs is a key feature of Fabry disease. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management[1,4,5] (Figure 1). ERT is less efficacious when started after the development of tissue injury and specifically, of tissue fibrosis[6]. ERT should be complemented by symptomatic therapy and by adjuvant therapy aimed at modifying the underlying pathogenic mechanisms of tissue injury, such as targeting the renin-angiotensin-aldosterone system (RAAS) to reduce proteinuria[4,5,7]. Novel therapeutic approaches based on a better understanding of pathogenic events are needed to complement ERT and optimize patient outcomes. In this review we discuss the current understanding of fibrosis in Fabry disease, and address following questions: What is the contribution of fibrosis to disease burden in Fabry disease? What are the cellular and molecular mechanisms of fibrosis? How can fibrosis be assessed? And what are the prospects for fibrosis-guided therapy?

Bottom Line: Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature.However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis.Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Medicine, Divisions of Cardiology and Nephrology, The Comprehensive Heart Failure Center at the University of Würzburg.

ABSTRACT
Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease.

Show MeSH
Related in: MedlinePlus