Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis

Jamalpoor, Amer; Othman, Amr; Levtchenko, Elena; Masereeuw, Rosalinde; Janssen, Manoe J.

doi:10.1016/j.molmed.2021.04.004

Cited by 25 publications

(22 citation statements)

References 107 publications

(139 reference statements)

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“…However, cysteamine treatment is hampered by side effects and poor tolerance, and it does not prevent or treat PT dysfunction [63]. Stem cells and gene therapy treatments, which rescued the eyes, kidneys, and thyroid in Ctns knockout (KO) mice, and are currently being tested in cystinosis patients, are limited by complexity and high costs [57,64]. Thus, there is an urgent need to identify safe and cost-effective therapeutics for patients with cystinosis.…”

Section: Cystinosis As a Paradigm Of Endolysosome Disease Causing Pt Dysfunctionmentioning

confidence: 99%

“…The molecular understanding of regulatory circuitries coupling endolysosome disease, autophagy, and epithelial dysfunction might thus guide the discovery and development of targeted therapeutics for cystinosis patients [57,64]. In this case, interventions that are aimed to target each step of the pathogenic cascade might mediate beneficial effects and potentially counteract the homeostatic perturbations imposed by cystinosin loss and the resulting cystine storage.…”

Section: Pharmacological Modulation Of Autophagy As a Targetable Pathway In Cystinosismentioning

confidence: 99%

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Defective Cystinosin, Aberrant Autophagy−Endolysosome Pathways, and Storage Disease: Towards Assembling the Puzzle

Rega

Leo

Nieri

et al. 2022

Cells

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Epithelial cells that form the kidney proximal tubule (PT) rely on an intertwined ecosystem of vesicular membrane trafficking pathways to ensure the reabsorption of essential nutrients—a key requisite for homeostasis. The endolysosome stands at the crossroads of this sophisticated network, internalizing molecules through endocytosis, sorting receptors and nutrient transporters, maintaining cellular quality control via autophagy, and toggling the balance between PT differentiation and cell proliferation. Dysregulation of such endolysosome-guided trafficking pathways might thus lead to a generalized dysfunction of PT cells, often causing chronic kidney disease and life-threatening complications. In this review, we highlight the biological functions of endolysosome-residing proteins from the perspectives of understanding—and potentially reversing—the pathophysiology of rare inherited diseases affecting the kidney PT. Using cystinosis as a paradigm of endolysosome disease causing PT dysfunction, we discuss how the endolysosome governs the homeostasis of specialized epithelial cells. This review also provides a critical analysis of the molecular mechanisms through which defects in autophagy pathways can contribute to PT dysfunction, and proposes potential interventions for affected tissues. These insights might ultimately accelerate the discovery and development of new therapeutics, not only for cystinosis, but also for other currently intractable endolysosome-related diseases, eventually transforming our ability to regulate homeostasis and health.

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Section: Cystinosis As a Paradigm Of Endolysosome Disease Causing Pt Dysfunctionmentioning

confidence: 99%

Section: Pharmacological Modulation Of Autophagy As a Targetable Pathway In Cystinosismentioning

confidence: 99%

Defective Cystinosin, Aberrant Autophagy−Endolysosome Pathways, and Storage Disease: Towards Assembling the Puzzle

Rega

Leo

Nieri

et al. 2022

Cells

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“…One of the first manifestations of cystinosis is the clinical presentation of renal Fanconi syndrome, characterized by a severe proximal tubule cell dysfunction at early stages of the disease, which results in a total loss of integrity of the proximal tubule [ 7 ]. Great efforts have been made to elucidate further the underlying pathological mechanisms of nephropathic cystinosis that revealed several hallmarks beyond cystine accumulation, including impaired autophagy, mTOR activation, disrupted vesicle dynamics (lysosomes-autophagosomes interactions), mitochondrial impairment, reactive oxygen species (ROS), and increased cell stress [ 8 , 9 , 10 , 11 , 12 , 13 ]. Despite clinical improvements in prognosis, there is, as of yet, no curative therapy available for cystinosis.…”

Section: Introductionmentioning

confidence: 99%

Bioengineered Cystinotic Kidney Tubules Recapitulate a Nephropathic Phenotype

Garví

Masereeuw

Janssen

2022

Cells

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Nephropathic cystinosis is a rare and severe disease caused by disruptions in the CTNS gene. Cystinosis is characterized by lysosomal cystine accumulation, vesicle trafficking impairment, oxidative stress, and apoptosis. Additionally, cystinotic patients exhibit weakening and leakage of the proximal tubular segment of the nephrons, leading to renal Fanconi syndrome and kidney failure early in life. Current in vitro cystinotic models cannot recapitulate all clinical features of the disease which limits their translational value. Therefore, the development of novel, complex in vitro models that better mimic the disease and exhibit characteristics not compatible with 2-dimensional cell culture is of crucial importance for novel therapies development. In this study, we developed a 3-dimensional bioengineered model of nephropathic cystinosis by culturing conditionally immortalized proximal tubule epithelial cells (ciPTECs) on hollow fiber membranes (HFM). Cystinotic kidney tubules showed lysosomal cystine accumulation, increased autophagy and vesicle trafficking deterioration, the impairment of several metabolic pathways, and the disruption of the epithelial monolayer tightness as compared to control kidney tubules. In particular, the loss of monolayer organization and leakage could be mimicked with the use of the cystinotic kidney tubules, which has not been possible before, using the standard 2-dimensional cell culture. Overall, bioengineered cystinotic kidney tubules recapitulate better the nephropathic phenotype at a molecular, structural, and functional proximal tubule level compared to 2-dimensional cell cultures.

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“…In INC, several mechanisms account for the phenotype ( 10 ). However, despite many efforts, it is still not fully known how these mechanisms are interlinked or how they impact upon the clinical course of the disease.…”

Section: Introductionmentioning

confidence: 99%

“…Following loss of function of cystinosin in INC, the amino-acid accumulates and crystallizes inside the lysosome ( 11 ). Alterations in mitochondrial metabolism, lysosomal dynamics, autophagy, apoptosis, the mTORC1-pathway and inflammatory responses have also been explored in INC ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

Patients With Infantile Nephropathic Cystinosis in Germany and Austria: A Retrospective Cohort Study

O'Connell

Arbeiter

et al. 2022

Front. Med.

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BackgroundInfantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder resulting in progressive chronic kidney disease (CKD) and a variety of extrarenal manifestations. This orphan disease remains a challenge for patients, their families and health care providers. There is currently no comprehensive study on patients' clinical course in Germany and Austria.MethodsA retrospective cohort study including 74 patients at eleven centers of care was conducted. Data on time of diagnosis, CKD stage, leukocyte cystine levels (LCL), extrarenal manifestations, and treatment was collected from medical charts and subsequently analyzed using explorative statistics. Age at initiation of kidney replacement therapy (KRT) was evaluated by Kaplan–Meier analyses for different groups of patients.ResultsPatients were diagnosed at a median age of 15 months (IQR: 10–29, range: 0–110), more recent year of birth was not associated with earlier diagnosis. Oral cystine-depleting therapy (i.e., cysteamine) was prescribed at a median dose of 1.26 g/m2 per day (IQR: 1.03–1.48, range: 0.22–1.99). 69.2% of all 198 LCL measurements of 67 patients were within the desired target range (≤ 1 nmol cystine/mg protein). Median time-averaged LCLs per patient (n = 65) amounted to 0.57 nmol cystine/mg protein (IQR: 0.33–0.98, range: 0.07–3.13) when considering only values at least 1 year after initiation of therapy. The overall median height of 242 measurements of 68 patients was at the 7th percentile (IQR: 1–25, range: 1–99). 40.5% of the values were ≤ the 3rd percentile. Patient sex and year of birth were not associated with age at initiation of KRT, but patients diagnosed before the age of 18 months required KRT significantly later than those patients diagnosed at the age of ≥ 18 months (p = 0.033): median renal survival was 21 years (95% CI: 16, -) vs. 13 years (95% CI, 10, -), respectively.ConclusionEarly diagnosis and initiation of cystine depleting therapy is important for renal survival in children with INC. Cysteamine doses and LCL showed that treatment in this cohort met international standards although there is great interindividual variety. Patient growth and other aspects of the disease should be managed more effectively in the future.

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Molecular Mechanisms and Treatment Options of Nephropathic Cystinosis

Cited by 25 publications

References 107 publications

Defective Cystinosin, Aberrant Autophagy−Endolysosome Pathways, and Storage Disease: Towards Assembling the Puzzle

Defective Cystinosin, Aberrant Autophagy−Endolysosome Pathways, and Storage Disease: Towards Assembling the Puzzle

Bioengineered Cystinotic Kidney Tubules Recapitulate a Nephropathic Phenotype

Patients With Infantile Nephropathic Cystinosis in Germany and Austria: A Retrospective Cohort Study

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