Targeting oxidative stress-induced lipid peroxidation enhances podocyte function in cystinosis.

Background: Cystinosis is a rare, incurable lysosomal storage disease caused by mutations in the CTNS gene encoding the cystine transporter cystinosin, which leads to lysosomal cystine accumulation in all cells of the body. Patients with cystinosis display signs of podocyte damage characterized by extensive loss of podocytes into the urine at early disease stages, glomerular proteinuria, and the development of focal segmental glomerulosclerosis (FSGS) lesions. Although standard treatment with cysteamine decreases cellular cystine levels, it neither reverses glomerular injury nor prevents the loss of podocytes.

depletion reduces cystine accumulation without improvement in proximal tubular function in experimental models for cystinosis.

Cystinosis is an autosomal recessive lysosomal storage disorder, caused by mutations in the gene, resulting in an absent or altered cystinosin (CTNS) protein. Cystinosin exports cystine out of the lysosome, with a malfunction resulting in cystine accumulation and a defect in other cystinosin-mediated pathways. Cystinosis is a systemic disease, but the kidneys are the first and most severely affected organs.

Evaluation of the efficacy of cystinosin supplementation through CTNS mRNA delivery in experimental models for cystinosis.

Messenger RNA (mRNA) therapies are emerging in different disease areas, but have not yet reached the kidney field. Our aim was to study the feasibility to treat the genetic defect in cystinosis using synthetic mRNA in cell models and ctns zebrafish embryos. Cystinosis is a prototype lysosomal storage disorder caused by mutations in the CTNS gene, encoding the lysosomal cystine-H symporter cystinosin, and leading to cystine accumulation in all cells of the body.

The Zebrafish Embryo as a Model Organism for Testing mRNA-Based Therapeutics.

mRNA-based therapeutics have revolutionized the world of molecular therapy and have proven their potential in the vaccination campaigns for SARS-CoV2 and clinical trials for hereditary disorders. Preclinical studies have mainly focused on in vitro and rodent studies. However, research in rodents is costly and labour intensive, and requires ethical approval for all interventions.

The Pitfall of White Blood Cell Cystine Measurement to Diagnose Juvenile Cystinosis.

Cystinosis is an autosomal recessive lysosomal storage disease, caused by mutations in the CTNS gene, resulting in multi-organ cystine accumulation. Three forms of cystinosis are distinguished: infantile and juvenile nephropathic cystinosis affecting kidneys and other organs such as the eyes, endocrine system, muscles, and brain, and adult ocular cystinosis affecting only the eyes. Currently, elevated white blood cell (WBC) cystine content is the gold standard for the diagnosis of cystinosis.

The potential of RNA-based therapy for kidney diseases.

Inherited kidney diseases (IKDs) are a large group of disorders affecting different nephron segments, many of which progress towards kidney failure due to the absence of curative therapies. With the current advances in genetic testing, the understanding of the molecular basis and pathophysiology of these disorders is increasing and reveals new potential therapeutic targets. RNA has revolutionized the world of molecular therapy and RNA-based therapeutics have started to emerge in the kidney field.

Urine-Derived Kidney Progenitor Cells in Cystinosis.

Nephropathic cystinosis is an inherited lysosomal storage disorder caused by pathogenic variants in the cystinosin () gene and is characterized by the excessive shedding of proximal tubular epithelial cells (PTECs) and podocytes into urine, development of the renal Fanconi syndrome and end-stage kidney disease (ESKD). We hypothesized that in compensation for epithelial cell losses, cystinosis kidneys undertake a regenerative effort, and searched for the presence of kidney progenitor cells (KPCs) in the urine of cystinosis patients. Urine was cultured in a specific progenitor medium to isolate undifferentiated cells.

Urine-Derived Epithelial Cells as Models for Genetic Kidney Diseases.

Epithelial cells exfoliated in human urine can include cells anywhere from the urinary tract and kidneys; however, podocytes and proximal tubular epithelial cells (PTECs) are by far the most relevant cell types for the study of genetic kidney diseases. When maintained in vitro, they have been proven extremely valuable for discovering disease mechanisms and for the development of new therapies. Furthermore, cultured patient cells can individually represent their human sources and their specific variants for personalized medicine studies, which are recently gaining much interest.