Dent Disease

Dent Disease is a rare kidney disorder inherited in an X-linked fashion, characterized by a malfunction of renal tubules, particularly the proximal tubules. This disorder has a progression pathway that includes low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, and often leads to end-stage renal failure. Protheragen provides drug and therapeutic development services for rare kidney diseases, including Dent disease.

Introduction to Dent Disease

Dent Disease is a rare X-linked renal tubulopathy with a prevalence estimate ranging from 1 in 100,000 to 1 in 500,000 live births. Males with the disorder are severely affected while females are usually asymptomatic carriers or manifest milder signs. The condition is chiefly linked to mutations in two genes, CLCN5 (Dent Disease 1) and OCRL (Dent Disease 2) which is less frequent. Both genes CLCN5 and OCRL encode for proteins required for the endosomal and lysosomal trafficking in the proximal tubules of the kidneys.

Pathogenesis of Dent Disease

Fig.1 Histological signs of proximal tubule dedifferentiation in the context of Dent disease type 1 and hypothesis on the pathogenesis of Dent disease type 1 (DD1). (de Combiens, Sakhi and Lourdel, 2024)

The pathogenesis of Dent Disease originates from mutations that affect the proximal tubule cell biology of certain essential proteins. In the case of Dent Disease 1, the mutations are located in the CLCN5 gene which disrupts the ClC-5 chloride channel leading to the malfunction of endosomal acidification and receptor-mediated endocytosis in renal proximal tubular cells. This malfunction results in insufficient reabsorption of the filtered proteins, which contributes to proteinuria, and calcium and phosphate metabolism is hampered, leading to hypercalciuria and hypophosphatemia. In Dent Disease 2, the OCRL gene mutation is associated with the same proximal tubular dysfunction. All of these disorders together compromise the reabsorptive function of the proximal tubules as a result of which there is chronic disturbance of electrolytes and progressive impaired renal function.

Therapeutic Development for Dent Disease

Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.

Our Services

Protheragen specializes in developing advanced disease models for Dent disease and offers comprehensive preclinical therapeutic development services. We focus on understanding the diverse genetic and cellular impacts that lead to Dent disease and its progressive renal manifestations.

Therapeutic Development Platform for Dent Disease

Protheragen combines deep expertise in renal tubular physiology, membrane transport, lysosomal biology, and rare genetic disorders with advanced molecular and cellular technologies to address the multifaceted mechanisms leading to Dent disease.

Disease Models Development for Dent Disease

Developing innovative and comprehensive disease models is central to advancing preclinical research for Dent disease. Our integrated platform effectively captures the tubular dysfunction, endosomal trafficking defects, and progressive kidney damage that cause Dent disease, supporting extensive drug discovery and mechanism-based investigations focused on renal physiology and pathology.

Cell-based & Organoid Models

• CLCN5-deficient proximal tubule cell
• OCRL1-deficient proximal tubule cell
• Megalin trafficking-defective epithelial model
• Patient-derived proximal tubule organoid
• Isogenic control renal organoid

Animal Models Development

• Clcn5 knockout mouse
• Proximal tubule-specific Clcn5 KO mouse
• Ocrl1 point mutation rat
• clcn5 morpholino knockdown zebrafish
• Humanized CLCN5 mutation rabbit

Drug Pharmacokinetics & Safety Evaluation Services

In Vitro ADME Services

• Renal Clearance Assay
• Drug-Transporter Interaction Screening
• Metabolic Stability Assay
• CYP Inhibition Screening
• Plasma Protein Binding

In Vivo Pharmacokinetics Services

• PK Studies in Renal Impairment Models
• Kidney Tissue Distribution Study
• Blood-to-Plasma Ratio
• Metabolite Profiling

Drug Safety Evaluation

• General Toxicology Evaluation
• Genetic Toxicology Evaluation
• Developmental and Reproductive Toxicity Evaluation

• Immunogenicity and Immunotoxicity Evaluation
• Local Toxicity Evaluation
• Phototoxicity Evaluation

• Tissue Cross-Reactivity Evaluation
• Safety Pharmacology Evaluation
• Toxicokinetic Evaluation

Protheragen offers integrated preclinical development solutions specifically designed for research in rare kidney disorders like Dent Disease. We specialize in disease model development, pharmacokinetics, and drug safety evaluation, enabling us to support your investigation from the initial stages to preclinical validation.

If you are interested in our services, please don't hesitate to contact us.

References

1. de Combiens, E., I. B. Sakhi, and S. Lourdel. "A Focus on the Proximal Tubule Dysfunction in Dent Disease Type 1." Genes (Basel) 15.9 (2024).
2. Gianesello, L., et al. "From Protein Uptake to Dent Disease: An Overview of the Clcn5 Gene." Gene 747 (2020): 144662.

All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.