Denys-Drash Syndrome

Protheragen is at the forefront of preclinical drug and therapy development for rare kidney diseases, including Denys-Drash syndrome. We provide comprehensive, one-stop services, from understanding complex genetic mechanisms to advanced therapeutic validation, with a specialized focus on renal manifestations.

Introduction to Denys-Drash Syndrome

Denys-Drash syndrome (DDS) is an ultra-rare and life-threatening genetic disorder that is caused by the dominant-negative mutations of the WT1 gene. This disorder is characterized by a triad of high-risk Wilms tumor, diffuse mesangial sclerosis nephropathy, and genital anomalies (46, XY DSD). Over 90% of the patients will progress to end-stage renal failure by 4 years of age and also have a greater than 90% risk of developing a Wilms tumor. This presents a dire and critical need for the development of life-saving therapies.

Pathogenesis of Denys-Drash Syndrome

Denys-Drash syndrome (DDS) is caused by heterozygous de novo or inherited germline mutations in the WILMS TUMOR SUPPRESSOR GENE (WT1). It is located on the chromosome 11p13 and is critical for the development of the kidneys and the gonads. The mutations, more frequently missense mutations in exons 8 and 9, which code for the zinc finger DNA binding domains, result in an abnormal WT1 protein. The mutated protein exhibits a "dominant-negative" effect that prevents the proper functioning of the unaffected WT1 allele. This dysfunction in the kidneys results in diffuse mesangial sclerosis, which rapidly progresses to end-stage renal disease (ESRD). There is also an increased risk of Wilms tumor due to the decreased protective effect of WT1 on cell proliferation and differentiation in the kidney.

Fig.1 The consensus DNA binding sequence of WT1. (Hashimoto, 2016)

Therapeutic Development for Denys-Drash Syndrome

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 is a comprehensive preclinical service provider dedicated to the discovery and development of novel therapeutics for Denys-Drash syndrome. Our extensive therapeutic development services incorporate the use of sophisticated disease models that effectively capture important features of this inherited disorder, with a particular focus on its renal manifestations and tumor predisposition.

Therapeutic Development Platform for Denys-Drash Syndrome

Protheragen offers a versatile suite of therapeutic development platforms, adaptable to the unique challenges of Denys-Drash syndrome and other rare kidney diseases. Our integrated approach supports the discovery and optimization of diverse therapeutic modalities.

Disease Models Development for Denys-Drash Syndrome

Protheragen offers innovative and comprehensive disease models to advance preclinical research into Denys-Drash syndrome. Our platform integrates advanced cell-based models, kidney organoids, and animal models to capture the genetic and developmental signatures of Denys-Drash syndrome, focusing on renal pathology, gonad development, and tumorigenesis, thereby supporting extensive drug discovery and mechanism-based investigations.

Cell-based & Organoid Models

• WT1^R394W mutant podocytes
• SIX2⁺ nephron progenitor cells
• TGF-β-hyperresponsive mesangial cells
• WT1^R394W mutant podocytes

Animal Models Development

• Nphs2-Cre; Wt1^R394W mice
• WT1ex9-mut transgenic rats
• Doxy-inducible Wt1-KD zebrafish
• PDX Wilms tumor models

Drug Safety Evaluation & Pharmacokinetics Services

In Vitro ADME Services

• Metabolic Stability Assay
• Plasma Protein Binding
• Renal Tubular Epithelial Cell Uptake & Efflux
• Drug-Transporter Interaction Profiling
• Cellular Permeability

In Vivo Pharmacokinetics Services

• Systemic Pharmacokinetics
• Kidney Tissue Distribution and Retention
• Renal Clearance and Excretion Studies
• Urinary Metabolite Profiling
• Blood-to-Plasma Ratio

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 provides integrated preclinical development solutions specifically designed for research in rare kidney diseases like Denys-Drash syndrome. 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. Bizzarri, C., et al. "Unusual Presentation of Denys-Drash Syndrome in a Girl with Undisclosed Consumption of Biotin." J Clin Res Pediatr Endocrinol 13.3 (2021): 347-52.
2. Hashimoto, H., et al. "Denys-Drash Syndrome Associated Wt1 Glutamine 369 Mutants Have Altered Sequence-Preferences and Altered Responses to Epigenetic Modifications." Nucleic Acids Res 44.21 (2016): 10165-76.

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