Renal-Hepatic-Pancreatic Dysplasia

Renal-Hepatic-Pancreatic Dysplasia (RHPD), or Ivemark II syndrome, is an exceptionally uncommon and frequently lethal globally underdiagnosed condition of the recessive type and is secondary to mutation in autosomal genes. Protheragen is actively working to develop treatments for rare renal disorders. In this section, we detail the entire set of services we offer for renal-hepatic-pancreatic dysplasia.

Introduction to Renal-Hepatic-Pancreatic Dysplasia

RHP is a rare renal disorder resulting in exogenous oligohydramnio with an occurrence less than 1 in one hundred thousand births. It is also known as one of the Ivemark syndromes whereby the dysmorphic kidney and congenital liver cysts that manifest are phenotypically linked to cystic pancreas. The condition is identified in the 2nd trimester and continues to multi organ failure in infancy, claiming 80% mortality by 2 years. Biallelic mutations driven by NPHP3, NEK8 and DZIP1L along with emerging genomic insights are shifting the paradigm with focus on the disrupted renal, hepatic, and pancreatic ciliary signaling.

Pathogenesis of Renal-Hepatic-Pancreatic Dysplasia

The pathogenesis of RHPD is associated with a defect in the genes that encode for ciliary proteins, placing it in the category of a severe ciliopathy. For RHPD Type 1 (RHPD1), the most prevalent genetic factor is biallelic pathogenic variants in NPHP3, which encodes for nephrocystin-3, a fundamental member of the primary cilium. RHPD Type 2 (RHPD2) is associated with NEK8 gene mutations. Primary cilia are vital organ appurtenances that act as sensory organelles and are important in cell signaling, differentiation, and the development of organs in many systems, including the kidney, liver, and pancreas.

Fig.1 Biallelic pathogenic variations in DNAJB11 cause renal-hepatic-pancreatic dysplasia. (Jordan et al., 2023)

The ciliary proteins involved are critical sensors for essential signaling pathways, and their dysfunction leads to disruption across organ systems, resulting in the characteristic embryonic dysplastic changes. Dysplastic changes in the kidneys include abnormal tubule architecture, cystic changes, and various degrees of blocked nephrogenesis. In the liver, this is associated with abnormal bile duct and fibrotic changes. In the pancreas, these changes lead to a fibrotic and cystic organ with decreased parenchyma and resultant endocrine and exocrine insufficiency. There is much variability in the clinical features and age of onset that is determined by the type and severity of genetic alterations, which emphasizes the complexity of these conditions termed ciliopathies.

Therapeutics Development for Renal-Hepatic-Pancreatic Dysplasia

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 advancing the understanding and potential therapeutic avenues for complex genetic disorders like RHPD. Our expertise in developmental genetics, sophisticated disease models, and therapeutic development platforms allows us to support research into its underlying mechanisms and associated syndromic conditions.

Therapeutic Development Platforms for Renal-Hepatic-Pancreatic Dysplasia

• Small Molecule Drug
• Cell Therapy
• Gene Therapy

• Therapeutic Antibody
• Therapeutic Peptide
• Therapeutic Protein

Disease Models Development for Renal-Hepatic-Pancreatic Dysplasia

Protheragen offers innovative and comprehensive disease models to advance the preclinical research of renal-hepatic-pancreatic dysplasia. Our platform integrates cell-based models, kidney organoids, and animal models to effectively capture the ciliary dysfunction and developmental defects that cause RHPD, supporting extensive drug discovery and mechanism-based investigations focused on multi-organ development and pathology.

Cell-based & Organoid Models

• NPHP3^R1377X mutant renal cholangiocytes
• NEK8-KO hepatic ductal organoids
• Pancreatic cystoids with DZIP1L mutations
• Tri-culture microphysiological systems

Animal Models

• Nphp3^del/del knockout mice
• Nek8^jck mice with pancreatic involvement
• dzip1l^vu77 zebrafish
• NPHP3^Y324C knock-in rabbits
• Human hepatopancreatic xenografts in FRGS rats

Drug Pharmacokinetics & Safety Evaluation Services

Protheragen provides integrated preclinical development solutions specifically designed for kidney research like renal-hepatic-pancreatic dysplasia. We specialize in disease model development, pharmacokinetics, and drug safety evaluation, enabling us to support your investigation.

Contact us today to accelerate your renal-hepatic-pancreatic dysplasia research with end-to-end solutions.

References

1. Gunther, K., et al. "Renal-Hepatic-Pancreatic Dysplasia Type 2: Perinatal Lethal Condition or a Multisystemic Disorder with Variable Expressivity." Mol Genet Genomic Med 11.4 (2023): e2135.
2. Jordan, P., et al. "Bi-Allelic Pathogenic Variations in Dnajb11 Cause Ivemark Ii Syndrome, a Renal-Hepatic-Pancreatic Dysplasia." Kidney Int 99.2 (2021): 405-09.

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