Joubert Syndrome (JS)

Joubert syndrome (JS) is a rare, autosomal recessive ciliopathy characterized by a distinctive midbrain-hindbrain malformation known as the "molar tooth sign" on brain imaging. Protheragen offers complete preclinical drug and therapy development services for understanding the complex genetic mechanisms of Joubert syndrome, with a strong focus on its renal manifestations.

Introduction to Joubert Syndrome

Joubert syndrome presents with cerebellar and brainstem malformations, the hallmark molar tooth sign on magnetic resonance imaging, marked hypotonia, ataxia, abnormal eye movements, and progressive developmental delays. Renal sequelae, most frequently manifesting as nephronophthisis and progressive tubulointerstitial nephritis, affect 25–30% of patients and frequently culminate in end-stage renal disease. JS has an estimated incidence of 1 in 80,000–100,000 births yet remains underrecognized, owing to a broad clinical spectrum and considerable genetic heterogeneity. To date, pathogenic variants in more than 35 genes have been documented, including CEP290, TMEM67, and AHI1, all of which encode proteins essential for the assembly and maintenance of the primary cilium.

Pathogenesis of Joubert Syndrome

Joubert syndrome is a genetically diverse condition arising from biallelic mutations in more than 40 distinct genes, all encoding proteins integral to the structure or functionality of the primary cilium or the basal body. Collectively termed the JBTS genes, examples include AHI1, CEP290, TMEM67, RPGRIP1L, and NPHP1. Primary cilia serve as vital sensory projections that detect and convey extracellular signals, thereby ensuring coordinated developmental and homeostatic processes in multiple organ systems.

Fig.1 The phenotypes associated with a loss of TALPID3 in the cell, embryo and human. (Fraser and Davey, 2020)

The pathogenic mutations compromise ciliary integrity, perturbing key signaling cascades that orchestrate organ development. Within the central nervous system, impaired cilia disrupt neuronal migration and differentiation, culminating in the characteristic abnormalities of the brainstem and cerebellum. Renally, mutated cilia in tubular epithelial cells thwart normal nephron maturation and tubular function, setting in motion the gradual dilation of tubules, progressive fibrosis, and a nephronophthisis-like syndrome. Such kidney involvement often underpins the morbidity and the early mortality that can accompany Joubert syndrome. The necessity of properly functioning cilia in diverse tissues accounts for the expansive phenotypic variability and the multi-organ presentation that defines this disorder.

Therapeutic Development for Joubert 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 Joubert 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.

Therapeutic Development Platform for Joubert Syndrome

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

Disease Models Development for Joubert Syndrome

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

Cell-based & Organoid Models

• Patient-derived iPSCs
• CEP290^−/− human proximal tubule cells (HK-2)
• 3D kidney organoids
• Cilia-deficient podocyte/renal tubule co-cultures

Animal Models Development

• Cep290^−/− knockout mice
• Tmem67 KO rats with progressive nephronophthisis
• Ahi1^−/− zebrafish
• Cep290 conditional knockout mice

Drug Pharmacokinetics & Safety Evaluation 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 kidney diseases like Joubert 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. Fraser, A. M., and M. G. Davey. "Talpid3 in Joubert Syndrome and Related Ciliopathy Disorders." Curr Opin Genet Dev 56 (2019): 41-48.
2. Tran, A. M., A. J. Jnah, and M. J. De Castro Pretelt. "Genetics Review: Joubert Syndrome." Neonatal Netw 44.3 (2025): 159-66.

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