Meckel–Gruber Syndrome (MKS)

Meckel–Gruber syndrome (MKS) is a severe, lethal, autosomal recessive ciliopathy characterized by a classic triad of occipital encephalocele, postaxial polydactyly, and multiple renal cysts. Protheragen provides comprehensive preclinical drug and therapy development services specifically tailored to address the unique mechanisms of MKS, with a focused expertise on renal-related therapeutic strategies.

Overview of Meckel–Gruber Syndrome

Meckel–Gruber syndrome is a rare recessive disorder estimated at ~1:13,000–140,000 live births, with markedly higher frequency in consanguineous populations. The clinical phenotype comprises progressive, bilateral multicystic kidneys, occipital encephalocele, and postaxial polydactyly, the latter sometimes limited to a single limb. Mutations in MKS1, TMEM67, CEP290, and at least a dozen additional ciliopathy genes have been implicated. Fatality commonly occurs before 28 weeks, and renal dysplasia is present in >90% of cases, placing MKS among the most devastating inherited renal conditions.

Pathogenesis of Meckel–Gruber Syndrome

MKS derives from double-hit inheritance, with any pair of mutations across 14 established loci (MKS1, TMEM67, CEP290, and the others) providing a lethal signal. The encoded proteins converge on the primary cilium, the basal body, or the centrosome, confirming the pivotal role of ciliary architecture in renal, cranial, and limb development. Such convergence makes MKS a quintessential model of ciliopathy, yet also establishes a therapeutic frontier for cilium-targeted interventions.

Fig.1 Ciliary proteins, including those mutated in Meckel-Gruber Syndrome (MKS) and related ciliopathies, contribute to the ciliary gate and selective transport of cargo proteins. (Hartill et al., 2017)

Mutations in the MKS genes give rise to pronounced deficits in the assembly, upkeep, or function of primary cilia. Such ciliary failure perturbs essential developmental programs, especially those orchestrating organ formation. Within the kidneys, compromised cilia in the epithelial cells of renal tubules trigger heightened cell proliferation, blunted tubular maturation, and extensive cystic dilation, culminating in life-threatening cystic kidney disease and eventual renal failure. The universal character of the ciliary defect accounts for the wide-ranging organ involvement, which includes malformations of the central nervous system and atypical limb development that characterize the MKS phenotype.

Therapeutics Development for Meckel–Gruber 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 Meckel–Gruber syndrome. Our extensive therapeutic development services incorporate the use of sophisticated disease models that effectively capture important features of this disorder, with a particular focus on its severe renal manifestations.

Therapeutic Development Platforms for Meckel–Gruber Syndrome

• Small Molecule Drug
• Cell Therapy
• Gene Therapy

• Therapeutic Antibody
• Therapeutic Peptide
• Therapeutic Protein

Disease Models Development for Meckel–Gruber Syndrome

Protheragen offers innovative and comprehensive disease models to advance preclinical research into Meckel–Gruber syndrome. Our platform integrates advanced cell-based models, kidney organoids, and animal models. These models are meticulously developed and characterized robust target identification and comprehensive therapeutic efficacy testing for MKS-specific pathways, particularly those impacting renal health.

Cell-based & Organoid Models

• Patient-derived iPSCs (from MKS patients)
• Ciliary gene mutant cell lines
• iPSC-based kidney organoids
• Ciliary gene mutant kidney organoids

Animal Models

• Tmem67 mutant zebrafish models
• Mks1 mutant zebrafish models
• Mks1 knockout mice
• Tmem67 mutant mice

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's integrated preclinical development solutions are specifically designed for research in rare kidney diseases and complex developmental disorders like Meckel–Gruber syndrome. We specialize in comprehensive disease model development, pharmacokinetics, and drug safety evaluation, enabling us to support your therapeutic investigations from initial target validation to IND-enabling studies.

Contact us today to accelerate your Meckel–Gruber syndrome research with end-to-end solutions.

References

1. Gupta, A., et al. "Meckel-Gruber Syndrome: Prenatal Diagnosis of a Lethal Ciliopathy with Multisystem Anomalies." J Obstet Gynaecol Can 47.1 (2025): 102716.
2. Hartill, V., et al. "Meckel-Gruber Syndrome: An Update on Diagnosis, Clinical Management, and Research Advances." Front Pediatr 5 (2017): 244.

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