Familial hypocalciuric hypercalcemia (FHH) is a genetic disorder of calcium metabolism that is characterized by the following: hypercalemia, relative hypocalciuria, and inappropriately normal or slightly elevated parathyroid hormone (PTH) levels. Protheragen delivers end-to-end preclinical development services to accelerate therapeutic innovation for familial hypocalciuric hypercalcaemia.
Overview of Familial Hypocalciuric Hypercalcaemia
Familial Hypocalciuric Hypercalcaemia (FHH) is a rare genetic disorder wherein calcium levels in the blood are elevated (hypercalcemia) and calcium is excreted in urine at a low rate (hypocalciuria). It has a mutation in the genes that control calcium and calcium parathyroid receptors (CaSR) which is responsible for calcium homeostasis. It is commonly transmitted in families in an autosomal dominant fashion. It can manifest in a broad spectrum of symptoms ring an asymptomatic condition towards more severe forms such as urinary lithiasis, nephrocalcinosis, and chronic renal failure. The prevalence of FHH is thought to be extremely low and there have been reports of FHH at 1 in 100000.
Pathogenesis of Familial Hypocalciuric Hypercalcaemia
Familial hypocalciuric hypercalcaemia (FHH) is a genetic disorder primarily due to mutations in the CaSR gene which encodes the calcium-sensing receptor (CaSR) of the body. Calcium homeostasis is maintained through precise control of calcium level, parathyroid hormone secretion, and calcium-sensing receptors in the body. Defects in CaSR gene mutations cause the receptor to lack sensitivity to calcium, which creates a disruption to the balance of calcium homeostasis. Patients suffering from FHH will therefore have elevated serum calcium level and diminished urinary calcium excretion in comparison to normal individuals in a hypercalcemic state.
Fig.1 Schematic model of calcium-sensing receptor and selected downstream pathways. (Sezer
et al., 2025)
More recent works studying the clinical diversity of FHH have also been contributing to the understanding of its genetic basis through the study of mutations in the GNA11 and AP2S1 genes which encode proteins of the CaSR signaling pathways. Defects of the calcium-sensing receptor can have a central change on the kidney, but also have peripheral effects on the bone and parathyroid gland.
Therapeutics Development for Familial Hypocalciuric Hypercalcaemia
| Drug Name |
Molecular Target |
Mechanism & Key Findings |
Development Stage |
| Cinacalcet |
CaSR |
Allosteric activator enhancing CaSR sensitivity to calcium, suppresses PTH secretion; maintains long-term normocalcemia |
Approved |
| Etelcalcetide |
CaSR |
Intravenous CaSR allosteric activator; mechanism identical to cinacalcet; explores extended indications |
Phase II |
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 dedicated to advancing the development of therapies for familial hypocalciuric hypercalcaemia. With our cutting-edge platforms, we provide comprehensive, end-to-end preclinical services for FHH therapeutic development. Our goal is to support the acceleration of novel treatments for hypercalcaemia-related renal diseases, from early-stage discovery through preclinical validation.
Therapeutic Development Platforms for Familial Hypocalciuric Hypercalcaemia
Disease Models Development for Familial Hypocalciuric Hypercalcaemia
Protheragen offers a suite of specialized disease models designed to accelerate the preclinical research and development of therapies for FHH. Our platform integrates state-of-the-art cell-based models, kidney organoids, and animal models. These models are developed and characterized using multi-omics approaches and techniques to support drug discovery and therapeutic efficacy testing specific to FHH pathways.
Cell-based & Organoid Models
- FHH patient-derived iPSC line
- CASR-mutant renal tubular epithelial cells
- Parathyroid chief cell differentiation model
- 3D nephron segment co-culture
- FHH patient-derived kidney tubuloid
Animal Models
- Tubule-specific Casr KO mouse
- Parathyroid CASR p.R185Q knock-in rat
- Casr morpholino knockdown zebrafish
- Humanized AP2S1 mutation rabbit
- Double mutant Casr/Gna11 mouse
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
Protheragen is committed to accelerating therapeutic development for rare kidney diseases like familial hypocalciuric hypercalcaemia. By leveraging our state-of-the-art platforms, we provide full-service preclinical support, disease model development to pharmacokinetics and safety evaluation. Our expertise ensures that you can move from target discovery to preclinical validation with the confidence that your therapeutic candidate is poised for success.
If you are interested in our specialized services, please do not hesitate to contact us.
References
- Getwan, M., et al. "Ttc30a Affects Tubulin Modifications in a Model for Ciliary Chondrodysplasia with Polycystic Kidney Disease." Proc Natl Acad Sci U S A 118.39 (2021). Print.
- Sezer, A., et al. "A Homozygous Frameshift Variant in the Cilk1 Gene Causes Familial Hypocalciuric Hypercalcaemia." Eur J Hum Genet (2025). Print.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
