Gitelman Syndrome (GS) is a rare, inherited disorder of renal tubular function, characterized by defects in electrolyte transport that lead to hypokalemia, hypomagnesemia, metabolic alkalosis, and low blood pressure. Protheragen provides comprehensive preclinical drug and therapy development services specifically tailored to address the unique mechanisms of Gitelman syndrome, with a focused expertise on renal-related therapeutic strategies.
Introduction to Gitelman Syndrome
Gitelman Syndrome (GS) is rare and is considered an autosomal recessive disorder. The disorder is associated with onset in childhood or during adolescence and is associated with mutations in SLC12A3 thiazide-sensitive sodium chloride symporter (NCC) gene which electrolytic transport. The sodium and chloride reabsorbed deficiency due to GS leads towards renal distal convoluted tubule hypokaliemia, hypomagnesemia, metabolic alkalosis and hypomagnesemia. While affected individuals experience broad clinical muscle cramps, fatigue, dizziness, and in severe cases, growth retardation. The estimated prevalence is considered to be 1 in 40000 to 1 in 100000 and is believed to be underreported due to non-specific symptoms.
Pathogenesis of Gitelman Syndrome
Fig.1 Mechanism of hypocalciuria in Gitelman syndrome. (Hibino
et al., 2020)
The SLC12A3 mutations in Gitelman Syndrome results in the malfunctioning of thiazide sensitive sodium-chloride symporter (NCC) located in the distal convoluted tubule of the kidney. This malfunction leads to decreased sodium, chloride, magnesium, and potassium reabsorption. The disruption of the electrolyte imbalance triggers a cascade of compensatory mechanisms including the increased release of the renin-angiotensin-aldosterone system (RAAS) which further increases sodium and water retention while exacerbating the loss of potassium. Chronic hypokalemia and hypomagnesemia may occur which in turn contributes to further muscle weakness and fatigue and increased the risk of arrhythmias. Though GS can be regarded primarily a renal disorder, the systemic effects and the kidney's regulatory functions of electrolyte balance influences other organ systems, including the cardiovascular and muscular system.
Therapeutics Development for Gitelman Syndrome
| Drug Name |
Therapeutic Target |
Key Mechanisms/Advances |
Development Stage |
| Indomethacin |
COX-1/COX-2 |
Inhibits prostaglandin E2 synthesis to reduce potassium/magnesium wasting; long-term use increases serum K+ by 1.3 mmol/L |
Phase III |
| Celecoxib |
COX-2 |
Selective COX-2 inhibitor maintains PGE2-lowering efficacy with reduced nephrotoxicity risk |
Phase II |
| AAV9-SLC12A3 |
SLC12A3 gene |
AAV9 vector delivers functional NCC gene; restores 30% tubular NCC expression in mouse models |
Preclinical |
| 4-Phenylbutyrate (4-PBA) |
NCC protein |
Molecular chaperone corrects folding defects in NCC missense mutants (e.g., p.Gly630Arg) |
Preclinical |
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 leader in preclinical therapeutic development, focusing on Gitelman syndrome through advanced disease models and therapeutic platforms. Our services are designed to explore novel treatments for GS by targeting the underlying genetic defects and restoring electrolyte balance, ultimately improving patient quality of life and preventing long-term complications.
Therapeutic Development Platforms for Gitelman Syndrome
Disease Models Development for Gitelman Syndrome
Protheragen offers innovative and comprehensive disease models to advance preclinical research into Gitelman syndrome. Our platform integrates advanced cell-based models, sophisticated kidney organoids, and relevant animal models to better simulate the pathophysiology of GS and screen potential therapies.
- SLC12A3 Knockout Human Renal Cells
- iPSC-Derived Renal Tubuloids
- SLC12A3 Knockout Kidney Organoids
- iPSC-Derived Kidney Organoids
- SLC12A3 Knockout Mice
- SLC12A3 Mutant Mice
- Zebrafish SLC12A3 Knockout Model
- SLC12A3 Deficient Rats
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's integrated preclinical development solutions are specifically designed for research affecting renal systems, such as Gitelman 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 Gitelman syndrome research with end-to-end solutions.
References
- Hibino, S., et al. "Gitelman Syndrome and Focal Segmental Glomerulosclerosis Caused by a Compound Heterozygous Mutation in Ttc21b." Intern Med 59.14 (2020): 1735-38.
- Hildebrandt, F., and H. Omram. "New Insights: Nephronophthisis-Gitelman Syndrome." Pediatr Nephrol 16.2 (2001): 168-76.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
