Familial kidney stone disease includes a collection of familial disorders where specific renal transport or metabolic pathways defect leads to a predisposition for kidney stone formation. Protheragen provides complete preclinical drug and therapy development services aimed at the distinguishing mechanisms of various kinds of familial kidney stone disease.
Overview of Familial Kidney Stone Disease
Familial kidney stone disease includes monogenic cystinuria due to mutations in SLC3A1/SLC7A9, and primary hyperoxaluria due to AGXT/GRHPR/HOGA1 mutations causing recurrent nephrolithiasis owing to impaired renal tubular transport or metabolic pathways. Recent research shows an increasing prevalence globally and it is estimated that almost 10 to 15 percent of all kidney stone cases are due to these disorders which can be attributed to the advancement in genetic screening.
Pathogenesis of Familial Kidney Stone Disease
Recurrent kidney stone disease is caused by an underlying genetic defect associated with familial kidney stone disease which disturbs renal tubular transport, a metabolic pathway, or the structure of the kidney leading to stone formation. Clinical and laboratory research has shown several important underlying mechanisms such as cysteinuria SLC3A1/SLC7A9, AGXT/GRHPR type primary hyperoxaluria, and CLCN5 associated pseudohypoparathyroid bone disease where reabsorption of cystine, oxalate, or calcium is not adequately performed, leading to the stagnation of urine rich in substances capable of forming crystals.
Fig.1 SLC26 protein structure. (Li, J.,
et al., 2023)
Therapeutics Development for Familial Kidney Stone Disease
| Therapeutic Strategy |
Drug Name |
Therapeutic Target / Mechanism of Action |
Relevant Familial Stone Disease(s) |
Key Findings / Notes |
Development Stage |
| RNA Interference (RNAi) Therapeutics |
Lumasiran (Oxlumo); Nedosiran (DCR-PHXC) |
Hepatic mRNA responsible for coding oxalate producing enzymes is cleaved, reducing hepatic oxalate overproduction. |
Primary Hyperoxaluria (PH1, PH2, PH3) |
Ranges in urinary and plasma oxalate levels significantly across PH subtypes. |
Approved / Clinical Trials |
| Small Molecule Inhibitors |
GNE-140 (Genentech); GSK 2857808A; Stiripentol |
Allows for modulation of certain enzymes or signal transduction pathways of metabolites that lead to stone formation. |
Primary Hyperoxaluria |
Early-stage candidates aiming at specific metabolic steps prior to the production of stone-forming substances. |
Preclinical |
| Engineered Enzyme Therapy |
OT-58; AEB-4104 (Pegtarviline); CDX-6512; Erymethionase |
Degradation of cystine in the blood becomes possible via infusion of an engineered enzyme, lowering cystine concentration in urine. |
Cystinuria |
Demonstrated animal studies resulted in lower plasma/urine levels of the stone-forming substance and lower stone formation. |
Preclinical |
| Bacteriotherapy / Synthetic Biotics |
Oxabact; SYNB8802; SYNB1353; ALLN-177; Lactobacillus UBLG-36 |
Live bacteria or engineered microbes capable of degrading stone-forming precursors are taken orally directly to the gut where enzyme action is intended. |
Primary Hyperoxaluria, Enteric Hyperoxaluria, Cystinuria |
Aims to reduce the absorption of the substances or their precursors forming stones from the gut. |
Clinical (Ongoing) / 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 comprehensive preclinical service provider focusing on the discovery and development of novel therapeutics for the familial kidney stone disease. Our comprehensive therapeutic development services include the use of sophisticated disease models of the disease which capture important features of these inherited disorders.
Therapeutic Development Platforms for Familial Kidney Stone Disease
Disease Models Development for Familial Kidney Stone Disease
Protheragen offers innovative and comprehensive disease models advance the preclinical research of the familial kidney stone disease. Our platform integrates cell-based models, kidney organoids, and animal models to capture the genetic and metabolic signatures of familial kidney stone disease and support extensive drug discovery and mechanism-based investigations.
Cell-based & Organoid Models
- Renal Proximal Tubular Epithelial Cells
- AGXT KO HEK293 cells
- SLC7A9 KO MDCK cells
- iPSC-Derived 3D Kidney Organoids
- Tubuloid Models
Animal Models
- Slc3a1−/− Mice
- Agxt KO Rats
- Clcn5 KO Mice
- Hyperoxaluric Zebrafish
- Slc7a9-Luciferase Knock-in Mice
Protheragen integrated preclinical development solutions specifically designed for research in kidney diseases. We specialize in disease model development, pharmacokinetics, and drug safety evaluation, enabling us to support your investigation from the initial stages to preclinical validation. Contact us today to accelerate your kidney disease research with integrated, end-to-end solutions.
References
- Cogal, A. G., et al. "Comprehensive Genetic Analysis Reveals Complexity of Monogenic Urinary Stone Disease." Kidney Int Rep 6.11 (2021): 2862-84.
- Li, J., et al. "Slc26 Family: A New Insight for Kidney Stone Disease." Front Physiol 14 (2023): 1118342.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
