APOL1 nephropathy is a notable genetic disorder of the kidney associated with specific variants of the APOL1 gene which increases vulnerability to several kidney diseases. APOL1 Nephropathy solutions from Protheragen harness industry-leading knowledge on genetic disorders of the kidney to deal with the complicated pathogenesis of this disease that impacts higher risk patients.
Introduction to APOL1 Nephropathy
The APOL1 nephropathy is caused by the deleterious variants of the APOL1 gene, calls G1 and G2 alleles, mainly in Africans. These mutations lead to podocyte damage and further progression of focal segmental glomerulosclerosis (FSGS) and hypertensive nephropathy. Clinically, it presents as proteinuria, reduced glomerular filtration rate (GFR) and increased risk of end-stage kidney failure.
Pathogenesis of APOL1 Nephropathy
APOL1 risk variants induce cytotoxicity through dysregulated ion channel activity and mitochondrial dysfunction. Key mechanisms include:
- Podocyte Injury: Lysosomal membrane disruption from APOL1 pore forming leads to subsequent cell death via inflammasome activation.
- Mitochondrial Stress: Alleviated mitophagy alongside excessive tubular and glomerular ROS production exacerbate tubular and glomerular damage.
- Inflammatory Cascade: APOL1 variants increase the amplification of inflammatory NF-κB signaling therefore increasing the renal cytokine and fibrosis production.
- Dysregulated Autophagy: Autophagy dysregulation caused by accumulation of damaged organelles resulting from defective interactions of APOL1 with ULK1.
Fig.1 The normal function of APOL1 in human kidneys is not known. (Freedman
et al., 2022)
Therapeutic Development for APOL1 Nephropathy
| Therapeutic Strategy |
Therapeutic Target |
Key Findings/Mechanism |
Development Stage |
| Inaxaplin (VX-147) |
APOL1 channel pore blockade |
60% proteinuria reduction in G1/G2 carriers; preserves eGFR vs placebo |
Phase III |
| IONIS-532 (ASO) |
APOL1 mRNA knockdown |
80% APOL1 reduction in primates; resolves IFNγ-induced podocyte injury |
Phase I/II |
| AZD2373/JAK Inhibitors |
JAK1/2 signaling inhibition |
Suppresses APOL1 expression by 70% in lupus nephritis models |
Phase II |
| PBI-4050 |
TGF-β/IL-6 pathway inhibition |
Reduces liver fibrosis by 30%; suppresses NLRP3 inflammasome in renal cells |
Phase IIb |
| Baricitinib |
JAK/STAT blockade |
40% APOL1 mRNA reduction in podocytes; improves mitochondrial function |
Repurposing Trial |
| Galunisertib |
TGF-β receptor kinase inhibition |
Attenuates collagen IV deposition by 62% in porcine APOL1 models |
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 specializes in developing advanced disease models for APOL1 nephropathy and offers comprehensive preclinical therapeutic development services. We focus on elucidating the diverse genetic and molecular impacts of APOL1 risk variants that lead to the renal manifestations of APOL1 nephropathy.
Therapeutic Development Platform for APOL1 Nephropathy
Protheragen combines deep expertise in kidney developmental biology, the genetics of congenital anomalies of the kidney and urinary tract (CAKUT) like TBS, and advanced molecular and cellular technologies. Our team delivers tailored solutions for TBS research.
Disease Models Development for APOL1 Nephropathy
Protheragen offers innovative and comprehensive disease models to advance the preclinical research of APOL1 nephropathy. Our platform integrates cell-based models, kidney organoids, and animal models to effectively capture the genetic and functional disruptions caused by APOL1 risk variants, supporting extensive drug discovery and mechanism-based investigations.
- Renal tubular epithelial cells
- iPSCs carrying APOL1 risk variants
- 3D kidney organoids
- Endothelial-podocyte co-culture systems
- Cell lines with inducible APOL1 expression
- Transgenic mice expressing human APOL1 risk variants
- APOL1 humanized knock-in mouse models
- Apol1 knockdown or overexpression zebrafish
- Patient-derived xenografts
Protheragen offers integrated preclinical therapeutics and drugs development solutions specifically designed for research in rare genetic kidney diseases like APOL1 nephropathy. We specialize in custom disease model development, pharmacokinetics, and drug safety evaluation, enabling us to support your investigation from initial discovery through to preclinical validation, offering a full-range, one-stop service for renal-related therapy development.
If you are interested in our services and advancing research for APOL1 nephropathy, please don't hesitate to contact us.
References
- Freedman, B. I., et al. "Apol1-Associated Nephropathy: A Key Contributor to Racial Disparities in Ckd." Am J Kidney Dis 72.5 Suppl 1 (2018): S8-S16.
- Tabachnikov, O., K. Skorecki, and E. Kruzel-Davila. "Apol1 Nephropathy - a Population Genetics Success Story." Curr Opin Nephrol Hypertens 33.4 (2024): 447-55.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
