Autosomal dominant polycystic kidney disease (ADPKD) is a multisystem disorder affecting kidney structure and function, characterized by the development of cysts and subsequent increase in kidney size, with most patients eventually requiring ESKD. As a leader in kidney disease research, Protheragen expeditiously propels drug development from target validation to IND- enabling studies, guaranteeing achievement at clinical milestones.
Introduction to Autosomal Dominant Polycystic Kidney Disease
ADPKD is the most prevalent and inherited form of kidney disease, resulting from mutations to PKD1 (85%) or PKD2 (15%), impacting one in every 1000 people worldwide. Its manifestation includes relentless growth of cyst cavities both in kidneys and liver, leading to organomegaly, Hypertension and ESKD (end stage kidney disease). The prognosis is quite bleak as more than 50% of patients tend to ESKD by 60 years of age. Clearly, there is dire need of therapeutics aimed at cystic growth and fibrosis.
Pathogenesis of Autosomal Dominant Polycystic Kidney Disease
ADPKD is the result of dysregulation of PKD1 and PKD2, which code for polycystin-1 (PC1) and polycystin-2 (PC2), respectively, causing disturbances in ciliary mechanosensation and calcium signalling within renal tubular cells. Disarrayed cAMP/PKA and mTOR pathways lead to excessive epithelial cell division, fluid extraction and cysts' growth while weakened cell adhesion coupled with matrix elution enhances structure fragility. Secondary to these changes exessive metabolic shift along with inflammatory fibrosis advance relentlessly to renal failture.
Fig.1 Schematic representation of endoplasmic reticulum maturation and N-glycosylation of nascent polycystin-1 (PC-1) and polycystin-2 (PC-2). (Lanktree
et al., 2021)
Therapeutics Development for Autosomal Dominant Polycystic Kidney Disease
| Therapeutic Strategy |
Mechanism |
Key Findings/Evidence |
Development Stage |
| cAMP Pathway Inhibitors |
| Tolvaptan |
Vasopressin V2 receptor antagonism cAMP |
TEMPO 3/4: Kidney growth; eGFR decline by 30% |
Approved |
| Octreotide |
Somatostatin analog cAMP production |
ALADIN: ↓Liver cyst volume by 29%; no renal benefit |
Phase III (Failed) |
| mTOR Pathway Inhibitors |
| Sirolimus |
mTORC1 inhibition cell proliferation |
18-month trial: No significant kidney volume/eGFR improvement |
Phase III (Failed) |
| Everolimus |
mTORC1 inhibition |
Short-term kidney volume by 15%; long-term inefficacy |
Discontinued |
| AMPK Activators |
| Metformin |
AMPK activation CFTR/mTOR pathways |
50% cyst growth inhibition in 3D organoids; cyst index by 40% in mice |
Phase II |
| AICAR |
Direct AMPK activation |
Inhibits cyst epithelial proliferation (IC50=10 μM) |
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 dedicated to the discovery and development of novel therapeutics for Autosomal Dominant Polycystic Kidney Disease. Our extensive therapeutic development services incorporate the use of sophisticated disease models that effectively capture important features of this inherited and progressive kidney disorder.
Therapeutic Development Platforms of ADPKD
Disease Models Development for ADPKD
Protheragen offers innovative and comprehensive disease models to advance preclinical research into ADPKD. Our platform integrates cell-based models, kidney organoids, and animal models to effectively capture the genetic and developmental signatures of PKD1 and PKD2 mutations and their impact on renal health and cystogenesis.
- PKD1/PKD2-mutated renal cyst epithelial cells
- PKD1/PKD2-KO renal cell lines
- Ciliary dysfunction model
- ADPKD kidney organoids
- 3D hydrogel-based cyst formation model
- Conditional Pkd1/Pkd2 knockout mice
- Pkd1 hypomorphic mice
- Pkhd1 knockout mice
- Zebrafish pkd2/pkd1a/b mutants
- Inducible Pkd1-deletion mouse model
Protheragen's integrated preclinical development solutions are specifically designed for research in complex renal and urological disorders like ADPKD. We specialize in custom disease model development, pharmacokinetics, and drug safety evaluation, enabling us to support your investigation from target validation to IND-enabling studies.
Contact us today to accelerate your ADPKD research with end-to-end solutions.
References
- Lanktree, M. B., et al. "Insights into Autosomal Dominant Polycystic Kidney Disease from Genetic Studies." Clin J Am Soc Nephrol 16.5 (2021): 790-99. Print.
- Reiterova, J., and V. Tesar. "Autosomal Dominant Polycystic Kidney Disease: From Pathophysiology of Cystogenesis to Advances in the Treatment." Int J Mol Sci 23.6 (2022).
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
