Kidney Week

Abstract: PO1558

Small-Molecule Allosteric Activators of Long-Form PDE4 Enzymes Suppress Cystogenesis in Models of ADPKD

Session Information

• Cystic Kidney Diseases: Emerging Concepts, Biomarkers, and Clinical Trials
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1001 Genetic Diseases of the Kidneys: Cystic

Authors

• Henderson, David James peter, Mironid Ltd, Glasgow, United Kingdom

David James peter Henderson,

• Wang, Xiaofang, Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States

Xiaofang Wang,

• Omar, Faisa, Mironid Ltd, Glasgow, United Kingdom

Faisa Omar,

• Carfray, Gemma, Mironid Ltd, Glasgow, United Kingdom

Gemma Carfray,

• Jiang, Li, Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States

Li Jiang,

• Adam, Julia M., Mironid Ltd, Glasgow, United Kingdom

Julia M. Adam,

• Rowley, Adele, Mironid Ltd, Glasgow, United Kingdom

Adele Rowley,

• Adams, David R., Mironid Ltd, Glasgow, United Kingdom

David R. Adams,

• Torres, Vicente E., Mayo Foundation for Medical Education and Research, Rochester, Minnesota, United States

Vicente E. Torres,

• Houslay, Miles D., Mironid Ltd, Glasgow, United Kingdom

Miles D. Houslay,

Background

In ADPKD, mutations in either PKD1 or PKD2 perturb intracellular calcium signalling and drive a chronic elevation of intracellular cAMP through de-suppression of calcium inhibited adenylyl cyclase 5/6. This elevation of cAMP signalling underpins the molecular pathology of ADPKD, promoting widespread cyst formation within the nephron epithelium, ultimately leading to renal failure. Phosphodiesterase 4 (PDE4) enzymes degrade intracellular cAMP in a localised manner, and their activity contributes to the compartmentalisation of sub-cellular cAMP dynamics. By modulating or terminating cAMP mediated signalling events, PDE4 isoforms are placed as a central regulator of many cAMP mediated biological processes. We have previously described the discovery and characterization of novel small-molecule compounds which allosterically activate long isoforms of PDE4, and here we further describe their therapeutic potential in suppressing the core cAMP drive behind the pathogenesis of ADPKD.

Methods

Biochemical assay, gene expression profiling and genetic manipulation of cell models were undertaken alongside primary human cell 3D-culture experiments and Mouse Pkd1^RC/RC metanephric organ culture to investigate the effects of pharmacological long-form PDE4 activation on intracellular cAMP and cyst dynamics.

Results

Our data show that within murine kidney epithelial cells PDE4 long-form variants from Pde4c and Pde4d predominate and that allosteric pharmacological activation of long-form Pde4 enzymes suppresses intracellular cAMP. We show that the PDE4 mediated suppression of cAMP signalling results in the suppression of cystogenesis in translational models of ADPKD, such as in Pkd1^RC/RC metanephric organ culture and primary human ADPKD cyst culture. This further supports the potential therapeutic benefit of allosteric activation of PDE4 in treating ADPKD.

Conclusion

Small-molecule activators of long-form PDE4 enzymes suppress aberrantly elevated cAMP signalling and exhibit potential utility as therapeutics in ADPKD.

Funding

• Commercial Support –