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Abstract: PO1243

Pharmacological Activation of Long-Form PDE4 Enzymes Suppresses Disease Progression in Pkd1RC/RC and Pkd1 Knockout (iKspCrePkd1lox,lox) Mouse Models of ADPKD

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Henderson, David James peter, Mironid Limited, Glasgow, United Kingdom
  • Wang, Xiaofang, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Jiang, Li, Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Houslay, Miles D., Mironid Limited, Glasgow, United Kingdom
  • Harris, Peter C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Adam, Julia M., Mironid Limited, Glasgow, United Kingdom
  • Adams, David R., Mironid Limited, Glasgow, United Kingdom
  • Rowley, Adele, Mironid Limited, Glasgow, United Kingdom
  • Torres, Vicente E., Mayo Clinic Minnesota, Rochester, Minnesota, United States
Background

Upregulation of cAMP signaling is thought to promote cystogenesis in ADPKD. Phosphodiesterase 4 (PDE4) enzymes degrade cAMP and contribute to its compartmentalized signaling. We have previously described novel small molecules that allosterically activate long isoforms of PDE4 and lower intracellular cAMP. Here we demonstrate significant efficacy with MR-L22, an advanced PDE4 activator compound, on suppressing cystic burden and preserving kidney health in orthologous models of ADPKD.

Methods

The effects of the long isoform PDE4 activator MR-L22 (administered by oral gavage) were assessed in rapidly (iKspCrePkd1lox,lox induced at P10, treated from P14 to P27) and slowly progressive (Pkd1RC/RC, treated from 4 to 16 weeks of age) mouse models of ADPKD. Test groups were compared to control groups receiving vehicle alone or V2 receptor antagonist.

Results

Compared to vehicle treated controls, MR-L22 treated Pkd1RC/RC mice exhibited reduced kidney cAMP levels, cystic indices, kidney weight/body weight ratios (Kw/Bw) and MRI measured total kidney volumes (TKV) (Table and Figure). Long isoform PDE4 activation significantly protected kidney function and, when compared to tolvaptan, animals receiving MR-L22 produced significantly less urine volume. MR-L22 also suppressed the aggressive cystic disease exhibited by tamoxifen induced (P10) iKspCrePkd1lox,lox mice, where Kw/Bw and cystic indices were reduced in comparison to vehicle control (results not shown).

Conclusion

Small-molecule activators of long isoforms of PDE4 suppress cystic disease progression in key translational models of ADPKD and may be better tolerated and more effective than vasopressin V2 receptor antagonists.

Funding

  • Commercial Support