Kidney Week

Abstract: TH-PO429

Navigating the Translation of LoAc Compound Efficacy in ADPKD

Session Information

• Cystic Kidney Diseases: Clinical Assessment and Therapeutic Directions
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

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

David James Peter Henderson, PhD

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

Julia M. Adam, MA, PhD

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

Xiaofang Wang

• Whitworth, Claire, Mironid Ltd, Glasgow, United Kingdom

Claire Whitworth, MSc, PhD

• Macdonald, Susan, Mironid Ltd, Glasgow, United Kingdom

Susan Macdonald, PhD

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

Li Jiang

• Moore, Tom, Mironid Ltd, Glasgow, United Kingdom

Tom Moore, MSc, PhD

• Kelleher, Catherine L., Mironid Ltd, Glasgow, United Kingdom

Catherine L. Kelleher, MD

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

Vicente E. Torres, MD, PhD

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

Adele Rowley, PhD

Background

Elevated cAMP signalling is known to promote cystogenesis in Autosomal Dominant Polycystic Kidney Disease (ADPKD). Phosphodiesterase 4 (PDE4) enzymes degrade cAMP and contribute to its compartmentalized signalling. We have previously described novel small molecules (LoAc^®) that allosterically activate long isoforms of PDE4 and lower intracellular cAMP both in vitro and in vivo. Here we discuss translation of the LoAc^® approach from bench to bedside, with an emphasis on differentiation and on biomarker development.

Methods

The effects of LoAc^® compound MR-L22 were examined in the Pkd1^RC/RC mouse model of ADPKD, dosed once daily by oral gavage from post-natal weeks 4-16. Test groups were compared to groups receiving vehicle alone or tolvaptan. Urinary biomarker assays were conducted in Han Wistar rats, where cAMP was measured by either ELISA or LC-MS. Ex vivo studies in primary human cells were used to demonstrate efficacy in samples from multiple ADPKD patient donors.

Results

LoAc^® treated Pkd1^RC/RC mice exhibit reduced kidney cystic indices, kidney weight/body weight ratios (Kw/Bw) and MRI measured total kidney volumes (TKV). LoAc^® administration protected kidney function and despite delivering similar reductions in renal cAMP, induced less polyuria than tolvaptan. Similarly, LoAc^®-driven changes in protein expression and phosphorylation overlap with, but are distinct from, those measured after tolvaptan treatment. Experiments using cells from human ADPKD donors show that LoAc^® compounds not only suppress AVP-stimulated cyst expansion but also the endogenous cystic disease drive, further differentiating LoAc^® from tolvaptan as well as against a range of other clinical strategies.
In rats, reduced cAMP in the urine can be detected after a single oral dose of LoAc^® compound and correlate with cystic disease in LoAc^® treated Pkd1^RC/RC mice. Urinary cAMP offers an accessible, mechanism-related, biomarker of LoAc^® compound activity in vivo and provides important step in managing the translation of the LoAc^® approach in ADPKD.

Conclusion

LoAc^® compounds suppress cystic disease progression in key translational models of ADPKD and are differentiated from clinically evaluated strategies. Urinary cAMP represents an accessible biomarker of LoAc^® compound activity for translation to clinical studies.

Funding

• Commercial Support – Mironid Limited