Abstract: FR-OR71
Snake Toxin for Treatment of Kidney Diseases: From Bench to, Hopefully, Bedside
Session Information
- Innovative AKI Strategies and Drug Discoveries
October 25, 2024 | Location: Room 7, Convention Center
Abstract Time: 05:40 PM - 05:50 PM
Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
- 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)
Authors
- Gilles, Nicolas, Commissariat a L'energie Atomique et Aux Energies Alternatives Siege Administratif, Gif-sur-Yvette, France
- Stanajic Petrovic, Goran, Universite Paris-Saclay, Gif-sur-Yvette, France
- Keck, Mathilde, Commissariat a L'energie Atomique et Aux Energies Alternatives Siege Administratif, Gif-sur-Yvette, France
- Palea, Stefano, Humana, Toulouse, France
- Servent, Denis, Commissariat a L'energie Atomique et Aux Energies Alternatives Siege Administratif, Gif-sur-Yvette, France
- Truillet, Charles, Universite Paris-Saclay, Gif-sur-Yvette, France
Group or Team Name
- Medicines and Healthcare Technologies Dept.
Background
V2R blockade is a validated therapeutic strategy for hyponatremia and the autosomal polycystic kidney disease. With the aim of discovering a safe V2R antagonists, we screened animal venoms and identified the MQ1 which shown sufficiently interesting properties to be the starting point for the development of a potential drug candidate.
Methods
Toxins were synthesized. Human T-cell assays was used to mitigate MQ1 immunogenicity risk, resulting in the MQ232. The MQ232 dynamic biodistribution in mice was done by positron emission tomography using an MQ232-derived imaging agent. PK, PD and toxicity tests were performed on healthy rats. A rat experimental model of dDAVP-induced hyponatremia, an ex vivo mice model of renal cysts and a mice orthologous model of ADPKD were used to validate MQ232 in these pathologies.
Results
4 mutations were introduced in MQ1 to generate the MQ232. The MQ232 safety was demonstrated by a first toxic dose as high as 3,000 nmol/kg and an absolute kidney organ selectivity by TEP imaging. In addition, TEP imaging shown almost no interaction between MQ232 and the liver. The MQ232 efficacy was demonstrated, first with an effective dose of 3 nmol/kg on hyponatremic model, second on models of kidney polycystic on which MQ232 significantly reduced cyst growth.
Conclusion
We showcased, employing diverse translational techniques MQ232's outstanding safety and efficacy. MQ232 selectively targets the kidney and showed an effective to toxic dose ratio of 1,000-fold. Its molecular identity, bio-distribution and creatinine-like clearance suggest a renal metabolism rather than a hepatic one. MQ232, as the head of a new biological class of vaptan-unrelated aquaretic agents, is a favorable candidate as a therapeutic option for untreated patients.