| Title: |
MQ232, A Snake Toxin Derivative for Treatment of Hyponatremia and Polycystic Kidney Diseases |
| Authors: |
Stanajic-Petrovic, Goran; Keck, Mathilde; Barbe, Peggy; Urman, Apolline; Correia, Evelyne; Isnard, Pierre; Duong van Huyen, Jean-Paul; Chmeis, Khawla; Diarra, Sékou Siramakan; Palea, Stefano; Theodoro, Frederic; Nguyen, Anvi-Laëtitia; Castelli, Florence; Pruvost, Alain; Zhao, Wenchao; Mendre, Christiane; Mouillac, Bernard; Bienaimé, Frank; Robin, Philippe; Kessler, Pascal; Llorens-Cortes, Catherine; Servent, Denis; Nozach, Hervé; Maillère, Bernard; Guo, Dong; Truillet, Charles; Gilles, Nicolas |
| Contributors: |
Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS); Médicaments et Technologies pour la Santé (MTS); Université Paris-Saclay-Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE); LaBoratoire d'Imagerie biOmédicale MultimodAle Paris-Saclay (BIOMAPS); Service Hospitalier Frédéric Joliot (SHFJ); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut des Sciences du Vivant Frédéric JOLIOT (JOLIOT); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS); Hôpital Necker - Enfants Malades AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Humana Biosciences, Prologue Biotech, 516 Rue Pierre et Marie Curie, 31670, Labège, France.; Xuzhou Medical University; Institut de Génomique Fonctionnelle (IGF); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM); Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)); Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité) |
| Source: |
ISSN: 1046-6673. |
| Publisher Information: |
CCSD; American Society of Nephrology |
| Publication Year: |
2025 |
| Subject Terms: |
[SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology; [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology |
| Description: |
International audience ; Background: Vaptans were developed at the end of the previous century as V2R antagonists. Tolvaptan is the most prescribed vaptan for hyponatremia and the autosomal polycystic kidney disease (ADPKD). However, its use is not as widespread as it should be due to price issues, a narrow therapeutic window and some side effects. With the aim of discovering new efficient and safer V2R antagonists, we screened animal venoms and identified several interesting peptide toxins. Among them, MQ1 displayed such unique biological properties in that regard that it was the starting point for the development of a potential drug candidate.Methods: Human T-cell assays and bioinformatics was used to mitigate MQ1 immunogenicity risk. The MQ232 biodistribution in mice was done by positron emission tomography (PET). Pharmacodynamics, pharmacokinetics, acute and chronic toxicity tests were performed on control 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 efficacy in these pathologies.Results: Three mutations were introduced in MQ1 to mitigate its immunogenicity risk. A fourth gain-of-function mutation was added to generate MQ232. MQ232's safety was demonstrated by a first toxic dose as high as 3,000 nmol/kg and a strong kidney organ selectivity by PET imaging, while showing almost no interaction with the liver. MQ232's efficacy was first demonstrated with an effective dose of 3 nmol/kg in a hyponatremic model, and then in polycystic kidney models on which MQ232 significantly reduced cyst growth.Conclusions: We demonstrated, employing diverse translational techniques and minimizing animal use, MQ232's safety and efficacy in several rodent models of hyponatremia and ADPKD. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/39431458; PUBMED: 39431458; PUBMEDCENTRAL: PMC11801765 |
| DOI: |
10.1681/ASN.0000000505 |
| Availability: |
https://hal.science/hal-04751150; https://hal.science/hal-04751150v1/document; https://hal.science/hal-04751150v1/file/Stanajic-Petrovic%20et%20al%202024.pdf; https://doi.org/10.1681/ASN.0000000505 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.410667DA |
| Database: |
BASE |