Novel compounds for the treatment of chronic kidney disease – treatCKD
Novel compounds for the treatment of chronic kidney disease
Chronic kidney disease (CKD) has a significant impact on global health, leading to decreased quality of life, increased risk of cardiovascular events, and high healthcare costs. It often progresses silently until advanced stages, requiring costly treatments like dialysis or transplantation. Early detection and intervention are crucial to slow disease progression and improve patient outcomes. The current project tested the efficacy of novel compounds in models of chronic kidney disease.
The general objective of the project was to verify the efficacy of potential anti-fibrotic compounds in chronic kidney disease protection.
The objective was to verify the novel compound efficacy in different models of chronic kidney disease including: 1) a mouse model of type I diabetes-induced chronic kidney disease (InsAkita). 2) a mouse model of type II diabetes-induced chronic kidney disease (db/db). 3) a mouse model of progressive chronic kidney disease (A-mice). 4) a rat model of chronic kidney disease (subtotal nephrectomy). These models represent high impact diseases (mouse model of type II diabetes and rat model of chronic kidney disease) and nice models (type I diabetes and A). As a second objective the detailed molecular mechanisms of the protective effects are being studied.
Mouse and cellular models
A review article was produced highlighting the mechanisms of chronic kidney disease in general and which needs to be targeted. Experimentally we have studied in the impact of DMAPT in relevant chronic kidney disease models in different species.
In mice:
- DMAPT-treatment of A-mice prevents increased albuminuria irrespective of sex, and prevents GFR reduction and uremia and creatinine increase in a female-specific manner.
- DMAPT prevents kidney hypertrophy in a female-specific manner in A-mice.
- DMAPT prevents kidney injury in a female-specific manner in A-mice .
- DMAPT prevents fibrosis, macrophage infiltration and inflammation in kidney of A-mice in a female-specific manner.
- The mouse db/db model did not clearly develop a kidney phenotype and hence was abandoned.
In rats:
- Reduced urinary albumin suggests a protective effect of DMAPT against renal damage in the rat SNX model.
- DMAPT reduces collagen I accumulation in the kidney in the rat SNX model.
- DMAPT reduces renal inflammation in the in the kidney of the rat SNX model as measured by MCP-1 expression.
- Overall the impact of DMAPT on kidney disease is comparable to current standard of use drugs Ramipril and Dapagliflozine.
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DMAPT appears to be a very interesting drug with protective capacities, at least as potent as standard of care drugs. Interestingly in case of studying the protective effects of DMAPT in mice we have identified a clear sex specific treatment impact. The added value of DMAPT to standard of care drugs and the mechanism of the potential sex specific impact of DMAPT remains to be investigated.
Around 850 million people were estimated to have CKD in 2017, representing ~11% the world population. The treatCKD project aims to accumulate preclinical evidence for two novel and innovative candidate compounds for the treatment of CKD. The compounds answer an unmet medical need by either focusing on a key mechanism (the appearance of myofibroblasts) in CKD or towards reversing the global glomerular CKD signature. treatCKD focusses on the validation of the efficacy of the compounds in a large panel of established male and female animal CKD models with a priority on their translational possibilities including humanized readouts, safety analysis, synergy with currently used drugs, and systems biology-based analysis of the molecular mechanisms of the compounds allowing validation of the targeted mechanisms and determination off-targets. In parallel to these scientific objectives we will design a path to valorisation in this private/academia endeavour.
Project coordination
Joost SCHANSTRA (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partnership
RDN RD Néphrologie SAS / Recherche et Développement
Inserm I2MC INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
Help of the ANR 456,203 euros
Beginning and duration of the scientific project:
December 2021
- 36 Months
