Rapidly progressive glomerulonephritis (RPGN) is a kidney syndrome characterized by a rapid loss of renal function, with severe damage of glomeruli, the filtering units of the kidney through glomerular crescent formation (crescent-shaped scars) seen on kidney biopsies.
RPGN rapidly progresses into acute renal failure and death within months if left untreated. Regardless of the underlying cause, RPGN involves severe injury to the kidneys' glomeruli, with many of the glomeruli containing characteristic glomerular crescents.
Currently, RPGN is treated with broad-spectrum immunosuppression causing remission of the immune injury achieved in the majority of patients. Nevertheless, the risk of end-stage renal failure at 5 years is still near 30 %, with a number of patients developing chronic kidney disease (CKD). Moreover, such treatments are associated with significant morbidity due to infections and malignancy.
ERC-supported efforts in our lab have unravelled local mediators and transcription factors that critically control the tolerance of intrinsic glomerular cells to an inflammatory insult. My team has shown that the PPARγ (peroxisome proliferator-activated receptors gamma) pathway is limiting the inflammatory response during immune-complex mediated RPGN, in large part through the protection of kidney cells, named podocytes.
We now plan to move forward to transform this finding from my previous Consolidator ERC project into a clinically effective innovative therapy that will be evaluated in a novel model of RPGN in pig, which offers great similarity to the man with regard to renal anatomy, physiology and immune system. We expect to bring original therapeutic effect by preventing podocytes death and dysfunction in addition to promoting anti-inflammatory actions.
The STOPIG project represents a unique opportunity to provide proof-of-concept for a new and cost-effective therapy for patients with RPGN based on stimulation of PPARγ with repurposed pioglitazone.
Innovative pathway and drug target: We have previously shown that pioglitazone, a thiazolidinedione, is extremely powerful to halt experimental rapidly progressive inflammatory irreversible kidney failure in a model of crescentic glomerulonephritis in mice (C. Henique et al., Journal of the American Society of Nephrology. 172, 2016) and patent WO2016071727.
This was an unsuspected effect of this drug that was primarily developed as an insulin-sensitizing agent to treat diabetes mellitus. The key results from the STOPIG project have enabled us to confirm this target involved in the control of the kidney's response to an inflammatory insult in a non-rodent animal model, which is closer to human physiology.
a) Innovative preclinical model: the STOPIG POC project was instrumental in supporting the ultimate development of an original pig model for crescentic RPGN with cellular crescent formations, neutrophil infiltrates, haematuria and nephrotic-range proteinuria. This preclinical model of glomerulonephritis in pigs will be helpful to screen other potential therapeutic agents for human diseases.
The STOPIG study innovation supports the relevance of a complementary therapeutic strategy to immunosuppression, based on the promotion of tolerance of the kidney glomeruli to inflammatory insult to prevent kidney failure.
b) Exploitability
Our strategy for exploitation is mainly focused on Orphan Drug Designation (ODD) to guarantee the operating monopoly of the product in the indication. Indeed, RPGN is a rare disease (ORPHA: 280569).
c) Impact
The STOPIG innovative add-on complementary strategy has several advantages:
(1) The drug pioglitazone is readily available for testing in a repurposing scheme, allowing for rapid initiation of a proof-of-concept clinical trial.
(2) The treatment could be rapidly effective in stopping kidney damage as observed in mice and pigs, even before the efficacy of immunosuppression.
(3) Finally, we expect additional significant clinical benefits:
(i) A sparing effect on steroid administration since the drug was very effective in the absence of corticosteroids (1 and the STOPIG data), with less morbidity, noteworthy, especially in the very young and the elderly, enabling lower incidence of infections and malignancies.
(ii) Better preservation of the kidney function, improved quality of life and health costs.
In conclusion, the key results indicate that pioglitazone administration in non-congenic pigs displayed antiproteinuric effect and limited the severity of kidney failure in a model of severe crescentic glomerulonephritis supporting the relevance of a clinical trial.
