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Preprint WatchModerateAugust 1st, 2026

Meta-analyses of the NEPTUNE dataset related to high and low risk FSGS and cellular APOL1 models identifies Calcium signalling, mTOR signaling and inflammation-associated pathways as operative in APOL1-mediated kidney disease.

Wruck, W.; Thimm, C.; Amin, T.; Somoano Sanchez, M. D.; Pulo, S.; Adjaye, J.

Transcriptomic meta-analysis of FSGS biopsies and APOL1 cellular models identifies calcium and mTOR signalling among the up-regulated programs in APOL1 high-risk variant carriers, with the mTOR inhibitor AZD-2014 nominated as a candidate reversal agent.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

The single mTOR failure on the Claidex record is the everolimus plus erlotinib Phase 2 in metastatic pancreatic cancer, terminated for futility (everolimus-erlotinib-mtor-egfr-pancreatic-cancer-phase2-futility-termination). That failure was an efficacy readout in an unselected oncology population. This preprint proposes mTOR pathway activity as a genotype-anchored feature of APOL1 high-risk kidney disease, which is a different proposition: the pathway is nominated by a defined genetic stratifier rather than by tumour histology. The severity here is driven by the efficacy archetype on the prior claim rather than by any direct contradiction, and the practical read is that mTOR inhibition in a genetically defined population should not inherit the prior probability of mTOR inhibition in unselected solid tumours.

Abstract excerpt

Background The variants G1 and G2 within the APOL1 gene confer a higher risk of APOL1-mediated kidney disease (AMKD) whilst associated with an evolutionary advantage against trypanosome-mediated sleeping sickness. Methods In this study, we analysed transcriptome data of kidney biopsies from FSGS patients with the APOL1 high-risk (HR) and low-risk (LR) variants and compared it to cellular models based on patient-specific podocytes, HEK cells with engineered over-expressing HR variants and HR variant single-cell-RNA-seq data from kidney organoids. Results We identified a signature of up- and down-regulated genes between biopsies from FSGS patients with APOL1 HR and LR variants. The up-regulated genes are functionally annotated to be associated with Calcium and mTOR signaling, whilst the down-regulated genes with inflammatory and immune response pathways. These pathways were confirmed by comparing with cellular models. Analysis of small molecules reverting the IFN-{gamma} stimulated gene expression to the non-stimulated gene expression in genome-edited APOL-G1 kidney organoids revealed several putative candidates such as the mTOR inhibitor AZD-2014. Conclusion We have unveiled a signature of up- and down-regulated genes between APOL1 HR and LR kidney biopsies which could be assigned as associated with Calcium and mTOR signaling and down-regulated immune response.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.