A Rapamycin Pharmacogenomic Approach for the Childhood Dementia N iemann‐ P ick C

2026/06/18 by Benjamín Szenfeld, Macarena Las Heras, Juan Carlos Rubilar +4 · 1 voice
Medicine · #Alzheimer's disease research and treatments #Amyotrophic Lateral Sclerosis Research #Autophagy in Disease and Therapy

paper · doi:10.1002/jimd.70214

openalex publication_date 2026/06/18 · openalex created_date 2026/06/19 · openalex updated_date 2026/07/30

Abstract

mice, Rapamycin, an autophagy inductor, yielded opposite results depending on genetic background, suggesting the presence of pharmacogenomic modifiers. To identify them, we used a genotyped yeast panel designed for gene mapping and the NPC-mimetic U18666A (U18-drug) in the presence and absence of rapamycin. We evaluated cell growth, vacuolar fragmentation, and transcriptomics across diverse strains. Linkage analysis based on cell growth identified a significant locus, leading to the prioritization of nine genes. Notably, ccs1 (copper chaperone for superoxide dismutase) and avo2 (TORC2 subunit) deletions decreased cell growth compared to U18-Rapa in WT cells, while irc21 (DNA damage and ceramide metabolism) increased it. Our results suggest that genomic variants within these genes should be assessed before using rapamycin for NPC. This study represents a crucial step towards personalized rapamycin therapeutics.

Citations

• limma powers differential expression analyses for RNA-sequencing and microarray studies
• Salmon provides fast and bias-aware quantification of transcript expression
• Efficacy and safety of arimoclomol in Niemann‐Pick disease type C: Results from a double‐blind, randomised, placebo‐controlled, multinational phase 2/3 trial of a novel treatment

Discussions

• Can genetics help predict who will benefit from rapamycin in Niemann-Pick disease type C? Using an NPC-like yeast model, Szenfeld et al. identified candidate modifier genes that influenced treatment [bsky, 1 points, 0 comments]

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