A Rapamycin Pharmacogenomic Approach for the Childhood Dementia Niemann-Pick C

Area of Science:

• Biochemistry
• Genetics
• Pharmacology

Background:

• Niemann-Pick type C (NPC) is a rare childhood dementia involving lysosomal lipid buildup.
• Rapamycin, an autophagy inducer, shows variable efficacy in NPC models, suggesting genetic influences.

Purpose of the Study:

• To identify pharmacogenomic modifiers affecting NPC treatment response to rapamycin.
• To explore genetic variations influencing cellular responses to NPC-mimetic drugs and rapamycin.

Main Methods:

• Utilized a genotyped yeast panel and the NPC-mimetic U18666A (U18-drug).
• Evaluated cell growth, vacuolar fragmentation, and transcriptomics across diverse yeast strains.
• Performed linkage analysis to identify significant genetic loci.

Main Results:

• Identified a significant genetic locus associated with cell growth.
• Prioritized nine candidate genes, including ccs1, avo2, and irc21.
• Demonstrated that specific gene deletions (ccs1, avo2, irc21) significantly altered cell growth in response to U18-drug and rapamycin.

Conclusions:

• Genomic variants in identified genes may impact rapamycin efficacy for NPC.
• Suggests pre-treatment assessment of these genes for personalized rapamycin therapy in NPC.
• This research is a vital step toward tailored rapamycin treatments for childhood dementia.