Abstract 19300: Drug Screening in Human Neutral Lipid Storage Disease iPSCells Identifies Modulators of Intracellular Lipid Metabolism That Reduce Disease Phenotype in vitro
Induced pluripotent stem cells (iPSCs) hold great promise as in vitro disease models for pathway discovery and therapeutic drug screening. Here, we generated an in vitro model of neutral lipid storage disease, myopathy subtype (NLSD-M), a condition characterized by a marked elevation of lipid accumulation in cardiac and skeletal muscle due to the loss of functional adipose triglyceride lipase (ATGL), by reprogramming patient fibroblasts into iPSCs. These hiPSCs were confirmed of carrying mutations in exon 5and exon 7 of the ATGL gene and were shown to recapitulate the disease phenotype by the presence of Oil Red O positive lipid granules in cardiomyocytes. To corroborate this finding, expression of metabolic genes such as Peroxisome proliferator-activated receptors (PPAR-a and PPAR-g) were significantly decreased in diseased cardiomyocytes compared to control. Furthermore, the down-regulation of PPAR-gamma coactivators (PGC-1a and PGC-1b) and PPAR target genes expression were associated with increased lipid accumulation in vitro. Utilizing the previously identified compounds that induces glycolysis and suppresses oxidative respiration, we found that the accumulation of intracellular lipids in cardiomyocytes was reduced in treated cells when compared with un-treated cells (0.041 ± 0.02 vs 0.186 ± 0.05). Strikingly, such a treatment effect was not observed when Wild Type iPSC derived cardiomyocytes was studied instead, suggesting a disease-specific effect of the identified drugs. Our results represent one of the first successful human induced Pluripotent Stem Cell validation of high throughput drug screening hits from murine iPSC lines. Given the increased prevalence of NLSD-Min the Japanese population, our findings raise the prospect that a treatment for this devastating disease using drug hits from in vitro iPSC screening may be feasible in the near future.
Author Disclosures: R. Kuppusamy: None. B. Feistritzer: None. M. Engels: None. A. Sturzu: None. K. Plonowska: None. G. Li: None. A. Sharma: None. K. Nakamura: None. H. John: None. X. Huang: None. W. Chuang: None. K. Hirano: None. S. Wu: None.
- © 2014 by American Heart Association, Inc.