Page 4 - P. Molecular medicine and imaging

[P. Molecular medicine and imaging-2]

Frataxin Replenishment Ameliorates Heart Dysfunction

Through Recovery Of Iron Metabolism In Frataxin Deficient

Mice

Wonheum Nah¹, Joonno Lee¹, Keumyoung Kang¹, Jeongheon Choi¹, SooJung Lee¹, Youngsil Choi¹,
Daewoong Jo¹

¹Cellivery R&D Institute, Cellivery Therapeutics, Seoul 03929, Korea

Friedreich’s ataxia (FRDA) is a progressive cardiac and neurodegenerative disease with early life mortality resulted

from cardiomyopathy. FRDA is caused by a deficiency of frataxin (FXN) which plays a role in regulating iron
metabolism. Since there is no treatment for FRDA, cell-permeable FXN (CP-FXN) has been developed by fusing

sequence-optimized advanced macromolecule transduction domain (aMTD) to replenish insufficient FXN in cells
and animals. To determine whether CP-FXN can rescue the iron metabolism pathway in heart-specific FXN deficient

mice, FXN conditional knockout mouse model which is specifically deleting exon 2 of FXN gene in heart and skeletal
muscle is currently being exploited. Animals were administered CP-FXN at a dose of 50 mg/kg for 6 weeks. In heart,

CP-FXN restores expression of ISC containing enzyme molecules (aconitase, SDH B, NDUFS3) and iron storage
molecule (H-ferritin). Also, aconitase activity (70%) and SDH activity (37%) were induced by CP-FXN. Histological

analyses demonstrate that CP-FXN suppresses cardiac iron accumulation, myocardial post-necrotic fibrosis and
cardiomyocyte apoptosis in FXN KO mice. These results suggest that CP-FXN has a therapeutic potential for FRDA
treatment by improving cardiac iron homeostasis.