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[F. Others] F-5

Mitochondria Delivery of FXN Ameliorates Abnormal Iron

Metabolism In FXN-Deficient Cells And Animal Models

Shinyoung Park¹, Jaewook Jung¹, Jeongheon Choi¹, Hoegon Ryu¹, Hakyoung Park¹, Eunna Chung¹,

Daewoong Jo¹*

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

Friedreich’s ataxia (FRDA) is a monogenic disease with neurodegeneration and cardiomyopathy. FRDA is caused by

a deficiency of the mitochondrial protein called frataxin (FXN), which is critical for ion-sulfur cluster (ISC) biosynthesis
and regulation of iron metabolism. To replenish insufficient mitochondria FXN in FRDA-mimicked cells and animals,

Cell-Permeable FXN (CP-FXN) recombinant protein has been developed by fusing advanced macromolecule
transduction domain (aMTD) to human mature FXN. In FXN-deficient cells, intramitochondrial-delivered CP-FXN

decreased iron accumulation by binding to iron and restored the activities of ISC-dependent aconitase and succinate
dehydrogenase (SDH). Cardiac FXN KO mice were treated with CP-FXN via different routes of administration (IP and

IV) with two different dosages (30 and 50 mg/kg). Brain-specific KO mice were administered with a single
intramuscular (IM) injection of 30 mg/kg CP-FXN. In cardiac-specific FXN knockout (KO) mice, from histology analysis

results, CP-FXN suppressed iron accumulation, myocardial post-necrotic fibrosis, and cardiomyocyte apoptosis in
the heart. Moreover, CP-FXN also showed restoration of aconitase/SDH activities in both cardiac-/brain- specific

mice. These data suggest that CP-FXN with superior intracellular & mitochondria targeting delivery may provide a
therapeutic potential for FRDA treatment by improving iron homeostasis in the heart and brain.