Page 2 - P. Molecular medicine and imaging

[P. Molecular medicine and imaging-1]

Mitochondrial Targeting Of Frataxin Rescues Abnormal Iron

Accumulation By Activating Iron-Sulfur Cluster Biosynthesis

Joonno Lee¹, Sookeun Yeon¹, Keumyoung Kang¹, Jeongheon Choi¹, Wonheum Na¹, Sujug Lee¹, Youngsil Choi¹,
Daewoong Jo¹˙*

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

Friedreich’s ataxia (FRDA) is monogenic autosomal recessive disease causing neurodegeneration and

cardiomyopathy. FRDA is attributed to partial depletion of the mitochondrial protein frataxin (FXN), which is caused
by a GAA expansion in first intron of the frataxin gene. FXN is well known to play a key role in iron metabolism in

iron-sulfur cluster (ISC) biogenesis and heme biosynthesis, both of which occur in mitochondria. Although treatment
options for FRDA patients include antioxidant and iron chelation, these therapies have not shown substantial clinical

improvement associated with neuronal loss. To overcome this problem, cell-permeable FXN (CP-FXN) has been
developed by fusing sequence-optimized advanced macromolecule transduction domain (aMTD) to deliver FXN

directly into cells and tissues. CP-FXN is delivered into mitochondria, blocks iron accumulation by binding to iron
and restores activity of ISC-dependent aconitase in FXN deficient cells. CP-FXN also shows cytoprotective effect

under iron-mediated oxidative stress in FRDA patient-derived fibroblast, suggesting that CP-FXN is able to facilitate
ISC biosynthesis, leading to maintaining cellular iron homeostasis. Based on these data, CP-FXN has a therapeutic

potential for FRDA treatment through mitochondrial delivery.