Page 3 - P. Molecular medicine and imaging

Frataxin Replenishment Ameliorates Heart Dysfunction
Through Recovery Of Iron Metabolism In Frataxin Deficient Mice

Wonheum Na, Joonno Lee, Hyunpyo Kim, Sookeun Yeon, Jeongheon Choi, Sujung Lee, Youngsil Choi, and Daewoong Jo
Drug Development Division for Neurodegenerative Disease, Cellivery R&D Institute, Cellivery Therapeutics, Inc., Seoul 03929, Korea.

BACKGROUND AIM
Friedreich’s ataxia (FRDA) is a progressive cardiac and neurodegenerative disease To determine whether CP-FXN can rescue the iron
with early life mortality resulted from cardiomyopathy. FRDA is caused by a metabolism pathway in heart-specific FXN deficient
deficiency of frataxin (FXN) which plays a role in regulating iron metabolism. Since mice, FXN conditional knockout mouse model which is
there is no treatment for FRDA, cell-permeable FXN (CP-FXN) has been developed specifically deleting exon 2 of FXN gene in heart is
by fusing sequence-optimized advanced macromolecule transduction domain currently being exploited.
(aMTD) to replenish insufficient FXN in cells and animals.

METHODS
To determine in vivo efficacy [administration route (IP & IV), dose (30 & 50 mg/kg) & frequency], CP-FXN was treated in FXN KO animal model.
In addition, CP-FXN was treated for determining in vivo efficacy in Doxorubicin (DOX) mediated cardiomyopathy animal model.

RESULTS
Figure 1. Intravenous (IV) Administration of Figure 4. High Dose Of CP-FXN Prevents
Figure 2. High Dose Of CP-FXN Is More Effective
CP-FXN Is More Effective Route To Expand To Prevent Body Weight Loss In FXN KO Animals Body Weight And Heart Rate Reduction
Life Span In FXN KO Animals In DOX-Mediated Cardiomyopathy Animals
Protocol Optimization: Route Protocol Optimization: Dose Protocol Optimization: Dose
(IP & IV, 50 mg/kg, 3 times/week) (IV, 30 & 100 mg/kg, 3 times/week) ((IV, 30, 50 & 100 mg/kg, 3/W) )

Histological Analysis
Aconitase Activity Iron Accumulation
Aconitase Activity

Heart Rate & ECG (electrocardiogram)

Histological Analysis Figure 3. Low & High Frequency Of CP-FXN Have
Similar Effect On Body Weight Change
In FXN KO Animals
Protocol Optimization: Frequency Figure 5. High Frequency Of CP-FXN Prevents
(IV, 100 mg/kg, 3/W & 7/W) Body Weight And Heart Rate Reduction
In DOX-Mediated Cardiomyopathy Animals
Protocol Optimization: Frequency
(IV, 100 mg/kg, 2/W & 3/W)

Apoptotic Cell Death Analysis
Histological Analysis

Heart Rate & ECG (electrocardiogram)

CONCLUSION REFERENCES Contact information
In FXN KO and DOX mouse models, CP- Chung et al. (2020) Science Advances, 6: eaba 1193 Minyong Jung
FXN recovers life span, iron metabolism and Lim et al. (2013) Clinical Cancer Research, 19: 680-690 New Drug & Business Development
heart function. These results suggest that Lim et al. (2013) Biomaterials, 34: 6261-6271 Cellivery Therapiutics, Inc.
CP-FXN has a therapeutic potential for Lim et al. (2012) Molecular Therapy, 20: 1540-1549
FRDA treatment by improving cardiac iron Jo et al. (2005) Nature Medicine, 11: 892-898 jungmy@cellivery.com
homeostasis. Jo et al. (2001) Nature Biotechnology, 19: 929-933 +82-2-3151-8900