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Dr. Mark PayneKindly supplied by Juan Carlos Baiges through the FAPG mailing-list

Accepted November 21, 2011.

Abstract

Friedreich’s Ataxia (FRDA) is the most common inherited human ataxia and results from a deficiency of the mitochondrial protein, frataxin, which is encoded in the nucleus. This deficiency is associated with an iron-sulfur (Fe-S) cluster enzyme deficit leading to progressive ataxia and a frequently fatal cardiomyopathy. There is no cure. To determine if exogenous replacement of the missing frataxin protein in mitochondria would repair the defect, we used the TAT protein transduction domain to deliver human frataxin protein to mitochondria in both cultured patient cells and a severe mouse model of Friedreich’s Ataxia. A TAT-Frataxin (TAT-FXN) fusion protein bound iron in vitro, transduced into mitochondria of FRDA deficient fibroblasts, and reduced caspase 3 activation in response to an exogenous iron oxidant stress.

Injection of TAT-FXN protein into mice with a conditional loss of frataxin increased their growth velocity and mean lifespan by 53%, increased their mean heart rate and cardiac output, increased activity of aconitase, and reversed abnormal mitochondrial proliferation and ultrastructure in heart. These results show that a cell penetrant peptide is capable of delivering a functional mitochondrial protein in vivo to rescue a very severe disease phenotype, and present the possibility of TAT-Frataxin as a protein replacement therapy.

Source: Human molecular Genetics

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Piyush M. Vyas1, Wendy J. Tomamichel1, P. Melanie Pride1, Clifford M. Babbey1, Qiujuan Wang1, Jennifer Mercier2, Elizabeth M. Martin1 and R. Mark Payne1,*
+ Author Affiliations
1Riley Heart Research Center, Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, 46202
2Wake Forest University School of Medicine, Winston-Salem, NC, 27157
?*Corresponding Author: R. Mark Payne, Riley Hospital for Children, Wells Center for Pediatric Research, 1044 West Walnut, R4366, Indianapolis, IN 46202, O: 317-278-6239, FAX: 317-278-9298; Email: rpayneATiupui.edu