Correction of cardiac abnormalities in fabry mice by direct intraventricular injection of a recombinant lentiviral vector that engineers expression of alpha-galactosidase A.
BACKGROUND
Recombinant lentiviral vectors (LVs) offer the possibility of stable, long-term expression of transgenes even in non-dividing cells. In the present study this vector system was applied to a clinically relevant cardiovascular problem.


RESULTS
Fabry disease results from deficient activity of alpha-galactosidase A (alpha-gal A) and cardiac abnormalities are a common and an important cause of death in patients with the disease. A therapeutic LV that delivers the alpha-gal A cDNA has been synthesized. In vitro studies established efficient transduction of the H9c2 rat cardiomyocytes and showed overexpression of enGFP (control) and alpha-gal A. In in vivo studies, the enGFP cDNA was transferred into C57BL/6 mouse hearts by direct intraventricular injection. Next, in a mouse model of Fabry disease, the recombinant therapeutic construct was delivered analogously. In cardiac tissue, alpha-gal A activity rose to 23% of normal levels at day 7 after LV injection, which is encouraging because levels of correction approximating 5% of normal may be curative for this disorder. There was also a corresponding reduction in globotriaosylceramide accumulation. Other organs assayed showed no detectable changes in alpha-gal A activity levels in injected animals.


CONCLUSIONS
A localized benefit of directly injecting a therapeutic LV into the heart has been shown, confirming the utility of this delivery system for research and therapy for a variety of cardiovascular disorders.
Yoshimitsu
Makoto
M
Division of Stem Cell and Developmental Biology, Ontario Cancer Institute, University Health Network, Toronto, Ontario M5G 2M1, Canada.
Higuchi
Koji
K
Dawood
Fayez
F
Rasaiah
Vanessa I
VI
Ayach
Bilal
B
Chen
Manyin
M
Liu
Peter
P
Medin
Jeffrey A
JA
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D000795:Fabry Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015971:Gene Expression Regulation, Enzymologic; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006352:Heart Ventricles; D016086:Lentivirus / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D019076:Transgenes / Q000235:genetics; D000519:alpha-Galactosidase / Q000235:genetics* / Q000378:metabolism*
D049452:Green Fluorescent Proteins; D000519:alpha-Galactosidase