Correction of cardiac abnormalities in fabry mice by direct intraventricular injection of a recombinant lentiviral vector that engineers expression of alpha-galactosidase A. Circ J 2006 Nov;70(11):1503-8
Date
10/26/2006Pubmed ID
17062978DOI
10.1253/circj.70.1503Scopus ID
2-s2.0-33750561515 (requires institutional sign-in at Scopus site) 31 CitationsAbstract
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.
METHODS AND 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.
CONCLUSION: 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.
Author List
Yoshimitsu M, Higuchi K, Dawood F, Rasaiah VI, Ayach B, Chen M, Liu P, Medin JAAuthor
Jeffrey A. Medin PhD Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Line
Disease Models, Animal
Fabry Disease
Gene Expression Regulation, Enzymologic
Genetic Therapy
Genetic Vectors
Green Fluorescent Proteins
Heart Ventricles
Lentivirus
Mice
Mice, Inbred C57BL
Myocytes, Cardiac
Rats
Transgenes
alpha-Galactosidase
