Improved cardiac gene transfer by transcriptional and transductional targeting of adeno-associated viral vectors

Cardiovasc Res. 2006 Apr 1;70(1):70-8. doi: 10.1016/j.cardiores.2005.12.017. Epub 2006 Jan 31.


Objective: Vectors based on recombinant adeno-associated virus 2 (AAV-2) are a promising tool for cardiac gene transfer. However, potential therapeutic applications need to consider the predominant transduction of the liver once AAV-2 vectors enter the systemic circulation. We therefore aimed to increase efficiency and specificity of cardiac vector delivery by combining transcriptional and cell surface targeting.

Methods: For analysis of transcriptional targeting, recombinant AAV vectors were generated harboring a luciferase reporter gene under control of the cytomegalovirus (CMV) promoter or the 1.5-kb cardiac myosin light chain promoter fused to the CMV immediate-early enhancer (CMV(enh)/MLC1.5). Luciferase activities were determined in representative organs three weeks after intravenous injection of the vector into adult mice. Transductional targeting was studied using luciferase-reporter constructs crosspackaged into capsids of AAV serotypes 1 to 6 and modified AAV-2 capsids devoid of binding their primary receptor heparan sulfate proteoglycan.

Results: Intravenous injections of AAV-2 vectors harboring the CMV(enh)/MLC1.5 promoter enabled a specific and 50-fold higher reporter gene expression in left ventricular myocardium of adult mice compared to vectors containing the CMV promoter. Comparison of AAV-2 vector genomes crosspackaged into capsids of AAV-1 to -6 showed that AAV-1, -4, -5, and -6 capsids increased cardiac transduction efficiency by about 10-fold. However, transduction of other organs such as the liver was also increased after systemic administration. In contrast, AAV-2-based vectors with ablated binding to their primary receptor heparan sulfate proteoglycan enabled a significantly increased efficiency of cardiac gene transfer and reduced transduction of the liver.

Conclusions: Combining transcriptional targeting by the CMV(enh)/MLC1.5 promoter and AAV vectors devoid of binding the AAV-2 primary receptor results in an efficient cardiac gene transfer with a significantly reduced hepatic transduction.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Capsid
  • Cells, Cultured
  • Cytomegalovirus / genetics
  • Dependovirus / genetics*
  • Female
  • Gene Targeting / methods*
  • Genetic Engineering
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage*
  • Genetic Vectors / genetics
  • Heart Diseases / therapy
  • Heparin / analogs & derivatives
  • Heparin / genetics
  • Injections, Intravenous
  • Liver / enzymology
  • Luciferases / analysis
  • Luciferases / genetics
  • Mice
  • Mice, Inbred Strains
  • Myocytes, Cardiac / enzymology*
  • Myosin Light Chains / genetics
  • Promoter Regions, Genetic
  • Proteoglycans / genetics
  • Rats
  • Rats, Sprague-Dawley
  • Transduction, Genetic / methods


  • Myosin Light Chains
  • Proteoglycans
  • heparin proteoglycan
  • Heparin
  • Luciferases