In:
Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 116, No. suppl_16 ( 2007-10-16)
Kurzfassung:
Background: Heart disease is the leading cause of morbidity and mortality, and its prevalence continues to rise. As a result, novel therapies are needed. Adeno-associated virus (AAV) mediated gene transfer may be an effective strategy since the low immunogenicity of AAV favors persistent transgene expression. In addition, the recently developed self-complementary AAV (scAAV) vectors have demonstrated higher expression than traditional, single stranded AAV (ssAAV) vectors. The goal of this study was to compare cardiac gene transfer efficiency of four AAV vectors using non-invasive, catheter based delivery in the dog. Methods: Four AAV vectors expressing GFP under control of the CB promoter were evaluated in this study–ssAAV9, scAAV9, scAAV8, scAAV6 –so that comparison could be made between ss and sc vectors as well as among serotypes 9, 8, and 6. Dogs (5–10kg, n=4 per group) underwent cardiac catheterization with introduction of an injection catheter into the LV under fluoroscopy. The interventricular septum (IVS) and LV free wall (LVFW) were targeted from base to apex with 40 injections of 250 ul. The total viral dose was either 2x10 13 gc/kg (ss) or 5x10 11 gc/kg (sc). At 7–10 days post-injection, hearts were explanted and divided into four equal sections from base to apex. GFP expression was quantified in four representative areas from IVS and LVFW in each section. TaqMan PCR was used to track biodistribution. Results: GFP expression in the scAAV6 group was approximately 10-fold higher than in the scAAV8 and scAAV9 groups, and GFP expression in the scAAV9 group was approximately 10-fold higher than in the ssAAV9 group, both in terms of total positive cells and total fluorescence (p 〈 0.01). Biodistribution studies revealed that vector genome copies were at least 10 times more abundant in the heart than in any other organ for scAAV6 (p≤0.05). Conclusion: scAAV is superior to ssAAV for cardiac gene transfer, and AAV6 has a higher cardiac tropism than AAV8 and AAV9 in the canine. Catheter based delivery of scAAV6 is a safe, effective method for achieving high level, global cardiac gene transfer to the LV. scAAV6 has great potential for transferring therapeutic transgenes to the failing canine heart and may be the vector of choice for clinical trials of cardiac gene transfer.
Materialart:
Online-Ressource
ISSN:
0009-7322
,
1524-4539
DOI:
10.1161/circ.116.suppl_16.II_65-b
Sprache:
Englisch
Verlag:
Ovid Technologies (Wolters Kluwer Health)
Publikationsdatum:
2007
ZDB Id:
1466401-X
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