title: Transendocardial delivery of AAV6 results in highly efficient and global cardiac gene transfer in rhesus macaques.
abstract: Heart disease is the leading cause of morbidity and mortality, and cardiac gene transfer has potential as a novel therapeutic approach. We previously demonstrated safe and efficient gene transfer to the canine heart using a percutaneous transendocardial injection procedure to deliver self-complementary (sc) adeno-associated virus 6 (AAV6) vector. In the present study, we proceed with our vertical translation study to evaluate cardiac gene transfer in nonhuman primates (NHPs). We screened approximately 30 adult male rhesus macaques for the presence of neutralizing antibodies against AAV6, AAV8, and AAV9, and then selected seven monkeys whose antibody titers against these three serotypes were lower than 1/5. The animals were then randomized to receive either scAAV6 (n=3), scAAV8 (n=1), or scAAV9 (n=3) vector expressing the enhanced green fluorescent protein (EGFP) reporter gene at a dose of 5.4×10(12) genome copies/kg, which was administered according to a modified version of our previously developed transendocardial injection procedure. One animal treated with scAAV6 died secondary to esophageal intubation. The remaining animals were euthanized 7 days after gene transfer, at which time tissue was collected for analysis of EGFP expression, histopathology, and biodistribution of the vector genome. We found that (i) transendocardial delivery of AAV is safe in the NHP, (ii) AAV6 and AAV8 provide efficient cardiac gene transfer at similar levels and are superior to AAV9, and (iii) AAV6 is more cardiac-specific than AAV8 and AAV9. The results of this NHP study may help guide the development AAV vectors for the treatment of cardiovascular disease in humans.
authors.affiliation: Gene Therapy Center, University of Massachusetts School of Medicine, Worcester, MA 01605, USA.
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
authors.forename: Lawrence T
authors.initials: LT
authors.lastname: Bish
authors.forename: Meg M
authors.initials: MM
authors.lastname: Sleeper
authors.forename: Xin
authors.initials: X
authors.lastname: Mu
authors.forename: Lan
authors.initials: L
authors.lastname: Sun
authors.forename: You
authors.initials: Y
authors.lastname: Lou
authors.forename: Jiachuan
authors.initials: J
authors.lastname: Duan
authors.forename: Chunyan
authors.initials: C
authors.lastname: Hu
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D011897:Random Allocation
chemical_list: C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins