Report Summary

Toxicity and Biodistribution Report of rAAV6-CMV-hSERCA2a Following Injection into the Heart in Canines

Study Summary

Overall Study Design 
Background The SERCA2a Ca2 pump plays a central role in defining cardiac contractile properties SERCA2a expression 
is decreased in heart failure HF Restoring SERCA2a in animal HF models improves cardiac function Recent studies 
suggest that AAV-mediated gene transfer may cause inflammation A canine model was used to test a the safety and 
efficacy of AAV6-mediated expression of human h SERCA2a and b the role of immunosuppression in modulating 
Design and Methods Dogs were tachy-paced to induce HF and then received direct LV wall injection with 5x1012 viral 
genomes of AAV6-hSERCA2a AAV or saline S Pacing continued post-injection and dogs were euthanized 2-week W 
AAV n5 S n2 or 6-W AAV n6 S n2 later Tissueserum samples were analyzed for hSERCA2a expression 
Western blot histology HE and immune responses AAV6-neutralizing antibodies NAB AAV-induced leukocyte 
production of interferon IFN Elispot Additional non-paced dogs were injected as above and analyzed at 12-W AAV n6 
S n2 a parallel cohort AAV n5 S n2 received prednisonecyclosporine PC immunosuppression beginning 4-W 
after injection 
Biodistribution studies were performed to determine the extent of vector genome presence in cardiac and non cardiac 
tissues and blood over the time course following vector administrationBlood samples and tissues were taken from dogs that 
received vector for detection of rAAV6-CMV-SERCA2a genomes 
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