Inadvertent germline transmission of AAV2 vector: findings in a rabbit model correlate with those in a human clinical trial.
The risk of germline transmission of vector sequences in humans is a major safety concern, because the enrollment of subjects of reproductive age in early-phase clinical trials of gene transfer continues to increase. In a study of adult men with hemophilia B, adeno-associated virus serotype 2 (AAV2) delivered to the liver via the hepatic artery resulted in unexpected transient vector dissemination to the semen. Here we report that intravenous AAV2 injection in rabbits proved a useful model to assess biologic parameters of vector dissemination to the semen. Detectable vector sequences in semen disappeared in a dose-dependent and time-dependent fashion. AAV infectious particles were present only as long as day 4 after injection and were undetectable thereafter. The kinetics of vector clearance was faster in the semen fractions enriched for motile sperm than in the total semen. In addition, increased frequency of semen sampling accelerated the clearance of vector sequences from semen. Long-term follow-up, spanning hundreds of spermatogenesis cycles, showed that there was no recurrence of detectable vector sequences in semen, thus reducing the probability of inadvertent transduction of early spermatogonia not committed to differentiation at the time of vector injection. We conclude that AAV2 presents minimal germline transmission risk for humans.
Schuettrumpf
Joerg
J
The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Liu
Jian-Hua
JH
Couto
Linda B
LB
Addya
Kathakaly
K
Leonard
Debra G B
DG
Zhen
Zhu
Z
Sommer
Jürg
J
Summer
Jürg
J
Arruda
Valder R
VR
D000818:Animals; D002478:Cells, Cultured; D002986:Clinical Trials as Topic; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002836:Hemophilia B / Q000235:genetics / Q000628:therapy; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D011817:Rabbits; D012661:Semen / Q000502:physiology / Q000821:virology*; D013094:Spermatozoa / Q000166:cytology / Q000821:virology; D013737:Testis / Q000502:physiology / Q000821:virology; D014161:Transduction, Genetic