Inadvertent germline transmission of AAV2 vector: findings in a rabbit model correlate with those in a human clinical trial

Molecular Therapy : the Journal of the American Society of Gene Therapy
Joerg SchuettrumpfValder R Arruda

Abstract

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 different...Continue Reading

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Citations

Nov 15, 2014·Human Gene Therapy·Katherine A High
Mar 19, 2009·Molecular Therapy : the Journal of the American Society of Gene Therapy·Patricia FavaroValder R Arruda
Dec 15, 2010·International Archives of Medicine·Faisal A Al-AllafMichael Themis
Aug 11, 2011·Molecular Therapy : the Journal of the American Society of Gene Therapy·Kathrina QuinnJohn A Chiorini
Feb 24, 2016·Expert Opinion on Orphan Drugs·Valder R Arruda, Ben J Samelson-Jones
Jul 13, 2007·Fertility and Sterility·Yoshiyuki KojimaKenjiro Kohri
May 13, 2009·Haemophilia : the Official Journal of the World Federation of Hemophilia·A Liras, S Olmedillas
Jan 24, 2007·Journal of Thrombosis and Haemostasis : JTH·V R Arruda, W Xiao
Nov 17, 2007·Haemophilia : the Official Journal of the World Federation of Hemophilia·J Kimmelman
May 20, 2008·Journal of Thrombosis and Haemostasis : JTH·S KasudaA Yoshioka
Sep 8, 2011·Pathology·Gerald BothGeoff Symonds
May 15, 2013·Journal of Reproductive Immunology·Andrea GarollaCarlo Foresta
Apr 8, 2016·Blood·Donald B KohnAndrew M Scharenberg
Jun 7, 2007·Molecular Therapy : the Journal of the American Society of Gene Therapy·Ichiro TaharaTakashi Shimada
Apr 19, 2011·Nature Reviews. Genetics·Federico Mingozzi, Katherine A High
Jan 17, 2015·Journal of Pediatric Gastroenterology and Nutrition·Norman JungeUlrich Baumann
Oct 9, 2018·Toxicologic Pathology·Basel T Assaf, Laurence O Whiteley
May 18, 2018·F1000Research·Valder R ArrudaBenjamin J Samelson-Jones
May 23, 2019·Haemophilia : the Official Journal of the World Federation of Hemophilia·Wolfgang MiesbachMike Makris

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