Successful liver transduction by re‐administration of different adeno‐associated virus vector serotypes in mice

• Published in: The journal of gene medicine 2023-08, Vol.25 (8), p.e3505-n/a
• Main Authors: Baatartsogt, Nemekhbayar, Kashiwakura, Yuji, Hiramoto, Takafumi, Hayakawa, Morisada, Kamoshita, Nobuhiko, Ohmori, Tsukasa
• Format: Article
• Language: English
• Subjects: Expression vectors; Gene therapy; genetic therapy; Homology; immune reaction; Intravenous administration; Liver; neutralizing; re‐administration; Serotypes; Transduction; virus vector
• ISSN: 1099-498X; 1521-2254
• DOI: 10.1002/jgm.3505

Background Intravenous administration of adeno‐associated virus (AAV) vectors is a promising gene therapy approach for monogenic diseases. However, re‐administration of the same AAV serotype is impossible because of the induction of anti‐AAV neutralizing antibodies (NAbs). Here, we examined the feasibility of re‐administrating AAV vector serotypes different from the initial AAV vector serotype. Methods Liver‐targeting AAV3B, AAV5, and AAV8 vectors were intravenously injected in C57BL/6 mice, and the emergence of NAbs and the transduction efficacy following re‐administration were evaluated. Results For all serotypes, re‐administration of the same serotype was not possible. Although the highest neutralizing activity of NAb was induced by AAV5, anti‐AAV5 NAbs did not react with other serotypes, resulting in successful re‐administration with the other serotypes. AAV5 re‐administration was also successful in all mice treated with AAV3B and AAV8. Effective secondary administration of AAV3B and AAV8 was observed in most mice initially administrated AAV8 and AAV3B, respectively. However, few mice developed NAbs cross‐reacting with the other serotypes, especially those with close sequence homology. Conclusions In summary, AAV vector administration induced NAbs relatively specific to the administrated serotype. Secondary administration of AAVs targeting liver transduction could be successfully achieved by switching AAV serotypes in mice. Systemic administration of AAVs targeting liver transduction induced high titer serotype‐specific neutralizing antibodies in mice. Here, the secondary administration was successfully achieved by switching AAV serotypes. Considering the re‐administration of AAV vectors to patients who have failed to respond to initial gene therapy or lost therapeutic effect over time, the development of several AAV preparations is crucial for targeting one disease.