Successful Repeated Hepatic Gene Delivery in Mice and Non-human Primates Achieved by Sequential Administration of AAV5(ch) and AAV1

Majowicz A, Salas D, Zabaleta N, et al. Successful Repeated Hepatic Gene Delivery in Mice and Non-human Primates Achieved by Sequential Administration of AAV5(ch) and AAV1. Molecular therapy : the journal of the American Society of Gene Therapy 2017;25:1831-1842.

Majowicz_2017_Mol Ther. Aug 2;25(8);1831-1842

At the moment the induction of antibodies against the AAV virus is a challenge in microdystrophin gene therapy, since it prevents re-injection of the AAV-microdystrophin if the effect fades. Using different types of AAV-viruses may be a solution. This article tests two of these for delivery of hepatic genes to the liver in non-human primates

 

Abstract

In the gene therapy field, re-administration of adeno-associated virus (AAV) is an important topic because a decrease in therapeutic protein expression might occur over time. However, an efficient re-administration with the same AAV serotype is impossible due to serotype-specific, anti-AAV neutralizing antibodies (NABs) that are produced after initial AAV treatment. To address this issue, we explored the feasibility of using chimeric AAV serotype 5 (AAV5(ch)) and AAV1 for repeated liver-targeted gene delivery. To develop a relevant model, we immunized animals with a high dose of AAV5(ch)-human secreted embryonic alkaline phosphatase (hSEAP) that generates high levels of anti-AAV5(ch) NAB. Secondary liver transduction with the same dose of AAV1-human factor IX (hFIX) in the presence of high levels of anti-AAV5(ch) NAB proved to be successful because expression/activity of both reporter transgenes was observed. This is the first time that two different transgenes are shown to be produced by non-human primate (NHP) liver after sequential administration of clinically relevant doses of both AAV5(ch) and AAV1. The levels of transgene proteins achieved after delivery with AAV5(ch) and AAV1 illustrate the possibility of both serotypes for liver targeting. Furthermore, transgene DNA and RNA biodistribution patterns provided insight into the potential cause of decrease or loss of transgene protein expression over time in NHPs.

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