Blockade of the costimulatory CD28-B7 family signal axis enables repeated application of AAV8 gene vectors.

Blockade of the costimulatory CD28-B7 family signal axis enables repeated application of AAV8 gene vectors. J Thromb Haemost. 2020 Feb 03;: Authors: Frentsch M, Japp AS, Dingeldey M, Matzmohr N, Thiel A, Scheiflinger F, Reipert BM, de la Rosa M Abstract Adeno-associated virus serotype 8 (AAV8) gene therapy has shown efficacy in several clinical trials and is considered a highly promising technology to treat monogenic diseases such as hemophilia A and B. However, a major drawback of AAV8 gene therapy is that it can be applied only once because anti-AAV8 immunity develops after the first treatment. Readministration may be required in patients who are expected to need redosing, e.g. due to organ growth, or to boost suboptimal expression levels, but no redosing-protocol has been established. We have developed a preventive immune-suppressive protocol for a human factor IX (FIX) vector with an intended dose of ~5x1011 vg/kg that inhibits the development of anti-AAV8 neutralizing-antibody (NAb) responses and anti-AAV8 T-cell responses using CTLA4-IgG (abatacept). In a preclinical model, transient treatment with abatacept during initial human factor IX (FIX) gene therapy efficiently inhibited the generation of AAV8-specific cellular and humoral responses, and thus permitted redosing of FIX. Furthermore, our data suggest that by suppression of anti-AAV8 NAb responses after the second higher dose (4x1012 vg/kg) this protocol can be used to ena...
Source: Thrombosis and Haemostasis - Category: Hematology Authors: Tags: J Thromb Haemost Source Type: research