Complexity of immune responses to AAV transgene products – Example of factor IX

Abstract

After two decades of research, in vivo gene transfer with adeno-associated viral (AAV) vectors has now resulted in successful treatments and even cures for several human diseases. However, the potential for immune responses against the therapeutic gene products remains one of the concerns as this approach is broadened to more patients, diverse diseases, and target organs. Immune responses following gene transfer of coagulation factor IX (FIX) for the treatment of the bleeding disorder hemophilia B has been extensively investigated in multiple animal models. Findings from these studies have not only influenced clinical trial design but have broader implications for other diseases. The impact of vector design and dose, as well as target organ/route of administration on humoral and cellular immune responses are reviewed. Furthermore, the potential for tolerance induction by hepatic gene transfer or combination with immune modulation is discussed.

Dual muscle-liver transduction imposes immune tolerance for muscle transgene engraftment despite preexisting immunity

“…This points out the important role of the genetic background of the host in the generation of transgene-specific T cells, and multiple genetic components concur in defining the immune response to a given transgene. As an example, cytotoxic CD8 + T cell responses were observed after human FIX gene transfer in C57BL/6 mice but were absent in other mouse strains (18). The target tissue itself is also an important factor influencing the outcome of immune responses after gene transfer (11) and rAAV muscle targeting is known to be highly immunogenic using model transgenes (19) but also with cell-associated transgene delivery to treat monogenic muscle disorders (20)(21)(22)(23).…”

Gene Therapy With Regulatory T Cells: A Beneficial Alliance

“…A transient increase in liver enzymes, presumably due to the reactivation of a memory CTL response to the vector, was earlier observed, although intervention with corticosteroid administration at the first sign of hepatocellular injury could halt the increases in liver enzymes and sustain FIX expression ( 34 ). Similarly, high endogenous levels of clotting factor have been reported in recent clinical trials for both hemophilia A and B ( 88 , 89 ).…”

Terapia genowa hemofilii – czy wkrótce będzie możliwe wyleczenie?

“…Ten wariant czynnika IX nazwano padewskim, ponieważ mutację powodującą podstawienie p.R338L odkryto w szpitalu uniwersyteckim w Padwie u pacjenta cierpiącego na wrodzoną trombofilię [35]. Wektory AAV do terapii genowej wytwarza się w hodowlach ludzkich zarodkowych komórek nerki (HEK293) oraz komórek jajnikowych owada z rzędu motyli, Spodoptera frugiperda (Sf9 i pokrewne klony tej linii) [32][33][34]36].…”