Open AccessLiver gene therapy with intein‐mediated F8 trans ‐splicing corrects mouse haemophilia A
Author(s) -
Esposito Federica,
Lyubenova Hristiana,
Tornabene Patrizia,
Auricchio Stefano,
Iuliano Antonella,
Nusco Edoardo,
Merlin Simone,
Olgasi Cristina,
Manni Giorgia,
Gargaro Marco,
Fallarino Francesca,
Follenzi Antonia,
Auricchio Alberto
Publication year - 2022
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202115199
Subject(s) - library science , biology , computer science
Liver gene therapy with adeno‐associated viral (AAV) vectors is under clinical investigation for haemophilia A (HemA), the most common inherited X‐linked bleeding disorder. Major limitations are the large size of the F8 transgene, which makes packaging in a single AAV vector a challenge, as well as the development of circulating anti‐F8 antibodies which neutralise F8 activity. Taking advantage of split‐intein‐mediated protein trans ‐splicing, we divided the coding sequence of the large and highly secreted F8‐N6 variant in two separate AAV‐intein vectors whose co‐administration to HemA mice results in the expression of therapeutic levels of F8 over time. This occurred without eliciting circulating anti‐F8 antibodies unlike animals treated with the single oversized AAV‐ F8 vector under clinical development. Therefore, liver gene therapy with AAV‐ F8 ‐N6 intein should be considered as a potential therapeutic strategy for HemA.