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F8 intein precise CodopN6 reconstitution

ABSTRACT: Liver gene therapy with adeno-associated viral (AAV) vectors is under clinical investigation for hemophilia 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 neutralize F8 activity. Taking advantage of split inteins-mediated protein trans-splicing, we divided the coding sequence of the large and highly secreted F8-N6 variant in two separate AAV split-inteins vectors whose co-administration to HemA mice results in F8 protein reconstitution and expression of therapeutic levels of F8 over time without anti-F8 antibodies development.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Federica Esposito

LAB HEAD: Alberto Auricchio

PROVIDER: PXD031884 | Pride | 2022-03-31

REPOSITORIES: Pride

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Liver gene therapy with intein-mediated F8 trans-splicing corrects mouse haemophilia A.

Esposito Federica F Lyubenova Hristiana H Tornabene Patrizia P Auricchio Stefano S Iuliano Antonella A Nusco Edoardo E Merlin Simone S Olgasi Cristina C Manni Giorgia G Gargaro Marco M Fallarino Francesca F Follenzi Antonia A Auricchio Alberto A

EMBO molecular medicine 20220502 6

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 ...[more]

PMID: 35491676

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