Scientific Publications by FDA Staff

Blood 2015 Jan 8;125(2):223-8

The intron-22-inverted F8 locus permits intracellular factor VIII synthesis, explaining its low inhibitor risk and suggesting a role for pharmacogenomics.

Sauna ZE, Lozier JN, Kasper CK, Yanover C, Nichols T, Howard TE

Intron-22-inversion (I22I)-patients express the entire FVIII-amino-acid sequence intracellularly as two non-secreted polypeptides and have a positive "intracellular (I)-FVIII-CRM-status". Mutations conferring a positive I-FVIII-CRM-status are associated with low inhibitor-risk and are "pharmacogenetically-relevant" because inhibitor-risk may be affected by the: nature of the therapeutic-FVIII-protein (tFVIII); affinity of any tFVIII-derived-foreign peptide (tFVIII-fp) for any HLA-class-II isomer (HLA-II) comprising individual-MHC-repertoires; and stability of any tFVIII-fp/HLA-II complex. We hypothesize that mutations conferring a completely- or substantially-negative I-FVIII-CRM-status are "pharmacogenetically-irrelevant" because inhibitor-risk is high with any tFVIII and individual-MHC-repertoire.