Nonetheless, cathepsin K inhibition, by two separate methods, resulted in significant phenotypic correction of the craniofacial phenotypes as assessed by both Alcian blue staining and type II collagen expression.
To evaluate phenotypic correction, a tail clip assay performed at the end of the study revealed reduced blood loss.
Robust phenotypic correction of diseases in mouse models has been achieved paving the way toward the first clinical trials.
HC-AdVs were shown to result in long-term persistence of transgene expression and phenotypic correction in small and large animal models with negligible toxicity.
Interestingly, mice treated with N6 showed long-term FVIII activity and phenotypic correction for up to 74 weeks, with low anti-FVIII antibody titer.
Because to date there are not relevant results for phenotypic correction in haemophilia, iPSCs technology could represent a potential alternative based on cellular therapy.
Recently, as first time in haemophilia, endothelial progenitor cells derived from iPSCs cells express FVIII protein effectively, engraft within the hepatic parenchyma, and functionally integrate to provide the therapeutic benefit for a phenotypic correction in haemophilia.
We conclude that transposase-encoding messenger RNA (mRNA) can be used to mediate stable non-viral gene therapy, resulting in complete phenotypic correction, and is thus an effective source of recombinase activity for use in human gene therapy.
Using an engineered factor VII that can be secreted as factor VIIa, viral-mediated delivery of this transgene in the mouse liver resulted in phenotypic correction of murine hemophilia B, at expression levels of ∼1 mg/ml.
Moreover, phenotypic correction assayed by tail clip challenge resulted in survival of all AAV1-F9 treanimalsinals, in contrast to naive mice and 50% of AAV2-treated hemophilia B mice, which failed to survive.
