Lentiviral vectors for treatment of haemophilia
2010
Haemophilia A and B are X‐linked recessive disorders caused by defects in coagulation
factors (F) VIII and IX, respectively. Severe cases of haemophilia are characterised by
episodes of spontaneous bleeding, predominantly into the joints and muscles, and can
result in permanent disability and even mortality if left untreated. The haemophilias
are compelling candidates for treatment with gene therapy as therapeutic benefit only
requires a modest increase in the endogenous coagulation factor level, response to
treatment can be easily monitored, and factor expression can be mediated by many cell
types in vivo. Integration deficient lentiviral vectors (IDLVs) offer marked advantages
over currently used integrating lentiviral vectors (ILVs) as side effects caused by
insertional mutagenesis are potentially minimised. Previous work has shown that
efficient and sustained transgene expression in non‐dividing cells, such as brain and
muscle tissue, using IDLVs can be achieved. ILVs have previously been used to mediate
long term expression of coagulation factors in vivo. In this study, we investigated the
use of IDLVs as treatment for haemophilia with muscle and liver tissue (primarily nondividing
hepatocytes) as principal targets. Transduction efficiency and relative
transgene expression in vivo from ILVs and IDLVs were assessed in both tissues, and a
number of strategies, including pseudotyping and tissue specific promoters, were
utilised to improve targeted expression. Overall, despite achieving sustained transgene
expression from IDLVs, in comparison to ILVs, the levels obtained were significantly
lower and IDLVs were unable to mediate expression of human FIX at therapeutic levels
in liver. Finally, the expression of bioengineered forms of human factor VIII (hFVIII) was
assessed using ILVs in vivo after neonatal delivery. Long‐term expression was achieved
and a 20‐fold increase in expression was observed after codon optimisation of the
hFVIII cDNA sequence. In conclusion, IDLVs can mediate sustained transgene
expression in vivo, however, vectors may need to be further optimised for increased
expression to achieve clinical benefit for haemophilia patients.
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