Journal
MOLECULAR THERAPY
Volume 15, Issue 12, Pages 2080-2087Publisher
CELL PRESS
DOI: 10.1038/sj.mt.6300308
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Funding
- NHLBI NIH HHS [HL52173, HL57346, R01 HL052173] Funding Source: Medline
- NIBIB NIH HHS [R01 EB005813] Funding Source: Medline
- NICHD NIH HHS [HD024064] Funding Source: Medline
- NIDDK NIH HHS [P30 DK56338, T32 DK060445, DK56787] Funding Source: Medline
- NIMH NIH HHS [R01 MH078775] Funding Source: Medline
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Bioengineering of the factor VIII (FVIII) molecule has led to the production of variants that overcome poor secretion and/or rapid inactivation. We tested six modified FVIII variants for in vivo efficacy by expressing them from helper-dependent adenoviral (HD-Ad) vectors. We constructed a wild-type (WT) variant, a B-domain-deleted (BDD) variant, a point mutant for improved secretion (F309S), a variant with a partial B-domain deletion for improved secretion (N6), a combination of the point mutant and partial BDD variant (F309N6), and an inactivation-resistant (IR8) FVIII variant. All the constructs expressed functional protein after injection of high-dose HD-Ad. Activity ranged from 20 to 50% with WT, to similar to 100% with the N6 and F309N6 variants. Interestingly, mice treated with N6 showed long-term FVIII activity and phenotypic correction for up to 74 weeks, with low anti-FVIII antibody titer. Importantly, the N6 variant was therapeutically efficacious even after a 50% reduction of viral dose, thereby indicating that transgene modification itself can improve the dose efficacy of HD-Ad. This finding is significant, because dose efficacy is a key factor in clinical application. In summary, bioengineering of the FVIII molecule may be an effective approach to improving the safety, immunogenicity, and efficacy of HD-Ad gene therapy in hemophilia A (HA).
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