Background: Several methods have been investigated to effectively and safely transmit
genes that stimulate cells to release therapeutic factor VIII (FVIII) and factor IX (FIX) into the circulation
of people with hemophilia (PWH).
Objective: To review the role of gene therapy (GT) in PWH.
Methods: A Cochrane Library and PubMed (MEDLINE) search related to the role of GT in hemophilia
Results: The most promising vectors for hemophilia GT are adeno-associated virus (AAV) and lentivirus.
Several gene methods are available to lessen risks related to random vector integration and insertional
mutagenesis, based on designer nucleases or CRISPR/Cas9 (clustered regularly interspaced short
palindromic repeats/CRISPR associated system). However, off-target issues need to be more meticulously
and widely evaluated. Some clinical studies on hemophilia B based on AAV have obtained transitory
or subtherapeutic levels of FIX expression. Another problem is possible transitory liver toxicity.
Therefore, to reduce unintentional immune responses, transitory immunosuppression must be used, particularly
when administering high-vector doses. Codon-optimized FVIII or FIX transgenes are able to
promote clotting factor expression levels. The inclusion of a hyper-active gain-of-function R338L mutation
in the FIX gene (FIX-R338L [FIX Padua]) makes the procedure more effective.
Conclusion: Achieving a safe and efficient remedy for hemophilia A and B by means of GT vector
engineering needs further improvement. No randomized or quasi-randomized clinical trials of GT for
hemophilia have been found. Given it is in its incipient period, there is need for well-designed clinical
trials to evaluate the long-term practicability, efficacy and risks of GT for PWH.