Advanced therapies for hemophilia: reality or fantasy?

Department of Physiology, Biological Sciences School, Complutense University of Madrid, Spain and Royal Foundation "Victoria Eugenia" of Haemophilia, Spain. .
Expert Review of Hematology (Impact Factor: 2.07). 06/2012; 5(3):245-7. DOI: 10.1586/ehm.12.25
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Available from: Antonio Liras, Mar 07, 2014
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    ABSTRACT: Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder. We infused a single dose of a serotype-8-pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months. AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values. Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; number, NCT00979238.).
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    ABSTRACT: Haemophilia is an ideal condition for gene therapy because of its monogenetic character and the fact that it requires only a small amount of the expressed protein to achieve palliation. To date, research in the field of gene therapy for haemophilia has largely relied on retroviruses, adenoviruses and adeno-associated viruses as transfer vectors and the major aims will be to achieve stable longlasting in vivo expression of factors VIII or IX (FVIII or FIX) at therapeutic levels. Two clinical trials have been approved by the US Food and Drug Administration (FDA), using miniadenovirus FVIII and the intrahepatic and intramuscular delivery of adeno-associated virus FIX. In the third millennium, haemophilia treatment should encompass more ambitious goals through gene replacement, to result in permanent and safe haemophilia 'eradication', making haemophilia a part of the history of medicine.
    Haemophilia 10/2001; 7(5):441-5. DOI:10.1046/j.1365-2516.2001.00554.x · 2.60 Impact Factor
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    ABSTRACT: High-purity plasma-derived and recombinant factors are currently safe and efficient treatment for haemophilia. The mid-term future of haemophilia treatment will involve the use of modified recombinant factors to achieve advantages such as decreased immunogenicity in inhibitor formation and enhanced efficacy as a result of their longer half-life. In the long-term, gene therapy and cell therapy strategies will have to be considered. Achievements in cell therapy to date have been using embryonic stem cells and hepatic sinusoidal endothelial cells. Current gene therapy strategies for haemophilia are based on gene transfer using adeno-associated viruses and non-viral vectors. Gene therapy for haemophilia is justified because it is a chronic disease and because a very regular factor infusion is required that may involve fatal risks and because it is very expensive. Haemophilia is a very good candidate for use of gene therapy protocols because it is a monogenic disease, and even low expression is able to achieve reversion from a severe to a moderate phenotype. The current trends in haemophilia using adeno-associated viral vectors are safe but also involve immunogenicity problems. The other alternatives are non-viral vectors. There have been in recent years relevant advances in non-viral transfection that raise hope for considering this possibility. Several research groups are opting for this experimental alternative. An expression over 5%, representing a moderate phenotype, for a few months with a high safety, regarding vector, transfected cells, and implantation procedure, would already be a great success. This may represent an intermediate protocol in which the expression levels and times obtained are lower and shorter respectively as compared to viral vectors, but which provide a potential greater patient safety. This may more readily win acceptance among both patients and haematologists because fatal events in the past due to HIV/HCV infection may constrain the implementation of viruses as vectors.
    Haemophilia 06/2009; 15(3):811-6. DOI:10.1111/j.1365-2516.2009.02010.x · 2.60 Impact Factor